[Federal Register: August 11, 1995 (Volume 60, Number 155)]
[Notices]
[Page 41621-41643]
From the Federal Register Online via GPO Access [wais.access.gpo.gov]

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[[Page 41621]]

B. INDUSTRY RESEARCH ON THE DRUG EFFECTS OF NICOTINE

    The tobacco industry has conducted and funded extensive research to
characterize nicotine's addictive potential and properties. This
research includes studies on nicotine's absorption into the bodies of
tobacco users, its effects on behavior, and its effects on the brain
and endocrine systems.<SUP>240 Sections II.B., C., and D. detail the
extensive research conducted and funded by the tobacco industry on: (1)
nicotine's pharmacological effects, Sec. II.B., infra; (2) how
consumers use tobacco products to obtain an adequate dose of nicotine,
Sec. II.C., infra; and (3) how to manipulate nicotine delivery from
tobacco to provide an adequate dose to consumers, Sec. II.D.,
infra.<SUP>240a

    \240\ The long history of tobacco and nicotine use for
pharmacological purposes is also well known to the tobacco industry.
Larson PS, Silvette H. Medical uses of tobacco (past and present),
(funded by a grant from the Tobacco Industry Research Committee and
presented at industry-sponsored symposium). In: VonEuler, ed.
Tobacco Alkaloids and Related Compounds. New York, NY: Pergamon
Press; 1965:3-11.
    See also Cohen, note 183, supra, at p. 1.
    \240a\ The extent of the industry's research on nicotine
pharmacology is very likely to be even greater than that reflected
in this section. According to a recent report in the New York Times,
Philip Morris conducted internal research on nicotine's
pharmacological effects on smokers from the late 1960's to the mid-
1980's. The Times reported that Charles Wall, a Philip Morris
lawyer, confirmed that company documents showed that Philip Morris
carried out extensive research on nicotine over many years. Hilts
PJ. ``Documents Disclose Philip Morris Studied Nicotine's Effect on
Body.'' New York Times. June 8, 1995. Documents later disclosed by
Congress provide detailed evidence of Philip Morris' long-term
research on nicotine pharmacology, including studies to isolate and
characterize nicotine receptors in the central nervous system, the
effects of nicotine/smoking on the electrical activity of the brain,
the effects of nicotine on human and animal behavior, self-
administration of nicotine by rats, nicotine discrimination in rats,
nicotine tolerance, and the effects of nicotine administration on
human physiologic function, including the relationship between blood
nicotine levels and central nervous system activity. 141 Cong. Rec.
H7470-76 (daily ed. July 24, 1995); 141 Cong. Rec. H7646-83 (daily
ed. July 25, 2995). Philip Morris has not contested the authenticity
of these documents. R.J. Reynolds, too, appears to have conducted
extensive research on nicotine pharmacology that is not fully
reflected here. In response to questions about that company's
research on nicotine, a spokeswoman for R.J. Reynolds Tobacco
Company stated that ``[w]e've not only done research on the
pharmacological effects of nicotine but we've published it in at
least 250 peer-reviewed journals and symposia. We're extremely proud
of the quality and number of the studies.'' Collins G. ``Legal
Attack on Tobacco Intensifies.'' New York Times. June 9, 1995.

[[Page 41622]]

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    It is important to understand why the tobacco industry has
conducted this research. Tobacco industry documents show that the
industry research described in the following sections was undertaken
because industry officials strongly suspected, more than 30 years ago,
that nicotine's pharmacological effects were vital to the successful
marketing of tobacco. For example, internal BATCO documents disclose
that the major BATCO-sponsored nicotine studies completed or underway
in the early 1960's were undertaken ``to elucidate the effects of
nicotine as a beneficent alkaloid drug'' <SUP>241 because of the belief
of Sir Charles Ellis, the leading BATCO scientist, that ``we are in a
nicotine rather than a tobacco industry.'' <SUP>242

    \241\ See Ellis, note 232, supra, at p. 16. On the same page
Ellis describes upcoming research ``to investigate whether cigarette
smoke produces effects on the central nervous system characteristic
of tranquilising or stimulating drugs and, if so, to see if such
activity is due solely to nicotine.''
    \242\ Johnson RR. Comments on nicotine. June 30, 1963. Pages 10-
11. This document goes on to reveal that these studies on nicotine's
pharmacological effects were part of a broader research initiative
that was being conducted by the industry and included altering
nicotine delivery:
    The Southampton group is going to be doing a large amount of
work on nicotine, and for some good reasons. To summarize:
    Project ARIEL [a cigarette alternative developed by BATCO]--This
is dormant for the moment. The first samples tried gave a tremendous
kick, even though the nicotine delivery was quite small. It would
appear that the project will be reinitiated within a few months.
    Dr. S.R. Evelyn is presently investigating the absorption of
extractable and non-extractable nicotine in the mouth * * *.
    Dr. J.D. Backhurst is setting up an analysis for pH of whole
smoke on a puff-by-puff basis. This correlates with his previous
interest in extractable nicotine.
    Mr. H.G. Horsewell continues to work with alkaline filter
additives which selectively increase nicotine delivery.
---------------------------------------------------------------------------

    Another nicotine study commissioned by BATCO in the early 1960's
similarly reveals that industry research on nicotine's pharmacological
effects was undertaken because of the industry's understanding that
consumers use tobacco to obtain those effects:

    There is increasing evidence that nicotine is the key factor in
controlling, through the central nervous system, a number of the
beneficial effects of tobacco smoke * * *. Detailed knowledge of
these effects of nicotine in the body

[[Page 41623]]
of a smoker is therefore of vital importance to the tobacco
industry.<SUP>243

    \243\ Geissbuhler H, Haselbach C. The Fate of Nicotine in the
Body. Battelle Memorial Institute. Geneva, Switzerland. May 1963.
Page 1. Report prepared by Battelle for BATCO. (Hereafter cited as:
BATCO. The Fate of Nicotine in the Body.).

    An annual report from the Council for Tobacco Research discloses
that the research it funded on nicotine's pharmacology was designed to
elucidate the effects of nicotine on the smoker's central nervous
---------------------------------------------------------------------------
system:

    Most of the pharmacological studies currently being supported by
The Council are concerned with the effects of nicotine and/or
smoking on the central nervous system (the brain) with the object of
learning more about why people like, want, or need to smoke.<SUP>244

    \244\ Report of the Scientific Director, 1969-1970. Council for
Tobacco Research-U.S.A. Page 13.

    The studies of nicotine's pharmacokinetics and pharmacodynamics
described in Sec. II.B., infra, were undertaken to assist the industry
in marketing products that would satisfy tobacco users' nicotine
requirements. This information relating to how nicotine acted in the
body was needed by the industry for additional studies specifically
designed to establish the dose of nicotine required by consumers,
Sec. II.C., infra. As noted in the report of one study whose purpose
was to validate a method for assaying nicotine and a metabolite in
---------------------------------------------------------------------------
urine:

    It can be concluded from the comparative studies that analysis
of nicotine and cotinine in urine is likely to be a good indicator
of whole body nicotine dose in man. This technique has an immediate
and direct relevance for * * * human behavioural studies in the
assessment of an individuals' [sic] nicotine dose in response to
modification in cigarette design. [Emphasis added.] <SUP>245

    \245\ BATCO Group R&D Centre. Nicotine Studies: A Second Report.
Estimation of Whole Body Nicotine Dose By Urinary Nicotine and
Cotinine Measurement. Report No. RD.1792. March 31, 1981. Page 1.
    Industry documents related to other basic research studies on
nicotine show a similar nexus with product development. For example,
the report from a 1974 Brown and Williamson study of nicotine's
brain effects states that:
    The development of new products and the modification of existing
ones requires that we have some knowledge of the smoker toward whom
these efforts are directed. The work described in this report is
focused on the acute, or immediate physiological response of
smokers.
    Brotzge RF, Kennedy JE. Brown and Williamson. Human Smoking
Studies: Acute Effect of Cigarette Smoke on Brain Wave Alpha
Rhythm--First Report. October 31, 1974. Report No. 74-20. Page 1.
    Similarly, a 1974 BATCO study on nicotine's effects on brain
electrical activity was intended to ``help elucidate the mode of
action of nicotine during smoking'' so as to better understand
smoker behavior in response to nicotine. BATCO Group Research &
Development. Comer AK, Thornton RE. Interaction of Smoke and the
Smoker Part 3: The Effect of Cigarette Smoking on the Contingent
Negative Variation. Report No. RD.1164-R. December 12, 1974. Page 2.

[[Page 41624]]

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    Thus, this research demonstrates the tobacco industry's fundamental
interest in the dose of nicotine absorbed into the systemic circulation
of the tobacco user (rather than simply the amount of nicotine
necessary to deliver sensory effects to the mouth of the user.)
    The ultimate purpose of the tobacco industry's studies on nicotine
was to better understand the nicotine requirements of tobacco users and
to develop products that delivered the desired pharmacological effects
of nicotine. Philip Morris officials stated that the rationale for the
company's extensive research program on nicotine pharmacology was that
the information would

strengthen Philip Morris R&D capability in developing new and
improved smoking products.<SUP>245a

    \245a\ Memorandum from W.L. Dunn to T.S. Osdene-Plans and
Objectives--1979. December 6, 1978. In 141 Cong. Rec. H7669 (daily
ed. July 25, 1995).

    Accordingly, the industry-sponsored studies described in the
following sections provide further evidence that tobacco manufacturers
intend to market their products to deliver the pharmacological effects
of nicotine to consumers.<SUP>246

    \246\ The full citations for the references in notes 247 through
279 can be found in Appendix 4. Entries under the heading ``OTHER''
include studies sponsored by the Smokeless Tobacco Research Council
(whose members include U.S. tobacco companies), Swedish Tobacco Co.
(which has corporate relationships with both Pinkerton and U.S.
Tobacco Co.), Svenska Tobaks (a subsidiary of Swedish Tobacco Co.),
the Tobacco Advisory Council and the Tobacco Research Council of the
U.K. (whose members included British-American Tobacco Co.), Imperial
Tobacco Co. (which has corporate relationships with British-American
Tobacco Co., and manufactures cigarettes that are marketed in the
U.S.), Carreras Rothmans Ltd. (whose affiliated companies
manufacture cigarettes that are marketed in the U.S.), Swiss
Association of Cigarette Manufacturers (whose members include
affiliates of U.S. tobacco companies, and the Canadian Tobacco
Manufacturers Council (whose members include affiliates of U.S.
tobacco companies).

[[Page 41625]]

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1. Industry Research on Nicotine's Effects on the Brain

    The tobacco industry has extensively studied, in its own
laboratories and through grants or contracts to other laboratories, the
effects of nicotine on the brain and other parts of the central nervous
system, including the sites in the brain on which nicotine
acts.<SUP>247

    \247\ COUNCIL FOR TOBACCO RESEARCH-USA
    Abood. Comparison of the binding of optically pure (-)- and (+)-
[3H] nicotine to rat brain membranes
    Abood. Electrophysiological, behavioral, and chemical evidence
for a noncholinergic, stereospecific site for nicotine in rat brain
    Abood. Receptor binding characteristics of a 3H-labeled
azetidine analogue of nicotine
    Abood. Tritiated methylcarbamylcholine a new radioligand for
studying brain nicotinic receptors
    Abood. Evidence for a noncholinergic site for nicotine's action
in brain: Psychopharmacological, electrophysiological and receptor
binding studies
    Abood. Acute and chronic effects of nicotine in rats and
evidence for a non-cholinergic site of action
    Andersson. Involvement of D1 dopamine receptors in the nicotine-
induced neuro-endocrine effects and depletion of diencephalic
catecholamine stores in the male rat
    Andersson. Effects of acute central and peripheral
administration of nicotine on hypothalamic catecholamine nerve
terminal systems and on the secretion of adenohypophyseal hormones
in the male rat
    Andersson. Interactions of nicotine and pentobarbitone in the
regulation of telencephalic and hypothalamic catecholamine levels
and turnover and of adenohypophyseal hormone secretion in the normal
male rat
    Andersson. Effects of single injections of nicotine on the
ascending dopamine pathways in the rat
    Andersson. Mecamylamine induced blockade of nicotine induced
inhibition of gonadotrophin and TSH secretion and of nicotine
induced increases of catecholamine turnover in the rat hypothalamus
    Andersson. Nicotine-induced increases of noradrenaline turnover
in discrete noradrenaline nerve terminal systems of the hypothalamus
and the median eminence of the rat and their relationship to changes
in the secretion of adenohypophyseal hormones
    Andersson. Involvement of cholinergic nicotine-like receptors as
modulators of amine turnover in various types of hypothalamic
dopamine and noradrenaline nerve terminal systems and of prolactin,
LH, FSH and TSH secretion in the castrated male rat
    Andersson. Effects of acute intermittent exposure to cigarette
smoke on catecholamine levels and turnover in various types of
hypothalamic DA and NA nerve terminal systems as well as on the
secretion of adenohypophyseal hormones and corticosterone
    Andersson. Effects of chronic exposure to cigarette smoke on
amine levels and turnover in various hypothalamic catecholamine
nerve terminal systems and on the secretion of pituitary hormones in
the male rat
    Andersson. Mecamylamine pretreatment counteracts cigarette smoke
induced changes in hypothalamic catecholamine neuron systems and in
anterior pituitary function
    Bhagat. Effects of chronic administration of nicotine on storage
and synthesis of noradrenaline in rat brain
    Bhagat. Influence of chronic administration of nicotine on the
turnover and metabolism of noradrenaline in the rat brain
    Bhagat. Effect of chronic administration of nicotine on the
concentrations of adrenal enzymes involved in the synthesis and
metabolism of adrenaline
    Bhattacharya. Influence of acute and chronic nicotine
administration on EEG reactivity to drugs in rabbits: 2.
Psychoactive agents
    Chance. A comparison of nicotine and structurally related
compounds as discriminative stimuli
    Chang. Effect of chronic administration of nicotine on
acetylcholinesterase activity in the hypothalamus and medulla
oblongata of the rat brain An ultrastructural study
    Davies. Evidence for a noncholinergic nicotine receptor on human
phagocytic leukocytes
    Domino. Electroencephalographic and behavioral arousal effects
of small doses of nicotine: A neuropsychopharmacological study
    Erwin. Nicotine alters catecholamines and electrocortical
activity in perfused mouse brain
    Essman. Changes in cholinergic activity and avoidance behavior
by nicotine in differentially housed mice
    Fuxe. Increases in dopamine utilization in certain limbic
dopamine terminal populations after a short period of intermittent
exposure of male rats to cigarette smoke
    Fuxe. Neurochemical mechanisms underlying the neuroendocrine
actions of nicotine: focus on the plasticity of central cholinergic
nicotinic receptors
    Grenhoff. Selective stimulation of limbic dopamine activity by
nicotine
    Grenhoff. Chronic continuous nicotine treatment causes decreased
burst firing of nigral dopamine neurons in rats partially
hemitransected at the meso-diencephalic junction
    Harfstrand. Distribution of nicotinic cholinergic receptors in
the rat tel- and diencephalon: a quantitative receptor
autoradiographical study using [3H]-acetylcholine, [alpha-
125I]bungarotoxin and [3H]nicotine
    Harsing. Dopamine efflux from striatum after chronic nicotine:
evidence for autoreceptor desensitization
    Huganir. Phosphorylation of the nicotinic acetylcholine receptor
regulates its rate of desensitization
    Kawamura. Differential actions of m and n cholinergic agonists
on the brainstem activating system
    Knapp. Action of nicotine on the ascending reticular activating
system
    Kramer. The effect of nicotine on catecholaminergic storage
vesicles
    Lapin. Dopamine-like action of nicotine: lack of tolerance and
reverse tolerance
    Lapin. Action of nicotine on accumbens dopamine and attenuation
with repeated administration

[[Page 41626]]

    Lindstrom. Structural and functional heterogeneity of nicotinic
receptors
    London. Glucose metabolism: An index of nicotine action in the
brain
    Lowy. Antagonism by cholinergic drugs of behavioural effects in
cats of an anticholinergic psychotomimetic drug and enhancement by
nicotine
    Lukas. Heterogeneity of high-affinity nicotinic
[3H]acetylcholine binding sites
    Lukas. Pharmacological distinctions between functional nicotinic
acetylcholine receptors on the PC12 rat pheochromocytoma and the
TE671 human medulloblastoma
    Marks. Characterization of nicotine binding in mouse brain and
comparison with the binding of alpha-bungarotoxin and quinuclidinyl
benzilate
    Martin. Nicotine binding sites and their localization in the
central nervous system
    Marty. Effects of nicotine on beta-endorphin, alpha MSH, and
ACTH secretion by isolated perfused mouse brains and pituitary
glands, in vitro Mitchell. Increases in tyrosine hydroxylase
messenger RNA in the locus coeruleus after a single dose of nicotine
are followed by time-dependent increases in enzyme activity and
noradrenaline release
    Mitchell. Role of the locus coeruleus in the noradrenergic
response to a systemic administration of nicotine
    Naftchi. Acute reduction of brain substance P induced by
nicotine
    Nelsen. Chronic nicotine treatment in rats: 2.
Electroencephalographic amplitude and variability changes occurring
within and between structures
    Owman. Chronic nicotine treatment eliminates asymmetry in
striatal glucose utilization following unilateral transection of the
mesostriatal dopamine pathway in rats
    Pradhan. Effects of nicotine on self-stimulation in rats
    Rosecrans. Noncholinergic Mechanisms involved in the behavioral
and stimulus effects of nicotine, and relationships to the process
of nicotine dependence
    Rosecrans. Nicotine as a discriminative stimulus: a
neurobehavioral approach to studying central cholinergic mechanisms
    Schaeppi. Nicotine treatment of selected areas of the cat brain:
effects upon EEG and autonomic system
    Sershen. Effect of nicotine and amphetamine on the neurotoxicity
of N-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) in mice
    Sershen. Noncholinergic, saturable binding of (+/-)-[3H]nicotine
to mouse brain
    Sershen. Nicotinic Binding Sites in the brain: properties,
regulation, and putative endogenous ligands
    Siegel. Rapid and discrete changes in hypothalamic catecholamine
nerve terminal systems induced by audiogenic stress, and their
modulation by nicotine-relatinship to neuroendocrine function
    Silvette. The actions of nicotine on central nervous system
functions
    Sorenson. The reducing agent dithiothreitol (DTT) does not
abolish the inhibitory nicotinic response recorded from rat
dorsolateral septal neurons
    Stadnicki. Nicotine changes in EEG and behavior after
intravenous infusion in awake unrestrained cats
    Stadnicki. Nicotine infusion into the fourth ventricle of
unrestrained cats: changes in EEG and behavior
    Stitzer. Effects of nicotine on fixed-interval behavior and
their modification by cholinergic antagonists
    Sugiyama. [3H]Nicotine binding sites in developing fetal brains
in rats
    Svensson. Effect of nicotine on dynamic function of brain
catecholamine neurons
    Toth. Effect of nicotine on extracellular levels of
neurotransmitters assessed by microdialysis in various brain
regions: role of glutamic acid
    Toth. Effect of nicotine on levels of extracellular amino acids
in regions of the rat brain in vivo
    Tung. Peripheral induction of burst firing in locus coeruleus
neurons by nicotine mediated via excitatory amino acids
    Vincek. Synthesis of 4,4-ditritio-(+)-nicotine: comparative
binding and distribution studies with natural enantiomer
    Westfall. Effect of nicotine and related substances upon amine
levels in the brain
    Whiting. Expression of nicotinic acetylcholine receptor subtypes
in brain and retina
    Wong. Pharmacology of nicotinic receptor-mediated inhibition in
rat dorsolateral septal neurones
    Wong. A direct nicotinic receptor-mediated inhibition recorded
intracellularly in vitro
    Yamamoto. Nicotine-induced EEG and behavioral arousal
    COUNCIL FOR TOBACCO RESEARCH--USA, Literature Review
    Edwards. Smoking, nicotine and electrocortical activity
    Fuxe. Neuroendocrine actions of nicotine and of exposure to
cigarette smoke: medical implications
    PHILIP MORRIS TOBACCO COMPANY
    DeNoble. Behavioral effects of intraventricularly administered
(-)-nicotine on fixed ratio schedules of food presentation in rats
    Sahley. Antinociceptive effects of central and systemic
administrations of nicotine
    Vezina. The effect of acute and repeated nicotine injections on
brain dopamine activation: Comparisons with morphine and amphetamine
    R.J. REYNOLDS COMPANY
    Bjercke. Anti-idiotypic antibody probes of neuronal nicotinic
receptors
    Brazell. Effect of acute administration of nicotine on in vivo
release of noradrenaline in the hippocampus of freely moving rats: a
dose-response and antagonist study
    Collins. Modulation of Nicotine Receptors by Chronic Exposure to
Nicotinic Agonists and Antagonists
    Gilbert. Effects of smoking/nicotine on anxiety, heart rate, and
lateralization of EEG during a stressful movie
    Lippiello. The Role of Desensitization in CNS Nicotinic receptor
function

[[Page 41627]]

    Lippiello. Characterization of nicotinic receptors on cultured
cortical neurons using anti-idiotypic antibodies and ligand binding
    Lippiello. The binding of L-[3H]nicotine to a single class of
high affinity sites in rat brain membranes
    Lippiello. Identification of putative high affinity nicotinic
receptors on cultured cortical neurons
    Lippiello. Kinetics and mechanism of L-[3H]nicotine binding to
putative high affinity receptor sites in rat brain
    Marks. Downregulation of nicotinic receptor function after
chronic nicotine infusion
    Mitchell. Nicotine-induced catecholamine synthesis after lesions
to the dorsal or ventral noradrenergic bundle
    Mitchell. Regionally specific effects of acute and chronic
nicotine on rates of catecholamine and 5-hydroxytryptamine synthesis
in rat brain
    Prince. Actions of the general anesthetic propofol (2,6-
diisopropylphenol) on the binding of [3H] nicotine to rat cortical
membranes
    Pritchard. Flexible effects of quantified cigarette-smoke
delivery on EEG dimensional complexity
    Smith. Effects of chronic and subchronic nicotine on tyrosine
hydroxylase activity in noradrenergic and dopaminergic neurones in
the rat brain
    Wonnacott. Presynaptic actions of nicotine in the CNS
    BROWN AND WILLIAMSON TOBACCO CORPORATION, Unpublished
    Brotzge. Human smoking studies: acute effect of cigarette smoke
on brain wave alpha rhythm-first report
    BRITISH-AMERICAN TOBACCO COMPANY, LTD.
    Golding. Arousing and de-arousing effects of cigarette smoking
under conditions of stress and mild sensory isolation
    Golding. Effects of cigarette smoking on resting EEG, visual
evoked potentials and photic driving
    BRITISH-AMERICAN TOBACCO COMPANY, LTD., Unpublished
    Ayres. Notes from the GR & DC Nicotine Conference
    Comer. Interaction of smoke and the smoker part 3: the effect of
cigarette smoking on the contingent negative variation
    BRITISH-AMERICAN TOBACCO COMPANY, LTD. Funded--Unpublished
Battelle Studies
    Haselbach. Final report on project HIPPO II
    Haselbach. A tentative hypothesis on nicotine addiction
    Hersch. Final report on project HIPPO I
    Libert. Report no 1 regarding project HIPPO II
    Willey. Effects of nicotine on the central nervous system
    INDUSTRY SUPPORTED AMA/EDUCATIONAL AND RESEARCH FOUNDATION (ERF)
STUDIES:
    Murphree. Elecroencephalographic changes in man following
smoking
    Rosecrans. Brain area nicotine levels in male and female rats
with different levels of spontaneous activity
    Rosecrans. Effects of nicotine on behavioral arousal and brain
5-hydroxytryptamine function in female rats selected for differences
in activity
    Rosecrans. Brain area nicotine levels in male and female rats of
two strains
    Schechter. Behavioral evidence for two types of cholinergic
receptors in the C.N.S.
    Schechter. Effect of mecamylamine on discrimination between
nicotine- and arecoline- produced cues
    Schechter. Nicotine as a discriminative cue in rats: inability
of related drugs to produce a nicotine-like cueing effect
    Schechter. Nicotine as a discriminative stimulus in rats
depleted of norepinephrine or 5-hydroxytryptamine
    TOBACCO RESEARCH COUNCIL LABS., U.K.
    Armitage. Pharmacological basis for the tobacco smoking habit
    Armitage. Some recent observations relating to the absorption of
nicotine from tobacco smoke
    Armitage. Effects of nicotine on electrocortical activity and
acetylcholine release from the cat cerebral cortex
    Armitage. Nicotine, Smoking and cortical activation
    Armitage. The effects of nicotine on the electrocorticogram and
spontaneous release of acetylcholine from the cerebral cortex of the
cat
    Armitage. Effects of nicotine and some nicotine-like compounds
injected into the cerebral ventricles of the cat
    Armitage. Further evidence relating to the mode of action of
nicotine in the central nervous system
    Balfour. A possible role for the pituitary-adrenal system in the
effects of nicotine on avoidance behaviour
    Bhagat. The effects of nicotine and other drugs on the release
of injected 3H-norepinephrine and on endogenous norepinephrine
levels in the rat brain
    Hall. Effects of nicotine and tobacco smoke on the electrical
activity of the cerebral cortex and olfactory bulb
    Morrison. A comparison of the effects of nicotine and
physostigmine on a measure of activity in the rat
    Wesnes. Effects of scopolamine and nicotine on human rapid
information processing performance
    Wesnes. The separate and combined effects of scopolamine and
nicotine on human information processing
    OTHER
    Adem. Distribution of nicotinic receptors in human thalamus as
visualized by 3H-nicotine and 3H-acetylcholine receptor
autoradiography
    Adem. Quantitative autoradiography of nicotinic receptors in
large cryosections of human brain hemispheres
    Andersson. Effects of acute central and peripheral
administration of nicotine on ascending dopamine pathways in the
male rat brain Evidence for nicotine induced increases of dopamine
turnover in various telencephalic dopamine nerve terminal systems
    Cohen. Monograph on the pharmacology and toxicology of nicotine
and its role in tobacco smoking
    Copeland. A comparison of the binding of nicotine and
nornicotine stereoisomers to nicotinic binding sites in rat brain
cortex
    Falkeborn. Chronic nicotine exposure in rat: a behavioural and
biochemical study of tolerance
    Fuxe. On the action of nicotine and cotinine on central 5-
hydroxytryptamine
    Fuxe. Reduction of [3H]nicotine binding in hypothalamic and
cortical membranes by dopamine D1 receptors
    Fuxe. Regulation of endocrine function by the nicotinic
cholinergic receptor
    Grenhoff. Nicotinic effects on the firing pattern of midbrain
dopamine neurons
    Hasenfratz. Smoking-related subjective and physiological
changes: pre- to postpuff and pre- to post cigarette
    Hasenfratz. Post-lunch smoking for pleasure seeking or arousal
maintenance?
    Knott. Effects of cigarette smoking on subjective and brain
evoked responses to electrical pain stimulationLarsson. Comparative
analysis of nicotine-like receptor-ligand interactions in rodent
brain homogenate
    Larsson. In vitro binding of 3H-acetylcholine to nicotinic
receptors in rodent and human brain
    Nisell. Systemic nicotine-induced dopamine release in the rat
nucleus accumbens is regulated by nicotinic receptors in the ventral
tegmental area
    Nordberg. Effect of long-term nicotine treatment on [3H]nicotine
binding sites in the rats brain
    Nordberg. Effect of acute and subchronic nicotine treatment on
cortical acetylcholine release and on nicotinic receptors in rats
and guinea-pigs
    Nordberg. Studies of muscarinic and nicotinic binding sites in
brain
    Perez de la Mora. Neurochemical effects of nicotine on glutamate
and GABA mechanisms in the rat brain
    Slotkin. Developmental Effects of Nicotine
    Slotkin. Effects of prenatal nicotine exposure on neuronal
development: selective actions on central and peripheral
catecholaminergic pathways
    Svensson. Effect of nicotine on single cell activity in the
noradrenergic nucleus locus coeruleus
    Zhang. Effects of chronic treatment with (+)- and (-)- nicotine
on nicotinic acetylcholine receptors and N-methyl-D-aspartate
receptors in rat brain
    OTHER, Literature Review
    Edwards. Smoking, nicotine and electrocortical activity

[[Page 41628]]

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    Mechanisms of action: receptors, neurotransmitters, and hormones.
The tobacco industry has supported sophisticated studies to identify
the sites and mechanisms of nicotine's actions, as well as how the
structure of the brain itself is altered by nicotine's effects on
nicotinic receptors. These studies have identified the receptors in the
central nervous system on which nicotine acts; shown that nicotinic
receptors present in the brain of both animals and man mediate the
behavioral effects of nicotine; and sought to define the location and
functional properties of these nicotinic receptors in the central
nervous system.<SUP>248

    \248\ COUNCIL FOR TOBACCO RESEARCH-USA
    Abood. Comparison of the binding of optically pure (-)- and (+)-
[3H]nicotine to rat brain membranes
    Abood. Electrophysiological, behavioral, and chemical evidence
for a noncholinergic, stereospecific site for nicotine in rat brain
    Abood. Evidence for a noncholinergic site for nicotine's action
in brain: Psychopharmacological, electrophysiological and receptor
binding studies
    Abood. Tritiated methylcarbamylcholine a new radioligand for
studying brain nicotinic receptors
    Andersson. Intravenous injections of nicotine induce very rapid
and discrete reductions of hypothalamic catecholamine levels
associated with increases of ACTH, vasopressin and prolactin
secretion
    Andersson. Effects of acute central and peripheral
administration of nicotine on hypothalamic catecholamine nerve
terminal systems and on the secretion of adenohypophyseal hormones
in the male rat
    Andersson. Nicotine-induced increases of noradrenaline turnover
in discrete noradrenaline nerve terminal systems of the hypothalamus
and the median eminence of the rat and their relationship to changes
in the secretion of adenohypophyseal hormones
    Andersson. Effects of single injections of nicotine on the
ascending dopamine pathways in the rat Evidence for increases of
dopamine turnover in the mesostriatal and mesolimbic dopamine
neurons
    Andersson. Effects of acute central and peripheral
administration of nicotine on ascending dopamine pathways in the
male rat brain Evidence for nicotine induced increases of dopamine
turnover in various telencephalic dopamine nerve terminal systems
    Britto. Immunohistochemical localization of nicotinic
acetylcholine receptor subunits in the mesencephalon and
diencephalon of the chick (Gallus gallus)
    Chance. A comparison of nicotine and structurally related
compounds as discriminative stimuli
    Davies. Evidence for a noncholinergic nicotine receptor on human
phagocytic leukocytes
    Fuxe. Neuroendocrine actions of nicotine and of exposure to
cigarette smoke: medical implications
    Fuxe. Neurochemical mechanisms underlying the neuroendocrine
actions of nicotine: focus on the plasticity of central cholinergic
nicotinic receptors
    Harfstand. Distribution of nicotinic cholinergic receptors in
the rat tel- and diencephalon: a quantitative receptor
autoradiographical study using [3H]-acetylcholine, [alpha-
125I]bungarotoxin and [3H]nicotine
    Huganir. Phosphorylation of the nicotinic acetylcholine receptor
regulates its rate of desensitization

[[Page 41629]]

    Lapin. Action of nicotine on accumbens dopamine and attenuation
with repeated administration
    Lindstrom. Structural and functional heterogeneity of nicotinic
receptors
    Lukas. Heterogeneity of high-affinity nicotinic
[3H]acetylcholine binding sites
    Lukas. Pharmacological distinctions between functional nicotinic
acetylcholine receptors on the PC12 rat pheochromocytoma and the
TE671 human medulloblastoma
    Marks. Characterization of nicotine binding in mouse brain and
comparison with the binding of alpha-bungarotoxin and quinuclidinyl
benzilate
    Martin. Nicotine binding sites and their localization in the
central nervous system
    Mitchell. Increases in tyrosine hydroxylase messenger RNA in the
locus coeruleus after a single dose of nicotine are followed by
time- dependent increases in enzyme activity and noradrenaline
release
    Mitchell. Role of the locus coeruleus in the noradrenergic
response to a systemic administration of nicotine
    Owman. Chronic nicotine treatment eliminates asymmetry in
striatal glucose utilization following unilateral transection of the
mesostriatal dopamine pathway in rats
    Pradhan. Effects of nicotine on self-stimulation in rats
    Rosecrans. Nicotine as a discriminative stimulus: a
neurobehavioral approach to studying central cholinergic mechanisms
    Rosecrans. Noncholinergic Mechanisms involved in the behavioral
and stimulus effects of nicotine, and relationships to the process
of nicotine dependence
    Schaeppi. Nicotine treatment of selected areas of the cat brain:
effects upon EEG and autonomic system
    Sershen. Nicotinic Binding Sites in the brain: properties,
regulation, and putative endogenous ligands
    Sershen. Noncholinergic, saturable binding of (+/-)-[3H]nicotine
to mouse brain
    Sorenson. The reducing agent dithiothreitol (DTT) does not
abolish the inhibitory nicotinic response recorded from rat
dorsolateral septal neurons
    Stitzer. Effects of nicotine on fixed-interval behavior and
their modification by cholinergic antagonists
    Sugiyama. [3H]Nicotine binding sites in developing fetal brains
in rats
    Svensson. Effect of nicotine on dynamic function of brain
catecholamine neurons
    Toth. Effect of nicotine on levels of extracellular amino acids
in regions of the rat brain in vivo
    Whiting. Expression of nicotinic acetylcholine receptor subtypes
in brain and retina
    Wong. A direct nicotinic receptor-mediated inhibition recorded
intracellularly in vitro
    Wong. Pharmacology of nicotinic receptor-mediated inhibition in
rat dorsolateral septal neurones
    COUNCIL FOR TOBACCO RESEARCH--USA, Literature Review
    Fuxe. Effects of Nicotine and exposure to cigarette smoke on
discrete dopamine and noradrenaline nerve terminal systems of the
telencephalon and diencephalon of the rat: Relationship to reward
mechanisms and neuroendocrine functions and distribution of
nicotinic binding sites in brain
    R.J. REYNOLDS COMPANY
    Bjercke. Anti-idiotypic antibody probes of neuronal nicotinic
receptors
    Collins. Modulation of Nicotine Receptors by Chronic Exposure to
Nicotinic Agonists and Antagonists
    Lippiello. The Role of Desensitization in CNS Nicotinic receptor
function
    Lippiello. Characterization of nicotinic receptors on cultured
cortical neurons using anti-idiotypic antibodies and ligand binding
    Lippiello. Identification of putative high affinity nicotinic
receptors on cultured cortical neurons
    Lippiello. Properties of putative nicotine receptors identified
on cultured cortical neurons
    Lippiello. Kinetics and mechanism of L-[3H]nicotine binding to
putative high affinity receptor sites in rat brain
    Lippiello. The binding of L-[3H]nicotine to a single class of
high affinity sites in rat brain membranes
    Marks. Downregulation of nicotinic receptor function after
chronic nicotine infusion
    Prince. Actions of the general anesthetic propofol (2,6-
diisopropylphenol) on the binding of [3H] nicotine to rat cortical
membranes
    BRITISH-AMERICAN TOBACCO COMPANY, LTD. Unpublished
    Ayres. Notes from the GR & DC Nicotine Conference
    PHILIP MORRIS TOBACCO COMPANY, Unpublished
    DeNoble. Brain Sites Involved in the Mediation of the Behavioral
Effects of Intraventricularly Administered (-)-nicotine
    DeNoble. Manuscript--Brain Sites Involved in the Mediation of
the Behavioral Effects of Intraventricularly Administered (-)-
nicotine
    INDUSTRY SUPPORTED AMA/ERF STUDIES
    Hirschhorn. Studies on the time course and the effect of
cholinergic and adrenergic receptor blockers on the stimulus effect
of nicotine
    Schechter. Behavioral evidence for two types of cholinergic
receptors in the CNS
    Schechter. Effect of mecamylamine on discrimination between
nicotine- and arecoline- produced cues
    Schechter. Nicotine as a discriminative stimulus in rats
depleted of norepinephrine or 5-hydroxytryptamine
    TOBACCO RESEARCH COUNCIL LABS., U.K.
    Wesnes. The separate and combined effects of scopolamine and
nicotine on human information processing
    Wesnes. Effects of scopolamine and nicotine on human rapid
information processing performance
    OTHER
    Adem. Quantitative autoradiography of nicotinic receptors in
large cryosections of human brain hemispheres
    Adem. Distribution of nicotinic receptors in human thalamus as
visualized by 3H-nicotine and 3H-acetylcholine receptor
autoradiography
    Copeland. A comparison of the binding of nicotine and
nornicotine stereoisomers to nicotinic binding sites in rat brain
cortex
    Fuxe. On the action of nicotine and cotinine on central 5-
hydroxytryptamine
    Fuxe. Reduction of [3H]nicotine binding in hypothalamic and
cortical membranes by dopamine D1 receptors
    Larsson. In vitro binding of 3H-acetylcholine to nicotinic
receptors in rodent and human brain
    Larsson. Comparative analysis of nicotine-like receptor-ligand
interactions in rodent brain homogenate
    Nisell. Systemic nicotine-induced dopamine release in the rat
nucleus accumbens is regulated by nicotinic receptors in the ventral
tegmental area
    Nordberg. Effect of long-term nicotine treatment on [3H]nicotine
binding sites in the rats brain
    Nordberg. Effect of acute and subchronic nicotine treatment on
cortical acetylcholine release and on nicotinic receptors in rats
and guinea-pigs
    Nordberg. Studies of muscarinic and nicotinic binding sites in
brain
    Slotkin. Developmental Effects of Nicotine
    Svensson. Effect of nicotine on single cell activity in the
noradrenergic nucleus
    Zhang. Effects of chronic treatment with (+)- and (-)- nicotine
on nicotinic acetylcholine receptors and N-methyl-D-aspartate
receptors in rat brain

[[Page 41630]]

---------------------------------------------------------------------------

    Neurotransmitters. Tobacco industry studies have shown that
nicotine and its metabolites produce neurochemical and metabolic
effects in the brain.<SUP>249

    \249\ COUNCIL FOR TOBACCO RESEARCH-USA
    Andersson. Effects of acute central and peripheral
administration. of nicotine on ascending dopamine pathways in the
male rat brain. Evidence for nicotine induced increases of dopamine
turnover in various telencephalic dopamine nerve terminal systems
    Andersson. Mecamylamine pretreatment counteracts cigarette smoke
induced changes in hypothalamic catecholamine neuron systems and in
anterior pituitary function
    Andersson. Intravenous injections of nicotine induce very rapid
and discrete reductions of hypothalamic catecholamine levels
associated with increases of ACTH, vasopressin and prolactin
secretion
    Andersson. Involvement of cholinergic nicotine-like receptors as
modulators of amine turnover in various types of hypothalamic
dopamine and noradrenaline nerve terminal systems and of prolactin,
LH, FSH and TSH secretion in the castrated male rat
    Andersson. Interactions of nicotine and pentobarbitone in the
regulation of telencephalic and hypothalamic catecholamine levels
and turnover and of adenohypophyseal hormone secretion in the normal
male rat
    Andersson. Effects of acute central and peripheral
administration of nicotine on hypothalamic catecholamine nerve
terminal systems and on the secretion of adenohypophyseal hormones
in the male rat
    Andersson. Effects of single injections of nicotine on the
ascending dopamine pathways in the rat: Evidence for increases of
dopamine turnover in the mesostriatal and mesolimbic dopamine
neurons
    Andersson. Nicotine-induced increases of noradrenaline turnover
in discrete noradrenaline nerve terminal systems of the hypothalamus
and the median eminence of the rat and their relationship to changes
in the secretion of adenohypophyseal hormones
    Andersson. Mecamylamine induced blockade of nicotine induced
inhibition of gonadotrophin and TSH secretion and of nicotine
induced increases of catecholamine turnover in the rat hypthalamus
    Andersson. Effects of acute intermittent exposure to cigarette
smoke on catecholamine levels and turnover in various types of
hypothalamic DA and NA nerve terminal systems as well as on the
secretion of adenohypophyseal hormones and corticosterone
    Andersson. Effects of chronic exposure to cigarette smoke on
amine levels and turnover in various hypothalamic catecholamine
nerve terminal systems and on the secretion of pituitary hormones in
the male rat
    Bhagat. Influence of chronic administration of nicotine on the
turnover and metabolism of noradrenaline in the rat brain
    Bhagat. Effect of chronic administration of nicotine on the
concentrations of adrenal enzymes involved in the synthesis and
metabolism of adrenaline
    Bhagat. Effects of chronic administration of nicotine on storage
and synthesis of noradrenaline in rat brain
    Chang. Effect of chronic administration of nicotine on
acetylcholinesterase activity in the hypothalamus and medulla
oblongata of the rat brain An ultrastructural study
    Chiou. The ability of various nicotinic agents to release
acetylcholine from synaptic vesicles
    Erwin. Nicotine alters catecholamines and electrocortical
activity in perfused mouse brain
    Essman. Changes in cholinergic activity and avoidance behavior
by nicotine in differentially housed mice
    Fuxe. Increases in dopamine utilization in certain limbic
dopamine terminal populations after a short period of intermittent
exposure of male rats to cigarette smoke
    Grenhoff. Chronic continuous nicotine treatment causes decreased
burst firing of nigral dopamine neurons in rats partially
hemitransected at the meso-diencephalic junction
    Grenhoff. Selective stimulation of limbic dopamine activity by
nicotine
    Harsing. Dopamine efflux from striatum after chronic nicotine:
evidence for autoreceptor desensitization
    Knapp. Action of nicotine on the ascending reticular activating
system
    Lapin. Dopamine-like action of nicotine: lack of tolerance and
reverse tolerance
    Lapin. Action of nicotine on accumbens dopamine and attenuation
with repeated administration
    Lowy. Antagonism by cholinergic drugs of behavioural effects in
cats of an anticholinergic psychotomimetic drug and enhancement by
nicotine
    Marty. Effects of nicotine on beta-endorphin, alpha MSH, and
ACTH secretion by isolated perfused mouse brains and pituitary
glands, in vitro
    Mitchell. Increases in tyrosine hydroxylase messenger RNA in the
locus coeruleus after a single dose of nicotine are followed by
time-dependent increases in enzyme activity and noradrenaline
release
    Mitchell. Role of the locus coeruleus in the noradrenergic
response to a systemic administration of nicotine
    Naftchi. Acute reduction of brain substance P induced by
nicotine
    Siegel. Rapid and discrete changes in hypothalamic catecholamine
nerve terminal systems induced by audiogenic stress, and their
modulation by nicotine-relatinship to neuroendocrine function
    Toth. Effect of nicotine on extracellular levels of
neurotransmitters assessed by microdialysis in various brain
regions: role of glutamic acid
    Toth. Effect of nicotine on levels of extracellular amino acids
in regions of the rat brain in vivo
    Tung. Peripheral induction of burst firing in locus coeruleus
neurons by nicotine mediated via excitatory amino acids
    Westfall. Effect of nicotine and related substances upon amine
levels in the brain
    Westfall. Effect of nicotine and other drugs on the release of
3H-norepinephrine and 3H-dopamine from rat brain slices
    R.J. REYNOLDS COMPANY
    Brazell. Effect of acute administration of nicotine on in vivo
release of noradrenaline in the hippocampus of freely moving rats: a
dose-response and antagonist study
    Mitchell. Nicotine-induced catecholamine synthesis after lesions
to the dorsal or ventral noradrenergic bundle
    Mitchell. Regionally specific effects of acute and chronic
nicotine onrates of catecholamine and 5-hydroxytryptamine synthesis
in rat brain
    Smith. Effects of chronic and subchronic nicotine on tyrosine
hydroxylase activity in noradrenergic and dopaminergic neurones in
the rat brain
    BRITISH-AMERICAN TOBACCO COMPANY, LTD. Unpublished
    Haselbach. Tentative Hypothesis on Nicotine Addiction
    Haselbach. Final Report on Project HIPPO II
    INDUSTRY SUPPORTED SYMPOSIA
    Joseph. Possible mechanisms underlying beneficial effects of
nicotine in cognitive function
    Nordberg. Assessment of cholinergic neuronal activity in the
brain
    INDUSTRY SUPPORTED AMA/ERF STUDIES
    Rosecrans. Effects of nicotine on behavioral arousal and brain
5-hydroxytryptamine function in female rats selected for differences
in activity
    Schechter. Nicotine as a discriminative stimulus in rats
depleted of norepinephrine or 5-hydroxytryptamine
    TOBACCO RESEARCH COUNCIL LABS., U.K.
    Armitage. Effects of nicotine on electrocortical activity and
acetylcholine release from the cat cerebral cortex
    Armitage. The effects of nicotine on the electrocorticogram and
spontaneous release of acetylcholine from the cerebral cortex of the
cat
    Armitage. Further evidence relating to the mode of action of
nicotine in the central nervous system
    Balfour. A possible role for the pituitary-adrenal system in the
effects of nicotine on avoidance behaviour
    Bhagat. The effects of nicotine and other drugs on the release
of injected 3H-norepinephrine and on endogenous norepinephrine
levels in the rat brain
    OTHER
    Fuxe. Regulation of endocrine function by the nicotinic
cholinergic receptor
    Fuxe. On the action of nicotine and cotinine on central 5-
hydroxytryptamine neurons
    Grenhoff. Nicotinic effects on the firing pattern of midbrain
dopamine neurons
    Nisell. Systemic nicotine-induced dopamine release in the rat
nucleus accumbens is regulated by nicotinic receptors in the ventral
tegmental area
    Nordberg. Effect of acute and subchronic nicotine treatment on
cortical acetylcholine release and on nicotinic receptors in rats
and guinea-pigs
    Perez de la Mora. Neurochemical effects of nicotine on glutamate
and GABA mechanisms in the rat brain
    Slotkin. Effects of prenatal nicotine exposure on neuronal
development: selective actions on central and peripheral
catecholaminergic pathways
    OTHER, Literature Review
    Edwards. Smoking, nicotine and electrocortical activity

[[Page 41631]]

---------------------------------------------------------------------------

    These studies show that nicotine exerts its behavior modifying
effects, in part, through the cascade of effects that are produced
through nicotine's actions on existing brain chemicals. Industry-
supported studies show that nicotine, like other addictive drugs, acts
on dopaminergic receptors <SUP>250 in the mesolimbic system to release

[[Page 41632]]
dopamine, a chemical in the brain associated with pleasurable feelings.

    \250\ COUNCIL FOR TOBACCO RESEARCH-U.S.A
    Abood. Receptor binding characteristics of a 3H-labeled
azetidine analogue of nicotine
    Andersson. Mecamylamine induced blockade of nicotine induced
inhibition of gonadotrophin and TSH secretion and of nicotine
induced increases of catecholamine turnover in the rat hypothalmus
    Andersson. Effects of acute intermittent exposure to cigarette
smoke on catecholamine levels and turnover in various types of
hypothalamic DA and NA nerve terminal systems as well as on the
secretion of adenohypophyseal hormones and corticosterone
    Andersson. Effects of single injections of nicotine on the
ascending dopamine pathways in the rat. Evidence for increases of
dopamine turnover in the mesostriatal and mesolimbic dopamine
neurons
    Andersson. Involvement of cholinergic nicotine-like receptors as
modulators of amine turnover in various types of hypothalamic
dopamine and noradrenaline nerve terminal systems and of prolactin,
LH, FSH and TSH secretion in the castrated male rat
    Andersson. Interactions of nicotine and pentobarbitone in the
regulation of telencephalic and hypothalamic catecholamine levels
and turnover and of adenohypophyseal hormone secretion in the normal
male rat
    Andersson. Effects of acute central and peripheral
administration of nicotine on hypothalamic catecholamine nerve
terminal systems and on the secretion of adenohypophyseal hormones
in the male rat
    Erwin. Nicotine alters catecholamines and electrocortical
activity in perfused mouse brain
    Fuxe. Increases in dopamine utilization in certain limbic
dopamine terminal populations after a short period of intermittent
exposure of male rats to cigarette smoke
    Grenhoff. Selective stimulation of limbic dopamine activity by
nicotine
    Harsing. N-type calcium channels are involved in the dopamine
releasing effect of nicotine
    Lapin. Action of nicotine on accumbens dopamine and attenuation
with repeated administration
    Lapin. Dopamine-like action of nicotine: lack of tolerance and
reverse tolerance
    Westfall. Effect of nicotine and other drugs on the release of
3H-norepinephrine and 3H-dopamine from rat brain slices
    R.J. REYNOLDS COMPANY
    Lippiello. The role of desensitization in CNS nicotinic receptor
function
    Marks. Downregulation of nicotinic receptor function after
chronic nicotine infusion
    INDUSTRY SUPPORTED SYMPOSIA
    Joseph. Possible mechanisms underlying beneficial effects of
nicotine in cognitive function
    OTHER
    Adem. Quantitative autoradiography of nicotinic receptors in
large cryosections of human brain hemispheres
    Andersson. Effects of acute central and peripheral
administration of nicotine on ascending dopamine pathways in the
male rat brain. Evidence for nicotine-induced increases of dopamine
turnover in various telencephalic dopamine nerve terminal systems
    Fuxe. Regulation of endocrine function by the nicotinic
cholinergic receptor
    Grenhoff. Nicotinic effects on the firing pattern of midbrain
dopamine neurons
    Nisell. Systemic nicotine-induced dopamine release in the rat
nucleus accumbens is regulated by nicotinic receptors in the ventral
tegmental area
---------------------------------------------------------------------------

    Mood modification and EEG effects. In tobacco industry-sponsored
trials, nicotine has been shown to induce both behavioral arousal and
calming effects.<SUP>251 These effects have been correlated with

[[Page 41633]]
electroencephalogram/electrocorticogram changes in electrical activity
in the brain.<SUP>252 Whether nicotine provides a stimulating or
calming effect depends on the dose of nicotine taken, the time elapsed
since the last dose, and other factors.<SUP>253

    \251\ COUNCIL FOR TOBACCO RESEARCH-USA
    Domino. Electroencephalographic and behavioral arousal effects
of small doses of nicotine: A neuropsychopharmacological study
    Heimstra. The effects of deprivation of cigarette smoking on
psychomotor performance
    Marks. Genetics of nicotine response in four inbred strains of
mice
    Nelsen. Improvement of performance on an attention task with
chronic nicotine treatment in rats
    Pradhan. Effects of nicotine on several schedules of behavior in
rats
    Schaeppi. Nicotine treatment of selected areas of the cat brain:
effects upon EEG and autonomic system
    Stadnicki. Nicotine infusion into the fourth ventricle of
unrestrained cats: changes in EEG and behavior
    Stadnicki. Nicotinic changes in EEG and behavior after
intravenous infusion in awake unrestrained cats
    Yamamoto. Nicotine-induced EEG and behavioral arousal
    COUNCIL FOR TOBACCO RESEARCH-USA, Literature Review
    Silvette. The actions of nicotine on central nervous system
functions
    R.J. REYNOLDS COMPANY
    Lippiello. Properties of putative nicotine receptors identified
on cultured cortical neurons
    Pritchard. Electroencephalographic effects of cigarette smoking
    Robinson. The role of nicotine in tobacco use
    BRITISH-AMERICAN TOBACCO COMPANY, LTD.
    Golding. Arousing and de-arousing effects of cigarette smoking
under conditions of stress and mild sensory isolation
    Mangan. The effects of cigarette smoking on vigilance
performance
    BRITISH-AMERICAN TOBACCO COMPANY, LTD. Unpublished
    Comer. Interaction of Smoke and the Smoker Part 3: The Effect of
Cigarette Smoking on the Contingent Negative Variation
    Thornton. Some ``Benefits'' of Smoking
    INDUSTRY SUPPORTED SYMPOSIA
    Joseph. Possible mechanisms underlying beneficial effects of
nicotine in cognitive function
    Wesnes. The effects of cigarette smoking and nicotine tablets
upon human attention
    INDUSTRY SUPPORTED AMA/ERF STUDIES
    Rosecrans. Effects of nicotine on behavioral arousal and brain
5-hydroxytryptamine function in female rats selected for differences
in activity
    TOBACCO RESEARCH COUNCIL LABS., U.K.
    Armitage. Effects of nicotine on electrocortical activity and
acetylcholine release from the cat cerebral cortex
    Armitage. Nicotine, smoking and cortical activation
    Hall. Effects of nicotine and tobacco smoke on the electrical
activity of the cerebral cortex and olfactory bulb
    Morrison. Antagonism by antimuscarinic and ganglion-blocking
drugs of some of the behavioural effects of nicotine
    Morrison. The occurrence of tolerance to a central depressant
effect of nicotine
    Warwick. Experimental studies of the behavioural effects of
nicotine
    OTHER
    Cohen. Monograph on the ``Pharmacology and Toxicology of
Nicotine and its Role in Tobacco Smoking Draft
    Edwards. Evidence of more rapid stimulus evaluation following
cigarette smoking
    Golding. Effects of cigarette smoking on measures of arousal,
response suppression, and excitation/inhibition balance
    Nordberg. Effect of nicotine on passive avoidance behaviour and
motoric activity in mice
    \252\ COUNCIL FOR TOBACCO RESEARCH-USA
    Domino. Electroencephalographic and behavioral arousal effects
of small doses of nicotine: A neuropsychopharmacological study
    Erwin. Nicotine alters catecholamines and electrocortical
activity in perfused mouse brain
    Kawamura. Differential actions of m and n cholinergic agonists
on the brainstem activating system
    Marty. Effects of nicotine on beta-endorphin, alpha MSH, and
ACTH secretion by isolated perfused mouse brains and pituitary
glands, in vitro
    Nelsen. Chronic nicotine treatment in rats 2
Electroencephalographic amplitude and variability changes occurring
within and between structures
    Schaeppi. Nicotine treatment of selected areas of the cat brain:
effects upon EEG and autonomic system
    Stadnicki. Nicotine infusion into the fourth ventricle of
unrestrained cats: changes in EEG and behavior
    Stadnicki. Nicotinic changes in EEG and behavior after
intravenous infusion in awake unrestrained cats
    Yamamoto. Nicotine-induced EEG and behavioral arousal
    COUNCIL FOR TOBACCO RESEARCH-USA, Literature Review
    Silvette. The actions of nicotine on central nervous system
functions
    PHILIP MORRIS TOBACCO COMPANY
    Mangan. Relationships between photic driving, nicotine and
memory
    (One Philip Morris document explains why the company decided to
conduct nicotine-related EEG research: ``We are establishing an EEG
laboratory in search of the reinforcing event. Brain waves are
neuro-physiological phenomena, but they are legitimate subject
matter for us in that brain events underlie behavioral events.
Smoke-related changes in brain waves can give us clues as to smoke-
related psychological changes.'' Philip Morris employee (almost
certainly W.L. Dunn). Smoker Psychology Program Review. October 19,
1977. Page 9.)
    R.J. REYNOLDS COMPANY
    Gilbert. Effects of smoking/nicotine on anxiety, heart rate, and
lateralization of EEG during a stressful movie
    Pritchard. Flexible effects of quantified cigarette-smoke
delivery on EEG dimensional complexity
    Pritchard. Electroencephalographic effects of cigarette smoking
    Robinson. Psychopharmacological effects of smoking a cigarette
with typical ``tar'' and carbon monoxide yields but minimal nicotine
    BROWN AND WILLIAMSON TOBACCO CORPORATION, Unpublished
    Brotzge. Human smoking studies: acute effect of cigarette smoke
on brain wave alpha rhythm-first report
    BRITISH-AMERICAN TOBACCO COMPANY, LTD.
    Golding. Effects of cigarette smoking on resting EEG, visual
evoked potentials and photic driving
    Golding. Arousing and de-arousing effects of cigarette smoking
under conditions of stress and mild sensory isolation
    Golding. Effects of cigarette smoking on measures of arousal,
response suppression, and excitation/inhibition balance
    BRITISH-AMERICAN TOBACCO COMPANY, LTD. Unpublished
    Comer. Interaction of smoke and the smoker. Part 3: The effect
of cigarette smoking on the contingent negative variation
    Willey. Effects of nicotine on the central nervous system
    INDUSTRY SUPPORTED AMA/ERF STUDIES
    Murphree. Elecroencephalographic changes in man following
smoking
    TOBACCO RESEARCH COUNCIL LABS., U.K.
    Armitage. Effects of nicotine on electrocortical activity and
acetylcholine release from the cat cerebral cortex
    Armitage. The effects of nicotine on the electrocorticogram and
spontaneous release of acetylcholine from the cerebral cortex of the
cat
    Armitage. Pharmacological basis for the tobacco smoking habit
    Ashton. The use of event-related slow potentials of the brain as
a means to analyse the effects of cigarette smoking and nicotine in
humans
    Hall. Effects of nicotine and tobacco smoke on the electrical
activity of the cerebral cortex and olfactory bulb
    OTHER
    Edwards. Smoking, nicotine and electrocortical activity
    Knott. Effects of cigarette smoking on subjective and brain
evoked responses to electrical pain stimulation
    Knott. Reaction time, noise distraction and autonomic
responsivity in smokers and non-smokers
    \253\ INDUSTRY SUPPORTED AMA/ERF STUDIES
    Rosecrans. Effects of nicotine on behavioral arousal and brain
5-hydroxytryptamine function in female rats selected for differences
in activity
    R.J. REYNOLDS COMPANY
    Robinson. Psychopharmacological effects of smoking a cigarette
with typical ``tar'' and carbon monoxide yields but minimal nicotine
    BRITISH-AMERICAN TOBACCO COMPANY, LTD.
    Mangan. The effects of cigarette smoking on vigilence
performance
    COUNCIL FOR TOBACCO RESEARCH-USA
    Domino. Electroencephalographic and behavioral arousal effects
of small doses of nicotine: A neuropsychopharmacological study
    Marks. Genetics of nicotine response in four inbred strains of
mice
    Pradhan. Effects of nicotine on several schedules of behavior in
rats
    Yamamoto. Nicotine-induced EEG and behavioral arousal
    TOBACCO RESEARCH COUNCIL LABS, U.K.
    Warwick. Experimental studies of the behavioral effects of
nicotine

[[Page 41634]]

---------------------------------------------------------------------------

    Effects on performance and behavior. Industry-funded scientists
have conducted research to characterize nicotine's effects on
behavioral performance and cognitive function.<SUP>254

    \254\ COUNCIL FOR TOBACCO RESEARCH-USA
    Bhagat. Effect of nicotine on the swimming endurance of rats
    Heimstra. The effects of deprivation of cigarette smoking on
psychomotor performance
    Levin. Memory enhancing effects of nicotine
    Marks. Genetics of nicotine response in four inbred strains of
mice
    Nelsen. Chronic nicotine treatment in rats
    Nelsen. Protection by nicotine from behavioral disruption caused
by reticular formation stimulation in the rat
    Nelsen. Improvement of performance on an attention task with
chronic nicotine treatment in rats
    COUNCIL FOR TOBACCO RESEARCH-USA, Literature Reviews
    Essman. Drug effects and learning and memory processes
    Silvette. The actions of nicotine on central nervous system
functions
    PHILIP MORRIS TOBACCO COMPANY
    Colrain. Effects of post-learning smoking on memory
consolidation.DeNoble. Behavioral effects of intraventricularly
administered (-)-nicotine on fixed ratio schedules of food
presentation in rats
    Mangan. Relationships between photic driving, nicotine and
memory
    Woodson. Effects of nicotine on the visual evoked response
    R.J. REYNOLDS COMPANY
    Pritchard. Enhancement of continuous performance task reaction
time by smoking in non-deprived smokers
    Pritchard. Electroencephalographic effects of cigarette smoking
    BRITISH-AMERICAN TOBACCO COMPANY, LTD.
    Mangan. The effects of cigarette smoking on vigilance
performance
    Mangan. The effects of smoking on memory consolidation
    INDUSTRY SUPPORTED AMA/ERF STUDIES
    Schechter. C.N.S. effect of nicotine as the discriminative
stimulus for the rat in a T-maze
    TOBACCO RESEARCH COUNCIL LABS., U.K.
    Armitage. Pharmacological basis for the tobacco smoking habit
    Balfour. A possible role for the pituitary-adrenal system in the
effects of nicotine on avoidance behaviour
    Morrison. Effects of nicotine on motor co-ordination and
spontaneous activity in mice
    Morrison. The effects of nicotine on punished behaviour
    Warwick. Experimental studies of the behavioral effects of
nicotine
    Wesnes. Effects of nicotine on stimulus sensitivity and response
bias in a visual vigilance task
    Wesnes. The separate and combined effects of scopolamine and
nicotine on human information processing
    Wesnes. Effects of scopolamine and nicotine on human rapid
information processing performance
    Wesnes. Effects of smoking on rapid information processing
performance
    TOBACCO RESEARCH COUNCIL, UK, Literature Reviews
    Hall. New evidence for a relationship between tobacco smoking,
nicotine dependence, and stress
    Wesnes. Smoking, nicotine and human performance
    OTHER
    Andersson. Effects of cigarette smoking on incidental memory
    Battig. The effect of pre- and post-trial application of
nicotine on the 12 problems of the Hebb-Williams-test in the rat
    Driscoll. Effects of nicotine on the shuttlebox behavior of
trained guinea pigs
    Hasenfratz. Action profiles of smoking and caffeine: Stoop
effect, EEG, and peripheral physiology
    Hasenfratz. Can smoking increase attention in rapid information
processing during noise?
    Knott. Reaction time, noise distraction and autonomic
responsivity in smokers and non-smokers
    Knott. Noise and task induced distraction effects on information
processing: Sex differences in smokers and non-smokers
    Nordberg. Effect of nicotine on passive avoidance behaviour and
motoric activity in mice
    Roth. Smoking deprivation in ``early'' and ``late'' smokers and
memory functions
    Wesnes. The effects of cigarettes of varying yield on rapid
information processing

[[Page 41635]]

---------------------------------------------------------------------------

    Neuroendocrine effects. Tobacco industry-supported studies have
demonstrated that nicotine affects hormone secretion and several
endocrine functions involved in modulation of mood and behavior. These
studies showed that nicotine stimulates the secretion of
corticosteroids and catecholamines and decreases the secretion of
thyroid stimulating hormone, leutinizing hormone, and
prolactin.<SUP>255

    \255\ COUNCIL FOR TOBACCO RESEARCH-USA
    Andersson. Involvement of D1 dopamine receptors in the nicotine-
induced neuro-endocrine effects and depletion of diencephalic
catecholamine stores in the male rat
    Andersson. Effects of withdrawal from chronic exposure to
cigarette smoke on hypothalamic and preoptic catecholamine nerve
terminal systems and on the secretion of pituitary hormones in the
male rat
    Andersson. Nicotine-induced increases of noradrenaline turnover
in discrete noradrenaline nerve terminal systems of the hypothalamus
and the median eminence of the rat and their relationship to changes
in the secretion of adenohypophyseal hormones
    Andersson. Mecamylamine induced blockade of nicotine induced
inhibition of gonadotrophin and TSH secretion and of nicotine
induced increases of catecholamine turnover in the rat hypothalamus
    Andersson. Effects of acute intermittent exposure to cigarette
smoke on catecholamine levels and turnover in various types of
hypothalamic DA and NA nerve terminal systems as well as on the
secretion of adenohypophyseal hormones and corticosterone
    Andersson. Involvement of cholinergic nicotine-like receptors as
modulators of amine turnover in various types of hypothalamic
dopamine and noradrenaline nerve terminal systems and of prolactin,
LH, FSH and TSH secretion in the castrated male rat
    Andersson. Effects of acute central and peripheral
administration of nicotine on hypothalamic catecholamine nerve
terminal systems and on the secretion of adenohypophyseal hormones
in the male rat
    Fuxe. Neuroendocrine actions of nicotine and of exposure to
cigarette smoke: medical implications
    Fuxe. Neurochemical mechanisms underlying the neuroendocrine
actions of nicotine: focus on the plasticity of central cholinergic
nicotinic receptors
    Fuxe. Effects of Nicotine and exposure to cigarette smoke on
discrete dopamine and noradrenaline nerve terminal systems of the
telencephalon and diencephalon of the rat: Relationship to reward
mechanisms and neuroendocrine functions and distribution of
nicotinic binding sites in brain
    Marty. Effects of nicotine on beta-endorphin, alpha MSH, and
ACTH secretion by isolated perfused mouse brains and pituitary
glands, in vitro
    Rubin.
    Nicotine-induced stimulation of steroidogenesis in
adrenocortical cells of the cat
    Siegel. Rapid and discrete changes in hypothalamic catecholamine
nerve terminal systems induced by audiogenic stress, and their
modulation by nicotine-relatinship to neuroendocrine function
    Westfall. Effect of 4.4'-biphenylenebis-[(2-oxoethylene)-bis-
(2,2'-diethoxyethyl)] dimethylammonium dibromide (DMAE) on
accumulation and nicotine-induced release of norepinephrine in the
heart
    Westfall. Specificity of blockade of the nicotine-induced
release of 3H-norepinephrine from adrenergic neurons of the guinea-
pig heart by various pharmacological agents
    R.J. REYNOLDS COMPANY
    Mitchell. Regionally specific effects of acute and chronic
nicotine on rates of catecholamine and 5-hydroxytryptamine synthesis
in rat brain
    TOBACCO RESEARCH COUNCIL LABS., U.K.
    Balfour. A possible role for the pituitary-adrenal system in the
effects of nicotine on avoidance behaviour
    OTHER
    Fuxe. Regulation of endocrine function by the nicotinic
cholinergic receptor
---------------------------------------------------------------------------

2. Industry Research on Nicotine Delivery to the Blood and Brain
    The tobacco industry has studied the bioavailability of nicotine in
tobacco products and how nicotine is distributed throughout the body,
after absorption into the bloodstream. This has led to the industry's
development of sophisticated techniques for determining, quantitatively
and qualitatively, the presence of nicotine and its metabolites in body
fluids.<SUP>256

    \256\ AMERICAN TOBACCO COMPANY
    Castro. Nicotine antibodies: comparison of ligand specificities
of antibodies produced against two nicotine conjugates
    COUNCIL FOR TOBACCO RESEARCH-USA
    Castro. Nicotine enzyme immunoassay
    Castro. Radioimmunoassays of drugs of abuse in humans: a review
    Haines. Radioimmunoassay of plasma nicotine in habituated and
naive smokers
    McNiven. Determination of nicotine in smokers' urine by gas
chromatography
    Monji. Plasma nicotine pharmacokinetics in dogs after
intravenous administration: determination by radioimmunassay
    R.J. REYNOLDS COMPANY
    Caldwell. Characterization of the glucuronide conjugate of
cotinine: a previously unidentified major metabolite of nicotine in
smokers' urine
    Davis. The determination of nicotine and cotinine in plasma
    Kyerematen. Radiometric high performance liquid chromatographic
assay for nicotine and twelve of its metabolites
    Kyerematen. Pharmacokinetics of nicotine and 12 metabolites in
the rat
    Langone. Idiotype-anti-idiotype hapten immunoassays: assay for
cotinine
    McManus. A new quantitative thermospray LC-MS method for
nicotine and its metabolites in biological fluids
    BRITISH-AMERICAN TOBACCO COMPANY, Unpublished
    Backhurst. Further work on extractable nicotine
    Isaac. The absorption and effects of nicotine from inhaled
tobacco smoke
    Read. Method for nicotine and cotinine in blood and urine
    Read. Nicotine studies: A second report. Estimation of whose
body nicotine dose by urinary nicotine and contine measurement
    BRITISH-AMERICAN TOBACCO COMPANY, LTD. Funded--Battelle
Unpublished Studies
    Geissbuhler. The fate of nicotine in the body
    Haselbach. A tentative hypothesis on nicotine addiction
    TOBACCO RESEARCH COUNCIL LABS., U.K.
    Armitage. The transfer of endogenous and exogenous
radioisotopically labelled nicotine to mainstream cigarette smoke
and its absorption into the blood of anaesthetized cats
    Beckett. Analysis of nicotine-1-N-oxide in urine, in the
presence of nicotine and cotinine, and its application to the study
of in vivo nicotine metabolism in man
    OTHER
    Biber. Determination of nicotine and cotinine in human serum and
urine: an interlaboratory study
    Isaac. Cigarette smoking and plasma levels of nicotine
    Schievelbein. Nicotine Workshop
    Schmiterlow. Distribution of Nicotine in the Central Nervous
System
    Schmiterlow. Tissue distribution of C14-nicotine and Related
Compounds
    Szuts. Long-term fate of [14C]nicotine in the mouse: retention
in the bronchi, melanin-containing tissues and urinary bladder wall

[[Page 41636]]

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    Nicotine pharmacokinetics. Numerous publications document the
tobacco industry's involvement in investigating all aspects of the
pharmacokinetics of nicotine. (Pharmacokinetics is the study of the
absorption, distribution, metabolism, and elimination of drugs in the
body.) Areas that the industry has researched include:
    <bullet> general pharmacokinetics of nicotine (absorption,
distribution, metabolism, elimination); <SUP>257

    \257\ COUNCIL FOR TOBACCO RESEARCH-USA
    Becker. Studies on nicotine absorption during pregnancy
    Haines. Radioimmunoassay of plasma nicotine in habituated and
naive smokers
    Hibberd. Enzymology of the metabolic pathway from nicotine to
cotinine, in vitro
    Kershbaum. Cigarette, cigar, and pipe smoking. Some differences
in biochemical effects
    Monji. Plasma nicotine pharmacokinetics in dogs after
intravenous administration: determination by radioimmunoassay
    Rama. Distribution and Retention of nicotine and its major
metabolite cotinine in the rat as a function of time
    COUNCIL FOR TOBACCO RESEARCH-USA, Literature Reviews
    Larson. Tobacco--Experimental and Clinical Studies
    Larson. Tobacco--Experimental and Clinical Studies--A
Comprehensive Account of the World Literature--Supplement I
    Larson. Tobacco--Experimental and Clinical Studies--A
Comprehensive Account of the World Literature--Supplement II
    Larson. Tobacco--Experimental and Clinical Studies--A
Comprehensive Account of the World Literature --Supplement III
    AMERICAN TOBACCO COMPANY
    Haag. Studies on the fate of nicotine in the body I: The effect
of pH on the urinary excretion of nicotine by tobacco smokers
    Larson. Studies on the fate of nicotine in the body VI:
Observations on the relative rate of elimination of nicotine by the
dog, cat, rabbit and mouse
    Larson. Studies on the fate of nicotine in the body II: On the
fate of nicotine in the dog
    Larson. Studies on the fate of nicotine in the body IV:
Observations on the chemical structure of an end product of nicotine
metabolism
    McKennis. N-methylation of nicotine and cotinine in vivo
    Owen. Studies on the fate of nicotine in the animal body. VIII:
Observations on the number and chemical nature of nicotine
metabolites in the dog and cat
    Weatherby. Rate of elimination of nicotine by the rabbit
    R.J. REYNOLDS COMPANY
    Caldwell. Characterization of the glucuronide conjugate of
cotinine: a previously unidentified major metabolite of nicotine in
smokers' urine
    Caldwell. Intragastric nitrosation of nicotine is not a
significant contributor to nitrosamine exposure
    deBethizy. Chemical and biological studies of a cigarette that
heats rather than burns tobacco
    deBethizy. Absorption of nicotine from a cigarette that does not
burn tobacco
    Hammond. Metabolism of nicotine by rat liver cytochromes P-450:
Assessment utilizing monoclonal antibodies to nicotine and cotinine
    Kyerematen. Pharmacokinetics of nicotine and 12 metabolites in
the rat
    Kyerematen. Disposition of nicotine and eight metabolites in
smokers and nonsmokers: Identification in Smokers of two metabolites
that are longer lived than cotinine
    BROWN AND WILLIAMSON TOBACCO CORPORATION, Unpublished
    Brotzge. Human smoking studies: acute effect of cigarette smoke
on brain wave alpha rhythm--first report
    BRITISH-AMERICAN TOBACCO COMPANY, LTD., Funded--Unpublished
Battelle Studies
    Geissbuhler. The fate of nicotine in the body
    TOBACCO RESEARCH COUNCIL LABS., U.K.
    Armitage. Absorption and metabolism of nicotine from cigarettes
    Armitage. Absorption of nicotine in cigarette and cigar smoke
through the oral mucosa
    Armitage. The transfer of endogenous and exogenous
radioisotopically labelled nicotine to mainstream cigarette smoke
and its absorption into the blood of anaesthetized cats
    Beckett. Effect of smoking on nicotine metabolism in vivo in man
    Beckett. Analysis of nicotine-1-N-oxide in urine, in the
presence of nicotine and cotinine, and its application to the study
of in vivo nicotine metabolism in man
    Beckett. Buccal absorption of basic drugs and its application as
an in vivo model of passive drug transfer through lipid membranes
    Jenner. Species variation in the metabolism of R-(+)- and S-(-)-
nicotine by alpha-C- and N-oxidation in vitro
    Jenner. Factors affecting the in vitro metabolism of R-(+)- and
S-(-)-nicotine by guinea-pig liver preparations
    OTHER
    Cholerton. Sources of inter-individual variability in nicotine
pharmacokinetics
    Cohen. Monograph on the Pharmacology and Toxicology of Nicotine
and its Role in Tobacco Smoking
    Hasenfratz. Development of central and peripheral smoking
effects over time
    Pilotti. Studies on the identification of tobacco alkaloids,
their mammalian metabolites and related compounds by gas
chromatography- -mass spectrometry
    Schievelbein. Nicotine Workshop
    Schmiterlow. Tissue distribution of C14-nicotine
    Schmiterlow. Distribution of nicotine in the central nervous
system
    Szuts. Long-term fate of [14C]nicotine in the mouse: retention
in the bronchi, melanin-containing tissues and urinary bladder wall
---------------------------------------------------------------------------

    <bullet> factors affecting the absorption of nicotine into the
bloodstream, including route of administration; <SUP>258

    \258\ COUNCIL FOR TOBACCO RESEARCH-USA
    Haines. Radioimmunoassay of plasma nicotine in habituated and
naive smokers
    Kershbaum. Cigarette, cigar, and pipe smoking. Some differences
in biochemical effects
    R.J. REYNOLDS COMPANY
    deBethizy. Chemical and biological studies of a cigarette that
heats rather than burns tobacco
    deBethizy. Absorption of nicotine from a cigarette that does not
burn tobacco
    BRITISH-AMERICAN TOBACCO COMPANY, LTD. Unpublished
    Backhurst. Further Work on Extractable Nicotine
    Evelyn. Retention of nicotine and phenols in the human mouth
    Evelyn. Transfer of nicotine from smoke into blood using a
perfused canine lung
    Evelyn. Absorption of nicotine via the mouth: studies using
animal models
    Isaac. The absorption and effects of nicotine from inhaled
tobacco smoke
    TOBACCO RESEARCH COUNCIL LABS., U.K.
    Armitage. Absorption of nicotine by man during cigar smoking
[proceedings]
    Armitage. Absorption of nicotine from small cigars
    Armitage. The transfer of endogenous and exogenous
radioisotopically labelled nicotine to mainstream cigarette smoke
and its absorption into the blood of anaesthetized cats
    Armitage. Absorption of nicotine in cigarette and cigar smoke
through the oral mucosa
    OTHER
    Hasenfratz. Development of central and peripheral smoking
effects over time
    Schievelbein. Nicotine workshop: Absorption of nicotine under
various conditions (an introductory review)

[[Page 41637]]

---------------------------------------------------------------------------

    <bullet> distribution of nicotine to the brain; <SUP>259 and

    \259\ COUNCIL FOR TOBACCO RESEARCH-USA
    Hatchell. The influence of genotype and sex on behavioral
sensitivity to nicotine in mice
    Vincek. Synthesis of 4,4-ditritio-(+)-nicotine: comparative
binding and distribution studies with natural enantiomer
    BRITISH-AMERICAN TOBACCO COMPANY, LTD. Unpublished
    Creighton. Relative contributions of nicotine and carbon
monoxide to human physiological response
    Creighton. Further studies on the effect of nicotine on human
physiological response
    Isaac. The Absorption and Effects of Nicotine from Inhaled
Tobacco Smoke
    INDUSTRY SUPPORTED AMA/ERF STUDIES
    Rosecrans. Brain area nicotine levels in male and female rats
with different levels of spontaneous activity
    Rosecrans. Brain area nicotine levels in male and female rats of
two strains
    OTHER
    Cholerton. Sources of inter-individual variability in nicotine
pharmacokinetics
    Schmiterlow. Distribution of Nicotine in the Central Nervous
System
    OTHER, Literature Review
    Edwards. Smoking, nicotine and electrocortical activity

[[Page 41638]]

---------------------------------------------------------------------------

    <bullet> plasma profiles of nicotine and its metabolites.<SUP>260

    \260\ COUNCIL FOR TOBACCO RESEARCH-USA
    Castro. Nicotine enzyme immunoassay
    Haines. Radioimmunoassay of plasma nicotine in habituated and
naive smokers
    Monji. A Plasma nicotine pharmacokinetics in dogs after
intravenous administration: Determination by radioimunassay
    Rama. Distribution and Retention of nicotine and its major
metabolite cotinine, in the rat as a function of time
    AMERICAN TOBACCO COMPANY
    Castro. Nicotine antibodies: comparison of ligand specificities
of antibodies produced against two nicotine conjugates
    R.J. REYNOLDS COMPANY
    Davis. The determination of nicotine and cotinine in plasma
    deBethizy. Absorption of nicotine from a cigarette that does not
burn tobacco
    Kyerematen. Pharmacokinetics of nicotine and 12 metabolites in
the rat Application of a new radiometric high performance liquid
chromatography assay
    Kyerematen. Radiometric high performance liquid chromatographic
assay for nicotine and twelve of its metabolites
    BRITISH-AMERICAN TOBACCO COMPANY, LTD. Unpublished
    Isaac. The absorption and effects of nicotine from inhaled
tobacco smoke
    TOBACCO RESEARCH COUNCIL LABS., U.K.
    Armitage. Absorption and metabolism of nicotine from cigarettes
    Armitage. Absorption of nicotine by man during cigar smoking
[proceedings]
    Armitage. Absorption of nicotine from small cigars
    Armitage. The transfer of endogenous and exogenous
radioisotopically labelled nicotine to mainstream cigarette smoke
and its absorption into the blood of anaesthetized catsStepney.
Behavioural regulation of nicotine intake in cigarette smokers
presented with a `shortened' cigarette [proceedings]
    OTHER
    Isaac. Cigarette smoking and plasma levels of nicotine
    Isaac. Blood levels of nicotine and physiological effects after
inhalation of tobacco smokeIsaac. Blood levels of nicotine and
physiological effects after inhalation of tobacco smoke
    Schievelbein. Nicotine Workshop
---------------------------------------------------------------------------

    Nicotine metabolism. The industry has investigated the metabolic
fate of nicotine, including the metabolites (breakdown products) of
nicotine.<SUP>261 Studies have also been done on the enzymatic systems
involved in nicotine

[[Page 41639]]
metabolism.<SUP>262 Industry-supported research shows that smokers
metabolize nicotine faster than non-smokers because one or more of the
substances in cigarette smoke increases the production of the enzymes
that metabolize nicotine.<SUP>263 Industry-funded studies have also
shown that there may be gender differences in the metabolism of
nicotine.<SUP>264

    \261\ COUNCIL FOR TOBACCO RESEARCH-U.S.A
    Abood. Specific binding and metabolism of (-)- and (+)-[3H]-
nicotine in isolated rat hepatocytes and hepatocyte membranes
    Hibberd. Nicotine delta 1' (5)' iminium ion: a reactive
intermediate in nicotine metabolism
    Vincek. Synthesis of 4,4-ditritio-(+)-nicotine: comparative
binding and distribution studies with natural enantiomer
    AMERICAN TOBACCO COMPANY
    Bowman. Studies on the metabolism of (-)-cotinine in the human
    Bowman. Disposition and fate of (-)-cotinine-H3 in the mouse
    Hucker. Studies on the metabolism of nornicotine in the dog
    Larson. Studies on the fate of nicotine in the body III: On the
pharmacology of some methylated and demethylated derivatives of
nicotine
    Larson. Studies on the fate of nicotine in the body IV:
Observations on the chemical structure of an end product of nicotine
metabolism
    McKennis. Gamma-(3-pyridyl)-gamma-methylaminobutyric acid as a
urinary metabolite of nicotine
    McKennis. The excretion and metabolism of nicotine
    McKennis. Mammalian degradation of (-)-nicotine to 3-
pyridylacetic acid and other compounds
    McKennis. Demethylation in the metabolism of (-)-nicotine
    McKennis. Metabolic release of methyl groups from a series of N-
methylpyridinium compounds
    McKennis. Metabolism of nicotine to (+)-gamma-(3-pyridyl)-gamma-
methylaminobutyric acid
    McKennis. Demethylation of cotinine in vivo
    McKennis. Metabolites of nicotine and a synthesis of nornicotine
    McKennis. Demethylation in the metabolism of (-)-nicotine in
vivo
    McKennis. N-methylation of nicotine and cotinine in vivo
    McKennis. The Metabolic Formation of Gamma-(3-Pyridyl)-Gamma-
Hydroxybutyric Acid and Its Possible Intermediary Role in the
Mammalian Metabolism of Nicotine
    McKennis. The isolation and structure of a ketoamide formed in
the metabolism of nicotine
    Meacham. Additional routes in the metabolism of nicotine to 3-
pyridylacetate
    Miller. Observations on the metabolism of nicotine by tissue
slices
    Owen. Studies on the fate of nicotine in the animal body VIII:
Observations on the nubmer and chemical nature of nicotine
metabolites in the dog and cat
    Schwartz. Studies on the degradation of the pyrrolidine ring of
(-)-nicotine in vivo
    Schwartz. Mammalian degradation of (-)-demethylcotinine
    R.J. REYNOLDS COMPANY
    Caldwell. Characterization of the glucuronide conjugate of
cotinine: a previously unidentified major metabolite of nicotine in
smokers' urine
    Kyerematen. Disposition of nicotine and eight metabolites in
smokers and nonsmokers: Identification in smokers of two metabolites
that are longer lived than cotinine
    TOBACCO RESEARCH COUNCIL LABS., U.K.
    Jenner. Factors affecting the in vitro metabolism of R-(+)- and
S-(-)-nicotine by guinea-pig liver preparations
    Jenner. Species variation in the metabolism of R-(+)- and S-(-)-
nicotine by alpha-C- and N-oxidation in vitro
    OTHER
    Fuxe. On the action of nicotine and cotinine on central 5-
hydroxytryptamine
    \262\ COUNCIL FOR TOBACCO RESEARCH-U.S.A
    Hibberd. Enzymology of the metabolic pathway from nicotine to
cotinine, in vitro
    Wilson. Nicotine-like actions of cis-metanicotine and trans-
metanicotine
    R.J. REYNOLDS COMPANY
    Hammond. Metabolism of nicotine by rat liver cytochromes P-450:
Assessment utilizing monclonal antibodies to nicotine and cotinine
    \263\ COUNCIL FOR TOBACCO RESEARCH-U.S.A
    Hatchell. The influence of genotype and sex on behavioral
sensitivity to nicotine in mice
    Jusko. Role of tobacco smoking in pharmacokinetics
    TOBACCO RESEARCH COUNCIL LABS., U.K.
    Beckett. The effect of smoking on nicotine metabolism in vivo in
man
    \264\ COUNCIL FOR TOBACCO RESEARCH-U.S.A
    Jusko. Role of tobacco smoking in pharmacokinetics
    TOBACCO RESEARCH COUNCIL LABS., U.K.
    Beckett. The effect of smoking on nicotine metabolism in vivo in
man
    OTHER
    Cohen. Monograph on the Pharmacology and Toxicology of Nicotine
and its Role in Tobacco Smoking
---------------------------------------------------------------------------

    Nicotine pharmacodynamics. The tobacco industry has studied a wide
range of factors related to the pharmacodynamics of nicotine and
nicotine delivery systems. (Pharmacodynamics is the study of a drug's
effects on the body over time. A pharmacodynamic study would involve,
for example, administering a drug and then evaluating its behavioral
and physiological effects over time.) The industry has funded research
on:
    <bullet> factors affecting the onset and duration of nicotine's
physiological effects on the body; <SUP>265

    \265\ COUNCIL FOR TOBACCO RESEARCH-USA
    Domino. Electroencephalographic and behavioral arousal effects
of small doses of nicotine: A neuropsychopharmacological study
    Hoff. Neurophysiological aspects of the action of nicotine
    Lapin. Dopamine-like action of nicotine: lack of tolerance and
reverse tolerance
    Stitzer. Effects of nicotine on fixed-interval behavior and
their modification by cholinergic antagonists
    TOBACCO RESEARCH COUNCIL LABS., U.K.
    Armitage. Absorption of nicotine in cigarette and cigar smoke
through the oral mucosa
    COUNCIL FOR TOBACCO RESEARCH-USA, Literature Reviews
    Larson. Tobacco--Experimental and Clinical Studies--A
Comprehensive Account of the World Literature--Supplement I
    Larson. Tobacco--Experimental and Clinical Studies--A
Comprehensive Account of the World Literature--Supplement II
    Larson. Tobacco--Experimental and Clinical Studies--A
Comprehensive Account of the World Literature--Supplement III
    OTHER
    Battig. Smoke yield of cigarettes and puffing behavior in men
and women
    Nordberg. Pharmacodynamic effects of nicotine and acetylcholine
biosynthesis in mouse brain

[[Page 41640]]

---------------------------------------------------------------------------

    <bullet> the relationship of nicotine's physiological effects on
the body to nicotine blood levels; <SUP>266 and

    \266\ COUNCIL FOR TOBACCO RESEARCH-U.S.A
    Hatchell. The influence of genotype and sex on behavioral
sensitivity to nicotine in mice
    Westfall. Influence of nicotine on catecholamine metabolism in
the rat
    R.J. REYNOLDS COMPANY
    Pritchard. Flexible effects of quantified cigarette-smoke
delivery on EEG dimensional complexity
    BRITISH-AMERICAN TOBACCO COMPANY, LTD. Unpublished
    Isaac. The absorption and effects of nicotine from inhaled
tobacco smoke
    OTHER
    Isaac. Blood levels of nicotine and physiological effects after
inhalation of tobacco smoke
---------------------------------------------------------------------------

    <bullet> physiological effects of nicotine on the brain and their
time-course.<SUP>267

    \267\ COUNCIL FOR TOBACCO RESEARCH-U.S.A
    Abood. Comparison of the binding of optically pure (-)- and (+)-
[3H]nicotine to rat brain membranes
    Andersson. Effects of withdrawal from chronic exposure to
cigarette smoke on hypothalamic and preoptic catecholamine nerve
terminal systems and on the secretion of pituitary hormones in the
male
    Andersson. Effects of acute intermittent exposure to cigarette
smoke on catecholamine levels and turnover in various types of
hypothalamic DA and NA nerve terminal systems as well as on the
secretion of adenohypophyseal hormones and corticosterone
    Bhagat. Influence of chronic administration of nicotine on the
turnover and metabolism of noradrenaline in the rat brain
    Fuxe. Increases in dopamine utilization in certain limbic
dopamine terminal populations after a short period of intermittent
exposure of male rats to cigarette smoke
    Fuxe. Effects of Nicotine and exposure to cigarette smoke on
discrete dopamine and noradrenaline nerve terminal systems of the
telencephalon and diencephalon of the rat: Relationship to reward
mechanisms and neuroendocrine functions and distribution of
nicotinic binding sites in brain
    Tung. Peripheral induction of burst firing in locus coeruleus
neurons by nicotine mediated via excitatory amino acids
    Wong. Pharmacology of nicotinic receptor-mediated inhibition in
rat dorsolateral septal neurones
    Yamamoto. Nicotine-induced EEG and behavioral arousal
    R.J. REYNOLDS COMPANY
    Byrd. Evidence for urinary excretion of glucuronide conjugates
of nicotine, cotinine, and trans-3'-hydroxycotinine in smokers
    INDUSTRY SUPPORTED SYMPOSIA
    Binnie. The effect of cigarette smoking on the contingent
negative variation (CNV) and eye movement
    INDUSTRY SUPPORTED AMA/ERF STUDIES
    Hirschhorn. Studies on the time course and the effect of
cholinergic and adrenergic receptor blockers on the stimulus effect
of nicotine
    Rosecrans. Brain area nicotine levels in male and female rats
with different levels of spontaneous activity
    TOBACCO RESEARCH COUNCIL LABS., U.K.
    Armitage. The effects of nicotine on the electrocorticogram and
spontaneous release of acetylcholine from the cerebral cortex of the
cat
    Wesnes. Smoking, nicotine and human performance
    OTHER
    Fuxe. On the action of nicotine and cotinine on central 5-
hydroxytryptamine neurons
    Hasenfratz. Development of central and peripheral smoking
effects over time
    Hasenfratz. Can smoking increase attention in rapid information
processing during noise? Electrocortical, physiological and
behavioral effects
    Perez de la Mora. Neurochemical effects of nicotine on glutamate
and GABA mechanisms in the rat brain
    OTHER, Literature Review
    Edwards. Smoking, nicotine and electrocortical activity
---------------------------------------------------------------------------

3. Industry Research Establishes That Nicotine Produces Pharmacological
Effects Similar to Those of Other Addictive Drugs

    The tobacco industry has conducted or sponsored studies which
demonstrate that nicotine produces pharmacological effects similar to
those of other addictive substances. See FINDINGS Sec. I.B., supra, for
a discussion of the properties of addictive substances. Indeed, a
number of industry-funded studies state that

[[Page 41641]]
nicotine is an addictive/dependence-producing drug.<SUP>268

    \268\ COUNCIL FOR TOBACCO RESEARCH-U.S.A
    Bosse. Age and addiction to smoking
    Martin. Tobacco Smoking and Nicotine: A Neurobiological Approach
    Rosecrans. Noncholinergic Mechanisms involved in the behavioral
and stimulus effects of nicotine, and relationships to the process
of nicotine dependence
    Rosecrans. Nicotine as a discriminative stimulus: a
neurobehavioral approach to studying central cholinergic mechanisms
    Svensson. Effect of nicotine on dynamic function of brain
catecholamine neurons
    Tung. Peripheral induction of burst firing in locus coeruleus
neurons by nicotine mediated via excitatory amino acids
    Williams. Stability of a factor-analytic description of smoking
behavior
    TOBACCO RESEARCH COUNCIL LABS., U.K.
    Hall. New evidence for a relationship between tobacco smoking,
nicotine dependence, and stress
    OTHER
    Andersson. Effects of acute central and peripheral
administration of nicotine on ascending dopamine pathways in the
male rat brain. Evidence for nicotine-induced increases of dopamine
turnover in various telencephalic dopamine nerve terminal systems
    Nisell. Systemic nicotine-induced dopamine release in the rat
nucleus accumbens is regulated by nicotinic receptors in the ventral
tegmental area
---------------------------------------------------------------------------

    Nicotine psychoactivity and discrimination studies. Industry
studies have shown that nicotine is psychoactive and produces clearly
discriminable stimulus effects <SUP>269 in both animals and
humans.<SUP>270

    \269\ These effects are evaluated in animals using drug
discrimination techniques which enable direct comparisons of the
effects of different drugs. Such studies evaluate whether an animal
experiences a psychoactive effect from a drug and facilitate
comparisons of the effect of the study drug with the effect of other
psychoactive drugs. Industry-funded studies have shown that animals
can distinguish (discriminate) nicotine from other drugs or a
placebo, and can communicate their identification of nicotine (as
distinct from other drugs) to the investigator by pressing a bar or
providing other behavioral signals. These studies also provide
information on the similarity of nicotine's effects to effects of
other dependence-producing drugs, including the degree to which
nicotine mimics the psychoactive effects of those other drugs. See
p. 95.
    \270\ INDUSTRY SUPPORTED AMA/ERF STUDIES
    Hirschhorn. Studies on the time course and the effect of
cholinergic and adrenergic receptor blockers on the stimulus effect
of nicotine
    Schechter. Behavioral evidence for two types of cholinergic
receptors in the C.N.S.
    Schechter. Behavioral tolerance to an effect of nicotine in the
rat
    Schechter. Effect of mecamylamine on discrimination between
nicotine- and arecoline- produced cues
    Schechter. Nicotine as a discriminative cue in rats: inability
of related drugs to produce a nicotine-like cueing effect
    Schechter. Nicotine as a discriminative stimulus in rats
depleted of norepinephrine or 5-hydroxytryptamine
    Schechter. C.N.S. effect of nicotine as the discriminative
stimulus for the rat in a T-maze
    COUNCIL FOR TOBACCO RESEARCH-U.S.A
    Chance. A comparison of nicotine and structurally related
compounds as discriminative stimuli
    Rosecrans. Nicotine as a discriminative stimulus: a
neurobehavioral approach to studying central cholinergic mechanisms
    PHILIP MORRIS TOBACCO COMPANY
    Kallman. Nicotine as a discriminative stimulus in human subjects
    TOBACCO RESEARCH COUNCIL LABS., U.K.
    Morrison. Nicotine injections as the conditioned stimulus in
discrimination learning
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    Nicotine reinforcement/self-administration studies. The industry
has examined nicotine's ability to serve as a positive reinforcer in
self-administration studies involving rats and monkeys. For example,
Philip Morris conducted studies in rats demonstrating that nicotine is
self-administered by rats and has other hallmark properties of
addictive susbstances.<SUP>271 The industry-supported research on
monkeys led prominent drug addiction researchers Deneau and Inoki to
conclude in a paper published in 1967 that nicotine ``may be one of

[[Page 41642]]
the substances in tobacco smoke which is responsible for man's use of
tobacco.'' <SUP>272 The industry has also funded studies demonstrating
that nicotine could enhance the rewarding effects of electrical brain
stimulation.<SUP>273 A book resulting from The International Smoking
Behaviour Conference held at Chelwood Vachery, Sussex, England, in
1978, which was edited by a senior scientist at British-American
Tobacco, included a ``Conference Overview'' stating: ``At this stage,
we hypothesize that nicotine (possible [sic] interacting with tar) is
the main reinforcing agent in cigarettes * * *.'' <SUP>274 Moreover, as
noted earlier, the industry has conducted studies showing that nicotine
is active in the same dopaminergic pathways that modulate cocaine's
effects. These studies are relevant to understanding how nicotine
causes addiction.

    \271\ PHILIP MORRIS TOBACCO COMPANY, Unpublished
    DeNoble. Manuscript: Nicotine as a Positive Reinforcer for Rats:
Effects of Infusion Dose and Fixed Ratio Size
    See also pp. 278-79, infra.
    INDUSTRY SUPPORTED AMA/ERF STUDIES
    Deneau. Nicotine self-administration in monkeys
    \272\ INDUSTRY SUPPORTED AMA/ERF STUDIES
    Deneau. Nicotine self-administration in monkeys
    \273\ COUNCIL FOR TOBACCO RESEARCH-U.S.A.
    Olds. Comparision of muscarinic and nicotinic cholinergic
agonists on self-stimulation behavior
    Pradan. Effects of nicotine on self-stimulation in rats
    \274\ INDUSTRY SUPPORTED SYMPOSIA
    Jarvik. Smoking Behaviour--Physiological and psychological
influences. 31. Conference overview
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    Tolerance to nicotine. Tolerance to the physiological and
behavioral effects of nicotine has been thoroughly studied by the
tobacco industry and has been demonstrated to occur in animals as a
result of nicotine use.<SUP>275

    \275\ COUNCIL FOR TOBACCO RESEARCH-U.S.A
    Abood. Acute and chronic effects of nicotine in rats and
evidence for a non-cholinergic site of action
    Abood. Behavioral and biochemical studies in rats after chronic
exposure to nicotine
    Andersson. Effects of withdrawal from chronic exposure to
cigarette smoke on hypothalamic and preoptic catecholamine nerve
terminal systems and on the secretion of pituitary hormones in the
male
    Cronan. Effects of chronically administered nicotine and saline
on motor activity in rats
    Domino. Tolerance to the effects of daily nicotine on rat bar
pressing behavior for water reinforcement
    Fuxe. Effects of nicotine and exposure to cigarette smoke on
discrete dopamine and noradrenaline nerve terminal systems of the
telencephalon and diencephalon of the rat: Relationship to reward
mechanisms and neuroendocrine functions and distribution of
nicotinic binding sites in brain
    Lapin. Dopamine-like action of nicotine: lack of tolerance and
reverse tolerance
    Nelsen. Improvement of performance on an attention task with
chronic nicotine treatment in rats

and stimulus effects of nicotine, and relationships to the process
of nicotine dependence
    Stitzer. Effects of nicotine on fixed-interval behavior and
their modification by cholinergic antagonists
    Wenzel. Studies on the acute and chronic depressor actions of
nicotine in the rat
    Westfall. Studies on the mechanism of tolerance to nicotine-
induced elevations of urinary catecholamines
    R.J. REYNOLDS COMPANY
    Bjercke. Anti-idiotypic antibody probes of neuronal nicotinic
receptors
    Collins. Modulation of nicotine receptors by chronic exposure to
nicotinic agonists and antagonists
    Marks. Downregulation of nicotinic receptor function after
chronic nicotine infusion
    PHILIP MORRIS TOBACCO COMPANY, Unpublished
    DeNoble. Manuscript: Development of behavioral tolerance
following chronic nicotine administration.
    INDUSTRY SUPPORTED AMA/ERF STUDIES
    Schechter. Behavioral tolerance to an effect of nicotine in the
rat
    TOBACCO RESEARCH COUNCIL LABS., U.K.
    Morrison. The occurrence of tolerance to a central depressant
effect of nicotine
    OTHER
    Larsson. Subchronic treatment of rats with nicotine: effects on
tolerance and on [3H]acetylcholine and [3H]nicotine binding in the
brain
    Nordberg. Effect of acute and subchronic nicotine treatment on
cortical acetylcholine release and on nicotinic receptors in rats
and guinea-pigs
    Nordberg. Effect of long-term nicotine treatment on [3H]nicotine
binding sites in the rats brain

[[Page 41643]]

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    Nicotine's withdrawal effects. Scientists funded by the tobacco
industry have conducted research on various aspects of withdrawal,
including potential neurochemical mechanisms <SUP>276 and the effects
of withdrawal on performance.<SUP>277 Symptoms of withdrawal may
include craving, irritability, nervousness, tension, emotional strain,
depression, inability to concentrate, sleep disturbance, sweating,
gastrointestinal changes, drop in blood pressure and pulse rate,
impaired performance, and changes in the electroencephalogram.<SUP>278

    \276\ COUNCIL FOR TOBACCO RESEARCH-U.S.A
    Andersson. Effects of withdrawal from chronic exposure to
cigarette smoke on hypothalamic and preoptic catecholamine nerve
terminal systems and on the secretion of pituitary hormones in the
male
    Fuxe. Effects of Nicotine and exposure to cigarette smoke on
discrete dopamine and noradrenaline nerve terminal systems of the
telencephalon and diencephalon of the rat: Relationship to reward
mechanisms and neuroendocrine functions and distribution of
nicotinic binding sites in brain
    Rosecrans. Noncholinergic Mechanisms involved in the behavioral
and stimulus effects of nicotine, and relatinships to the process of
nicotine dependence
    COUNCIL FOR TOBACCO RESEARCH-U.S.A., Literature Reviews
    Larson. Tobacco--Experimental and Clinical Studies--A
Comprehensive Account of the World Literature--Supplement II
    Larson. Tobacco--Experimental and Clinical Studies--A
Comprehensive Account of the World Literature--Supplement III
    AMERICAN TOBACCO COMPANY
    Finnegan. The role of nicotine in the cigarette habit
    \277\ COUNCIL FOR TOBACCO RESEARCH-U.S.A
    Heimstra. The effects of deprivation of cigarette smoking on
psychomotor performance
    Heimstra. Effects of smoking upon sustained performance in a
simulated driving task
    COUNCIL FOR TOBACCO RESEARCH-U.S.A., Literature Reviews
    Fuxe. Neuroendocrine actions of nicotine and of exposure to
cigarette smoke: medical implications
    Larson. Tobacco--Experimental and Clinical Studies--A
Comprehensive Account of the World Literature--Supplement III
    OTHER
    Hasenfratz. Psychophysiological reactions during active and
passive stress coping following smoking cessation
    \278\ COUNCIL FOR TOBACCO RESEARCH-U.S.A., Literature Reviews
    Larson. Tobacco--Experimental and Clinical Studies--A
Comprehensive Account of the World Literature--Supplement II
    Larson. Tobacco--Experimental and Clinical Studies--A
Comprehensive Account of the World Literature--Supplement III
    AMERICAN TOBACCO COMPANY
    Finnegan. The role of nicotine in the cigarette habit
---------------------------------------------------------------------------

    The industry has also funded studies showing that tobacco users
report ``craving'' for tobacco.<SUP>279 Continued use of tobacco
despite attempts to quit. As described in Sec. II.C.4., infra, the
tobacco industry has conducted a number of studies documenting the
large percentage of tobacco users who have attempted to quit using
tobacco and the very small percentage who have succeeded.

    \279\ R.J. REYNOLDS COMPANY
    Robinson. The meaning of addiction: reply to West
    OTHER
    Hasenfratz. Development of central and peripheral smoking
effects over time
    Hasenfratz. Post-lunch smoking for pleasure seeking or arousal
maintenance?
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