bluuebunny/crossref_metadata_2025 huggingface dataset:
On the possible role of central monoaminergic systems in the central nervous system actions of vinpocetine
Authors: Kiss Béla , Szporny László
Published: January 2005

The effects of vinpocetine, a recently described cerebral blood flow enhancer having antihypoxic, anti‐ischemic, and cognitive‐function‐improving actions, on rat brain monoaminergic neurotransmission have been studied under normoxic and hypoxic conditions. Vinpocetine slightly affected the steady‐state levels of monoamines and their metabolites in whole brain, but a tendency was seen to increase dopamine (DA) and its metabolites in lower brain parts and to reduce noradrenaline (NA) in “terminal” regions. MHPG‐SO4 levels were enhanced in whole brain and in almost all regions examined. There was a tendency to increase 5‐hydroxyindole‐acetic acid (5‐HIAA) in some areas. It accelerated the whole brain NA turnover dose‐dependenntly, but left that of DA unchanaged. Enhancement of NA turnover was most noted in the lower brain areas. On the other hand, no change was found in DA accumulation, an index of heart NA turnover after inhibition of dopamine‐beta‐hydroxylase. The rate of probenecideinduced accumulation of cerebral MHPG‐SO4 and, to a lesser extent, that of 5‐HIAA was also increased. No change was seen in the pargyline‐induced serotonin (5‐HT) accumulation. Although vinpocetine had slight or no effects on regional levels of monoamines and their metabolites, and did not alter their in vivo biosynthesis rate under normoxic conditions, it was able partially or totally to prevent reductions in the biosynthesis rate of monoamines and antagonized the decrease of NA, 5‐HT, and 5‐HIAA (but not that of DA) induced by normobaric hypoxia. This effect was mainly confined to lower brain areas. From the results, we conclude that vinpocetine primarily affects cell body regions (e.g., brainstem) of the rat brain. Enhancement of the activity of ascending noradrengergic and, perhaps, serotoninergic pathways may very likely participate in the cognitive function‐imporving actions of the drug under normoxic conditions. Vinpocetine was able to prevent monoamigergic neurotransmission against deleterious effects of hypoxia.
Effect of nootropic drugs on age‐dependent changes in transmitter release
Authors: Schmidt Joachim , Wustmann Christian , Rudolph Erika , Zschorn Eva‐Maria , Fischer Hans‐Dieter
Published: January 2005

Dopamine release from rat striatum slices shows marked age‐dependent changes. In 9‐month‐old animals the potassium‐stimulated efflux is reduced by more than one‐half compared with the maximum release seen at an age of 2–6 months. That means that the vesicle storage pool loses its functional maximum size at a relative early age. The mechanisms underlying these changes are complex and unclear as yet. Experimental data show interesting relationships between age‐dependent and hypoxia‐induced changes in cerebral neurotransmission. The posthypoxic changes in transmitter release are prevented by single high doses of nootropics and related drugs, and long‐term treatment with lower, not protective doses leads to a marked acceleration of the restitution. Therefore, we studied the effect of a long‐term treatment of aging rats with nootropics and related drugs. Piracetam meclofenoxate, or vinpocetine given to old rats in low doses twice a day for 3 weeks cause a significant diminution of the age‐dependent lowering of dopamine release. This result leads to the assumption that nootropic drugs retard in part age‐dependent processes in the CNS.
Electrophysiologic effects of vinpocetine and vincamine on isolated rabbit papillary muscle in normal‐ and low‐potassium medium
Authors: Leboeuf J. , Lamar J. C. , Massingham R.
Published: January 2005

The electrophysiologic effects of vinpocetine (VP) on the action potential (AP) of the isolated rabbit papillary muscle were compared with those of vincamine (VC) in normal (5.6 mM)‐ and low (2.7 mM)‐potassium concentrations. In 5.6 mM K+ medium, VC (1 and 10 μM) did not affect the resting potential (RP) but increased AP duration at 50% and 90% of repolarization (APD50 and APD90). At 10 μM, a decrease in maximal depolarization velocity (Vmax) was also observed. Under these conditions, VP (1 and 10 μM) hyperpolarized the RP and at 10 μM increased both Vmax and AP amplitude. VP (1 μM) shortened AP duration at 30% of repolarizaton (APD30), but did not significantly modify APD50 and APD90 at 1 and 10 μM. The effects of VP on APD30, APD50, APD90, and Vmax were significantly different from those of VC. Reducing extracellular K+ from 5.6 to 2.7 mM did not significantly modify the effects of VC on AP, except for the RP, which was hyperpolarized. The changes in RP and Vmax caused by VP (1 μM) in low‐K− medium were significantly different from those caused by the compound in normal‐K+ medium were significantly different from those caused by the compound in normal‐K+ medium. However, the decrease in Vmax and increase in APD30, APD50, and APD90 obtained with VC were significantly different from those seen with VP. VC increased AP duration in both normal‐ and low‐K+ concentration. As such, VC poses the risk of “torsades de pointe” dysrhythmia, associated with a long QT interval, even in patients with normal serum K+ levels. On the other hand, our results indicate that such dysrhythmias are not expected with VP even in patients with hypokalemia.
Effect of vinpocetine on the sleep‐wake cycle of rats
Authors: Sarkadi Adam , Laszy Judit , Szporny Lászlö
Published: January 2005

Vinpocetine given orally for five consecutive days in weekly, ascending doses produced changes in the sleep‐wake cycle of the rat, as measured by the electrocorticogram. The effect of vinpocetine on the sleep‐wake cycle was interpreted as an increase in alertness, and was most prevalent at the highest dose of 30 mg/kg/day p.o. This effect lasted for two weeks following the discontinuation of the treatment. Hypoxia‐induced sleep disturbances were not improved by daily administration of vinpocetine in rats. These data support three conclusions: (1) vinpocetine may evoke functional and/or metabolic processes in the brain that are related enhanced alertness; (2) within the dose range examined vinpocetine had no “antihypoxic” activity during moderate hypoxic episodes; and (3) the effect of vinpocetine appears to be extended beyond the treatment period.
Variation of muscarinic activities of oxotremorine analogues
Authors: Brown Frank , Clark Michael , Graves Diane , Hadley Michael , Hatcher John , McArthur Robert , Riley Graham , Semple James
Published: January 2005

Close analogues of oxotremorine (a potent muscarinic agonist with marked CNS actions) were examined for inhibition of ligand binding in rat cortex membranes using 3H‐oxotremorine‐M and 3H‐quinuclidinyl benzilate, and in simple tests in vivo for autonomic and behavioural effects (induction of salivation, hypothermia, tremor, inhibition of locomotion in mice; inhibition of sparring and rearing behaviours in rats). The combined use of these tests indicated whether compounds were agonists, antagonists, or inactive at muscarinic receptors, and gave preliminary details of their pharmacological profile and selectivity on different muscarinic responses. The analogue known as BM5 was a partial agonist with a selective profile. It was considered of interest for further study as a possible candidate for therapeutic use in the memory impairment (and acetylcholine deficit) of Alzheimer's disease. In studies in tests for long‐term (24‐hr passive avoidance) and short‐term, working (5‐min arena maze) memory/cognition in rats, no evidence of enhancement was obtained with BM5.
Experimentally established geropsychotropic properties of 3‐hydroxypyridine antioxidant
Authors: Voronina T. A. , Kutepova O. A.
Published: January 2005

The free radical hypothesis is one of the most widely accepted theories of aging. In this respect antioxidant agents, stabilizing free radical‐induced damage of biological membranes, can be considered as possible geropsychotropic drugs. Comparative experimental investigation of 3‐ and 18‐month‐old albino male rats demonstrated age‐related functional insufficiency in some behavioural tests in elderly animals. Consumption of the antioxidant 2‐ethyl‐6‐methyl‐3‐hydroxypyridine (3‐HP) (40–75 mg/kg/day) for two months normalized memory function, motor‐skill learning, and motor coordination in 18‐month‐old rats. Furthermore, 3‐HP ingestion during chronic alcohol administration improved learning in alcohol‐treated mice. The beneficial effect of 3‐HP on age‐related and alcohol‐induced decline of memory and learning ability may be due to its ability to increase cell resistance to different disturbing actions.
Comparison of the effects of vinpocetine, vincamine, and nicergoline on the normal and hypoxia‐damaged learning process in spontaneously hypertensive rats
Authors: Groó Dóra , Pálosi Éva , Szporny László
Published: January 2005

Vinpocetine (Cavinton®), vincamine, and nicergoline (Sermion®) were evaluated for the ability to protect cognitive function of spontaneously hypertensive rats from the damaging effect of hypoxia. Normobaric hypoxia (6% oxygen) was applied during the acquisition of a two‐way active avoidance task (3 sessions, 50 trials/session). Hypoxia decreased the percentage of conditioned avoidance responses by 50% on day 3. Vinpocetine (1.25–10 mg/kg) administered orally 60 min prior to the daily sessions did not significantly improve learning in normoxic conditions; however, it prevented hypoxia‐induced learning deficit (1.25 mg/kg peak effect dose). The dose‐response relationship for the compound is an inverted U‐shaped curve. Vincamine (2.5–20 mg/kg p.o.) did not facilitate learning under normoxic conditions, but afforded protection against hypoxia at the 20‐mg/kg dose. Nicergoline (2.5–20 mg/kg p.o.) did not increase acquisition of the normoxic avoidance response, and it also showed a moderate antihypoxic effect. Vinpocetine, and to a lesser degree vincamine and nicergoline–‐drugs useful in the therapy of cognitive disturbances following cerebral ischemichypoxic states–‐proved effective in the prevention of a hypoxia‐induced learning deficit.
Dextronatrin: A potent atrial natriuretic peptide analog; Vascular and natriuretic effects
Authors: Deghenghi R. , Immer H. U. , Beaulieu G. , Muirhead C. R.
Published: January 2005

A shortened 23 amino acid analog (dextronatrin) of rat ANP(1–28) in which, in position 6 next to Cys, there is a D‐Tyr residue, has been compared to rat ANP(1–28) for its diuretic and electrolyte‐excreting properties in male normotensive rats. Both compounds elicited an equally large but short‐lasting diuresis. The natriuresis was also short‐lasting as were the changes in Cl− and K+ excretion.

In a rabbit aortic strip preparation dextronatrin antagonized the vasoconstricting effects of noradrenaline but to a lesser extent than rat ANP(1–28).
Current hypotheses of Alzheimer disease neuropathology and dementia
Authors: Wisniewski H. M. , Merz G. S. , Rabe A. , Barcikowska M. , Moretz R. C. , Devine‐Gage E. A.
Published: January 2005

Immunology and biochemical studies of paired helical filaments (PHF) revealed the presence of the following proteins: (1) phosphorylated tau, (2) ubiquitin, and (3) neurofilament peptides. Quantitative biochemical studies of the PHF peptides are in progress, and as yet it is not known which of the above proteins or possibly, a novel protein is the initiator and major constitutent of PHF. The peptide‐forming amyloid fibers in the meninges, brain vessels, and neuritic plaques are a product of a host gene localized on chromosome 21. The reason for the formation of the amyloid fibers in normal aged people and in Alzheimer disease is unknown. However, in Down syndrome, it may be a result of a gene dose effect. Imbalance between the production of the amyloid fiber precursor protein and the ability to degrade it may also be the result of gene mutation of the amyloid peptide‐producing cell or a result of an enzyme defect or deficiency of the amyloidogenic peptide processor cells.
Human cerebral amyloidosis
Authors: Frangione Blas
Published: January 2005

Two types of familial cerebral amyloid angiopathy or hereditary cerebral hemorrhage with amyloidosis (HCHWA) have been described: the Icelandic type (HCHWA‐I) and the Dutch type (HCHWA‐D). Both are autosomal‐dominant forms of amyloidosis restricted to the small vasculature of the brain and are clinically characterized by recurrent strokes leading to an early death. In spite of their clinico‐pathological similarities, the amyloid fibrils are structurally different. In the case of HCHWA‐I, the amyloid protein is a degradation product of Cystatin C, a normal serum protein and an inhibitor of cysteine proteases. On the other hand, the amyloid protein in HCHWA‐D has been shown to be related to Alzheimerapos;s disease β‐protein, and preliminary observations indicate that similar amyloid subunits are present in sporadic cerebral amyloid angiopathy and asymptomatic elderly people with amyloidosis. The processing of the β‐protein precursor in different cell types may account for the heterogeneous pattern of clinical manifestations and amyloid deposition in this group of disorders, which we designate “beta‐amayloid diseases.”
Uptake of normal immunoglobins by motor neurons in the rat: A study using radioiodinated IgG
Authors: Fabian Roderic H.
Published: January 2005

Sprague‐Dawley rats were anesthetized and the mystatial vibrissae was injected with 0.3‐120 pmol of 125I‐labeled affinity‐purified nonspecific rat IgG with and without additional unlabeled IgG in 50 μL of normal saline. Following a survival of 2 days, the rats were deeply anesthetized and perfused with saline and buffered formalin. The brains were removed and punch sample taken that included the facial nuclei. Uptake of radioiodinated IgG by the facial nucleus was determined by subtracting background activity, which was determined from the facial nucleus punch sample contralateral to the injection, from the ipsilateral facial nucleus. Uptake of radiolabeled IgG established a linear relationship with the amount of radiolabeled IgG injected, and only a very small amount was taken up (0.21 fmol per nmol injected). Addition of unlabeled IgG had no effect on the uptake of radiolabeled IgG. This evidence supports immunohistochemical evidence indicating that nonspecific serum IgG is taken up by motor neurons of the CNS with axons projecting the periphery. An increased understanding of this and other aspects of the relationship between the nervous system and the humoral immune system may provide insight concerning the pathogenesis of certain types of autoimmune nervous system disease.
Nervous‐system‐associated mast cells: Gatekeepers of neural and immune interactions
Authors: Orr Edward L.
Published: January 2005

Although mast cells have been described in or near certain areas of the central and peripheral nervous systems, the present investigation demonstrates that nervous‐system‐associated mast cells in the mouse are strategically located along the vasculature that supply or drain these tissues. Of particular interest are the mast cells present in the velum interpositum of the transverse fissure. These mast cells are distributed along blood vessels that perfuse or drain the thalmus, hippocampal formation, corpus striatum, corpora quadrigemini, and the choroid plexi of the lateral ventricles. Such a distribution suggests that mast cells and their vasoactive products (e.g., histamine, serotonin, leucotrienes) may be involved in regulating the regional permeability of the vessels supplying or draining these important brain regions. In addition, numerous periganglionic mast cells were found to be distributed in and around vessels of the dorsal root ganglia and spinal roots. Consequently, periganglionic mast cells may control the permeability of the blood vessels perfusing or draining the dorsal root ganglia and spinal roots and thereby control the ability of immune components to access these tissues, the spinal cord, and the adjacent subarachnoid space. Thus, nervous‐system‐associated mast cells may serve as cellular gatekeepers of interactions between the immune and nervous systems.
Tritiated D‐ala1‐peptide T binding: A pharmacologic basis for the design of drugs which inhibit HIV receptor binding
Authors: Smith Craig C. , Hallberg Paul L. , Sacerdote Paola , Williams Patricia , Sternberg Esther M. , Martin Brian M. , Pert Candace B. , Ruff Michael R.
Published: January 2005

The HIV virus initiates its infectious cycle through a high‐affinity binding interaction between the envelope protein gp 120 and its receptor, the T4 (or CD4) molecule. An octapeptide sequence, termed peptide T, present in the second variable region of gp 120 from the ARV isolate, has been implicated as the attachement site. The core peptide required for activity has been further refined to a pentapeptide, and homologous pentapeptides are similarly positioned in 21 other sequenced HIV isolates. Utilizing a novel direct binding assay of 3H‐D‐ala1‐peptide T, we now report that synthetic peptides derived from these other isolates are potent competitors of peptide T binding to T4‐positive lymphocytes and brain membranes. Direct peptide T binding is also competable by purified virion gp 120, indicating that these ligands are interactive at the same receptor. Peptide T has sequence relatedness to the peptide vasoactive intestinal peptide (VIP), and VIP and its relevant homologous pentapeptide, VIP[7–11], are also potent inhibitors of peptide T binding. To determine the essential structural features responsible for receptor activity we have studied a series of synthetic peptides substituted with single D‐amino acid residues. These data reveal that the tyrosine of position 7 in peptide T, present in all natural viral isolates, is obligate for receptor activity. Structure/function analysis for a large number of analogs is presented. Significantly, this binding assay is highly correlated with peptide bioactivity in several independent systems, indicating that this methodology can be used for rapid screening of novel, potential anti‐AIDS therapeutics whose target is inhibition of virus gpl20 binding.
Neurochemical profile in vitro of irindalone: A5‐HT2‐receptor antagonist
Authors: Hyttel John , BøGesø Klaus , LembøL Hanne LøVe , Larsen Jens‐JøRgen , Meier Eddi
Published: January 2005

A new potential antihypertensive drug, irindalone (Lu 21‐098;(+)‐(1R,3S)‐1‐[2‐[4‐[3‐(p‐fluorophenyl)‐1‐indanyl]‐1‐piperazinyl] ‐ethyl]‐2‐imidazolidinone), has been characterized by a series of in vitro methods. Irindalone competitively inhibits peripheral and central serotonin2 (5‐HT2) receptors as measured by 5‐HT‐induced contractions of rabbit pulmonary artery and receptor binding methodology with 3H‐ketanserin as a ligand. The inhibitory effect on 5‐HT receptors is confirmed using other organs in vitro (rat stomach fundus, rat jugular vein, guinea pig trachea). Irindalone has lower affinity for α1‐adrenoceptors and histamine‐H1 receptors and only negligible affinity for α2‐adrenoceptors and muscarine cholinergic receptors. No inhibition of the uptake of noradrenaline (NA), dopamine (DA), or 5‐HT is seen. The neurochemical profile resembles that of ketanserin, which has slightly higher affinity for 5‐HT2 receptors. In the rat fundus, irindalone inhibits 5‐HT‐induced contractions, differing in this respect from ketanserin and cinanserin. Irindalone clearly deviates from the neuroleptics haloperidol and tefludazine, and from prazosin with which irindalone has been compared. The (‐)enantiomer of irindalone, Lu 21‐099, is considerably weaker than irindalone in the different test systems. Due to the strong blockade of 5‐HT2 receptors and the somewhat weaker blockade of α‐adrenoceptors, irindalone is expected to lower blood pressure potently and thus be a candidate for the treatment of hypertension.
Conditioned response to amphetamine injection with the operant paradigm
Authors: Duncan Perry M. , Barry Theresa , Ellis Roger , Hinkle Elizabeth
Published: January 2005

Conditioned responses to amphetamine treatment at three doses were investigated with the “conditioned emotional response” paradigm, in which an auditory‐visual stimulus was presented 3 min before i.p. drug injection to rats lever pressing for food pellets. Conditioned responses to this preinjection stimulus were indicated by changes from baseline response rate during each of eight conditioning sessions and after water injections (again preceded by the A‐V stimulus) on a final extinction‐test day. In experiment 1, the reinforcement schedule was tandem VI‐30 sec/FR4, and the amphetamine dose was 3.0 mg/kg, which produced nearly complete response suppression by the end of the 20‐min postinjection period. Suppression to the preinjection CS was seen after two conditioning sessions, and marked condition suppression also occurred after water injection on the test day. In a second experiment, using additional animals, the reinforcement schedule was VI‐60 sec, and two drugged groups were used to determine lower‐dose amphetamine effects. Significant preinjection suppression (of a lesser degree than seen in experiment 1) developed after six conditioning sessions with amphetamine 1.5, but not 0.8 mg/kg. Similar dose differences were seen in the postinjection‐conditioned responses. These results provide dose‐response information on conditioned responses to a CNS stimulant in the conditioned suppression paradigm.
Partial generalization in pigeons trained to discriminate morphine from saline: Applications of receptor theory
Authors: Koek Wouter , Woods James H.
Published: January 2005

In pigeons trained to discriminate 5.6 mg/kg of morphine from saline, cyclazocine, l‐N‐allyl‐normetazocine (l‐NANM, l‐SKF10,047), and ketamine, but not U50,488, produced partial generalization, i.e., a maximum level of drug‐appropriate responding between the levels produced by saline and by the training drug. The generalization gradient of cyclazocine and of l‐NANM, but not that of ketamine, was less steep than the gradient of morphine. Cyclazocine and l‐NANM, but not U50,488 and ketamine, antagonized partially the discriminative stimulus (DS) effects of morphine. Naltrexone antagonized the DS effects of morphine, cyclazocine, and l‐NANM, but not ketamine. Increasing the training dose of morphine shifted the morphine gradient to the right, increased the antagonist effects of cyclazocine and of l‐NANM, and decreased their agonist effects, but did not alter the effects of ketamine. Decreasing the training dose of morphine shifted the morphine gradient to the left and increased the agonist effects of cyclazocine, but did not alter the effects of l‐NANM and ketamine. The full generalization produced by cyclazocine when the training dose of morphine was lowered could be blocked completely by naltrexone and l‐NANM, but not by ketamine. These results suggest that cyclazocine and l‐NANM, but not ketamine, produced partial generalization because of their low efficacy at the receptor that underlies the DS effects of morphine. However, the results obtained with ketamine suggest that partial generalization may also be produced through other mechanisms.
Conditioned taste aversions as a behavioral baseline for drug discrimination learning: Assessment with the dipsogenic compound pentobarbital
Authors: Riley Anthony L. , Jeffreys Ronald D. , Pournaghash Said , Titley Tracey L. , Kufera Angela M.
Published: January 2005

Animals injected with pentobarbital prior to the presentation of a saccharin‐LiCl pairing and its vehicle prior to saccharin alone rapidly acquired the drug discrimination, avoiding saccharin following the administration of pentobarbital and consuming saccharin in its absence. That drug discrimination was acquired within the taste aversion design even though the stimulus drug itself (i.e., pentobarbital) produced significant increases in consumption in nonconditioned control subjects suggests that the dipsogenic properties of a compound are not necessarily a problem for the assessment of drug discrimination learning within the aversion procedure. The present data, along with prior reports on the effectiveness of the taste aversion design with the stimulus drugs phencyclidine and naloxone, indicate that the conditioned taste aversion procedure may be effective as a general method in the assessment of drug discrimination learning.
Pavlovian‐conditioned changes in body temperature induced by alcohol and morphine
Authors: Cunningham Christopher L. , Schwarz Karen S.
Published: January 2005

Several theoretical analyses of drug‐taking behavior posit an important mediating role for Pavlovian‐conditioned drug responses that develop as a result of stimulus‐drug pairings imbedded within the self‐administration paradigm. Some of these analyses focus attention on the learning of physiological responses that appear to counteract or compensate for the direct effects of a drug, thereby producing tolerance and encouraging increased drug taking. Others place greater emphasis on the learning of responses that mimic the drug's effect and presumably increase drug taking through a positive incentive mechanism. Our laboratory has been especially interested in the determinants of drug‐induced conditioned changes in body temperature and the roles that such responses might play in drug tolerance, sensitization, and self‐administration. Our research has involved both alcohol and morphine, drugs that produce a similar conditioned thermal response despite the fact that the direct thermal effects of these drug are completely different.

In the case of alcohol, our initial studies showed that environmental (cage) cues paired with intraperitoneal (i.p.) injection of the drug acquire the ability to evoke a conditioned hyperthermic response that reduces the hypothermic reaction to ethanol (i.e., tolerance). More recent studies have explored the nature of the events capable of serving as conditioned stimuli (CSs) for such learning. These studies show that interoceptive thermal cues can mediate tolerance to alcohol's thermal effect, but taste cues cannot. The inability of taste cues to mediate tolerance may have special implications for the study of responses that are conditioned during oral self‐administration of alchol, a procedure that offers very salient gustatory cues.

In the case of morphine, we have developed an experimental preparation that permits precise temporal control over the CS (a noise‐light compound) and unconditioned stimulus (intravenous morphine) while using techniques that minimize the stress that is induced by drug administration or temperature measurement. These studies show development of a conditioned hyperthermic response that summates with morphine‐induced hyperthermia, resulting in sensitization.

The similarity in the conditioned thermal responses induced by alcohol and morphine has encouraged us to consider the possibility that these responses are not directly related to specific drug effects on the thermoregulatory system but instead reflect a nonspecific anticipatory “arousal” response. This notion receives some support from recent studies in our laboratory showing that environmental cues associated with non‐drug reinforcers differing in hedonic value (i.e., shock and sucrose) also acquire the ability to elicit conditioned hyperthermia. It could well be that drug‐induced conditioned changes in body temperature index the acquired motivational processes that maintain drug‐taking and encourage relapse.
Spiroxatrine as a discriminative stimulus: Effects depend on pharmacological history
Authors: Barrett J. E. , Olmstead S. N.
Published: January 2005

Spiroxatrine, a compound with effects on both dopamine (DA) and serotonin (5‐HT) neurotransmitter systems, was established as a discriminative stimulus in pigeons. Along with novel anxiolytic nonbenzodiazepine compounds such as buspirone and ipsapirone, spiroxatrine has been suggested to interact at the 5‐HT1A receptor subtype. Following the administration of 0.3 mg/kg spiroxatrine, every 30th consecutive peck on one key produced food, whereas following saline administration, pecks on the alternate key produced food. After dose‐response curves with spiroxatrine were obtained, two pigeons were tested first with buspirone, which, like spiroxatrine, also has effects on both 5‐HT1A and DA systems, and two pigeons were tested first with the more specific 5‐HT1A compounds 2‐mPP (1‐[2‐methoxyphenyl]piperazine) or 8‐OH‐DPAT (8‐hydroxy‐2‐[di‐n‐propylamino]tetralin). All pigeons responded on the drug‐appropriate key when these compounds were the initial drugs substituted for spiroxatrine. Pigeons tested first with 2‐mPP or 8‐OH‐DPAT also responded on the drug‐appropriate key when buspirone was administered in subsequent tests. However, when first tested with buspirone then tested subsequently with 8‐OH‐DPAT, pigeons responded on the saline key at all 8‐OH‐DPAT doses and did so throughout the study whenever any selective 5‐HT1A ligand was substituted. Drug history may enhance or diminish specific stimulus effects of drugs with multiple stimulus dimensions. Drugs with multiple stimulus effects may permit the specific study of behavioral and pharmacological variables that affect the discriminative stimulus effects of drugs and, perhaps, also their behavioral effects under other circumstances.
Individual differences in the discriminative stimulus effects of d‐amphetamine in humans
Authors: Chait Larry D. , Uhlenhuth Eberhard H. , Johnson Chris‐Ellyn
Published: January 2005

The discriminative stimulus (DS) and subjective effects of d‐amphetamine (AMP) were examined in male and female normal healthy adults. Subjects were trained to discriminate between oral AMP (10 mg) and placebo. Of the 100 subjects who underwent discrimination training, 53 reliably learned the discrimination. These “discriminators” (Ds) were compared with the 47 “nondiscriminators” (NDs) on a variety of measures. Ds and NDs did not differ qualitatively in their response to AMP. As a group Ds were more certain than NDs of their ability to discriminate between AMP and placebo and were more accurate in labelling AMP as a stimulant. AMP also had a greater effect for Ds than for NDs on ratings of drug liking and general activity level during the day. Although Ds generally showed a stronger subjective response to AMP, Ds differed significantly from NDs on only 4 of 18 mood scales affected by AMP (2 anxiety scales and analog ratings of “stimulated” and “high”). Ds did not differ from NDs on any of the following measures: body weight, gender, current or lifetime drug use, baseline mood state, subjective response to placebo, or a variety of personality traits. The results demonstrate considerable individual differences in sensitivity to AMP and suggest a relationship between the DS effects of AMP and specific mood states.
Fluoxetine: A serotonergic appetite suppressant drug
Authors: Fuller Ray W. , Wong David T.
Published: January 2005

Fluoxetine is a selective inhibitor of serotonin uptake that does not have direct effects on catecholaminergic neurons. Like other serotonergic drugs, fluoxetine reduces food intake in rats, and the characteristics of these serotonergic drugs differ from those of amphetaminelike drugs. For instance, fluoxetine and other serotonergic drugs have been reported to suppress stress‐induced eating, to suppress carbohydrate intake selectively, and to suppress eating elicited by insulin injection. Tolerance to the food intake‐reducing effect of fluoxetine has not been seen in experimental conditions in which other anorectic agents have shown tolerance. Clinical trials in overweight, depressed patients and in nondepressed obese subjects have shown the ability of fluoxetine to reduce body weight in humans. Fluoxetine may represent a new appetite suppressant drug that will be useful in the management of obesity.
Comparative hypotensive activity of REV 6207 and enalapril in the conscious furosemide‐treated monkey
Authors: Hubbard John W. , Hintze Thomas H. , Shapiro Jeffrey T. , Kaley Gabor , Smith Ronald D. , Wolf Peter S.
Published: January 2005

The cardiovascular effects of ascending doses (0.03, 0.1, 0.3, 1.0, and 3.0 mg/kg i.v.) of two angiotensin l‐converting enzyme (ACE) inhibitors, REV 6207 and enalapril, were assessed in conscious furosemide‐treated (3 mg/kg s.c.) monkeys. Both ACE inhibitors produced a dose‐related inhibition of the pressor response to angiotensin l (0.66 μ/kg i.v.) with concomitant decreases in mean arterial pressure and no change in heart rate. The calculated ED50 values for REV 6207 (0.316 mg/kg) and enalapril (0.275 mg/kg) were similar and both abolished the pressor response to angiotensin l at a dose of 3 mg/kg. The results of the study show that REV 6207 is a potent nonsulfhydryl‐containing ACE‐inhibitor with blood‐pressure‐lowering activity comparable to enalapril in the conscious monkey with high renin activity.
Current views of zinc as a gastrohepatic protective agent
Authors: Cho C. H.
Published: January 2005

The protective effects of zinc on gastrohepatic lesions induced by various agents are reviewed. Acute gastric glandular mucosal damage produced by parenteral injection of reserpine, cold‐restraint stress or by oral administration of ethanol are prevented by zinc compounds. Hepatic lesions induced by CCl4, ethanol, alkylating agents, or cadmium are also antagonized by zinc ions. The pathological changes evoked by these agents or stress are postulated to be due to free radical production and labilization of biomembranes. These actions are thought to be sequestered or stabilized by zinc. The role of glutathione in the protective action and the involvement of mast cell degranulation in ulceration are further discussed. The data available so far indicate that zinc compounds could be used as protective agents for gastrohepatic diseases.
Psychopharmacology of ritanserin: Comparison with chlordiazepoxide
Authors: Meert T. F. , Janssen P. A. J.
Published: January 2005

Ritanserin, a central serotonin 5‐HT2 antagonist with complete LSD‐antagonist properties, was compared with the benzodiazepine chlordiazepoxide (CDZ) in different animal models of anxiety. In conflict procedures using electric shock as an inhibitory stimulus, a dose‐related disinhibition was observed with CDZ but not with ritanserin. In various other anxiety tests involving more natural aversive stimuli, ritanserin disinhibited exploratory behavior over a broad dose range while CDZ was marginally active. Clear differences between ritanserin and CDZ were also seen in drug discrimination test procedures. CDZ but not ritanserin had intrinsic discriminative stimulus properties. Furthermore, ritanserin did not generalize with CDZ or with fentanyl, LSD, cocaine, d‐amphetamine, or 8‐OHDPAT. These results suggest that ritanserin is unlikely to possess abuse potential. Unlike the benzodiazepine, ritanserin did not induce motor incoordination or sedation, was devoid of interaction with alcohol, and produced no state dependency. These experimental studies indicate that ritanserin possesses disinhibitory effects on exploratory behavior with a profile of activity diferent from that of benzodiazepines. Ritanserin thus has anxiety‐ and stress‐reducing effects in animal models of anxiety and the drug appears to be an original psychopharmacological compound, clinically characterized as a thymosthenic agent.
Agents enhancing γ‐aminobutyric acid receptor‐coupled chloride ionophore function. Effects in a social interaction model of anxiety in the rat
Authors: Guy Andrew P. , Gardner Colin R.
Published: January 2005

A recently described social interaction (SI) model which is sensitive to single doses of benzodiazepines and novel non‐sedative anxiolytic agents has been used. Activities of drugs were compared in both an anxious (animals housed in pairs, tested with a novel partner) and a non‐anxious (animals housed in pairs, tested with the cage mate) condition. Diazepam displays a typical anxiolytic response, increasing SI in the anxious but not in the non‐anxious condition. This was associated with a decrease in aggression (AGG) and in locomotion (LOCO) at higher doses. Seven agents were tested which are thought to enhance central nervous system γ‐aminobutyric acid (GABA)‐mediated neurotransmission by increasing the activity of a receptor‐coupled chloride ionophore system as a major component of their action. Tracazolate, RL348, methaqualone, etomidate, LY81067, and pentobarbitone all significantly increased SI in the anxious but not the non‐anxious condition. In the anxious condition tracazolate and RL348 reduced AGG and all of these compounds except LY81067 reduced LOCO. Methaqualone and etomidate also reduced LOCO in the non‐anxious condition. In addition, an agent which reduces GABA function (picrotoxin) significantly reduced SI in already‐anxious animals, consistent with its known anxiogenic properties. Picrotoxin also reduced LOCO in both conditions. Phenobarbitone induced a non‐specific effect on SI (increased SI in both anxious and non‐anxious conditions), as well as reducing AGG in the anxious condition and LOCO in both conditions. These data suggest that agents enhancing GABA receptor‐coupled chloride ionophore function possess anxiolytic properties which may be attributed to this activity.
Potassium channels as targets for antiarrhythmic drug action
Authors: Colatsky T. J. , Follmer C. H.
Published: January 2005

Recent cellular electrophysiologic studies have begun to clarify the basis of antiarrhythmic drug action. The Class I agents have been shown to block cardiac sodium channels in a use‐dependent manner, and the kinetics and potency of sodium channel block correlated with molecular weight and lipid solubility of drug. The Class IA agents, like quinidine, which increase cardiac action potential duration and refractory period in addition to their effects on conduction, also appear to have potent blocking actions on the potassium channels responsible for repolarization in myocardial cells, whereas the Class IB agents, like lidocaine, shorten action potential duration and are relatively specific in their block of sodium channels. In contrast, Class III agents, which prolong the action potential without slowing conduction, appear to exert their primary blocking action on the potassium channel only. Conversion from Class I to Class III electrophysiologic profiles can be achieved by the substitution of electron‐withdrawing groups (e.g., NO2) in place of electron‐donating groups (e.g., NH2) on the aromatic portion of the basic local anesthetic pharmacophore. Class III agents appear to be most effective against ventricular fibrillation and ventricular tachycardia due to re‐entry, but are generally without activity in the 24 hr Harris dog arrhythmia model. Further evaluation of the mechanism of antiarrhythmic drug action will require use of well‐defined arrhythmia models in a combination with a detailed understanding of drug‐channel interactions.
DuP 996 (3,3‐bis(4‐pyrindinylmethyl)‐1‐phenylindolin‐2‐one) enhances the stimulus‐induced release of acetylcholine from rat brain in vitro and in vivo
Authors: Nickolson Victor J. , William Tam S. , Myers Melvin J. , Cook Leonard
Published: January 2005

DuP 996, in micromolar concentrations, enhances the K+ ‐stimulated release of acetylcholine (ACh) in rat cerebral cortex, hippocampus, and caudate nucleus slices in vitro, without effect on basal release. DuP 996 has very weak affinity for rat brain muscarinic or nicotinic receptors and does not inhibit acetylcholinesterase activity of rat brain. Upon subcutaneous administration, DuP 996, in doses of 0.1 to 1 mg/kg, increase the output of ACh from the cerebral cortex of awake, freely moving rats. In the mouse, scopolamine‐induced hyperactivity is reduced by DuP 996 in doses of 0.3–0.5 mg/kg (s.c.). In addition, pancuronium HBr‐induced neuromuscular blockade is reversed by DuP 996 (ED50 = 1.7 mg/kg s.c.). The enhancement by DuP 996 of K+ ‐stimulated transmitter release is not limited to the cholinergic system but is also observed in the dopaminergic system in the rat caudate nucleus and in serotonergic systems. K+ ‐stimulated release of gamma‐aminobutyric acid and glutamic acid in rat cerebral cortex, however, is only slightly enchanced by DuP 996, whereas no effects are observed on K+ ‐stimulated release of cortical norepinephrine. DuP 996 may have therapeutic value in the treatment of diseases involving chlinergic and minoaminergic deterioration, like Alzheimer's Disease.
On the mechanism of increased potassium conductance by the potassium channel opener BRL 34915 in Isolated ventricular myocytes
Authors: Liu Bo , McCullough John R. , Vassalle Mario
Published: January 2005

The potassium conductance increased by BRL 34915 (BRL, cromakalim) was studied in single guinea pig ventricular myocytes by using a whole cell voltage‐clamp technique. In control voltage‐clamp recordings, the late current‐voltage relation showed a distinct inward rectification. BRL (1–100 μM) shortened the action potential and diminished or abolished inward rectification but had no effect on the slope conductance and currents flowing during hyperpolarizing clamp steps. BRL did not decrease the slow inward current but accelerated the time constant of activation and amplitude of the outward current. Cd markedly decreased (0.2 mM) or abolished (0.4–0.6 mM) the slow inward current and BRL induced a faster outward shift of late current to a greater value. Glybenclamide (10 μM), a blocker of ATP‐sensitive K+ channels, had little effect of its own on action potential, membrane currents, and I‐V relation. However, in the presence of BRL, glybenclamide abolished BRL effects on action potential and currents and restored inward rectification. It is concluded that the mechanism by which BRL shortens the action potential is a faster growth of an outward current due to the reduction or abolition of the inward rectification of an ATP‐dependent potassium channel. The reduction in force in non‐isolated tissues appears to be an indirect result of the action potential shortening and not of a decreased slow inward current.
Tolerance to drug stimulus control
Authors: Young Alice M.
Published: January 2005

A psychoactive drug can acquire discriminative stimulus control of behavior through differential reinforcement processes. Development of tolerance to drug stimulus control reflects a dynamic interaction of conditioning and pharmacodynamic processes. Development of tolerance requires the interplay of drug maintenance regimens appropriate to the agent under study and behavioral conditions that limit an organism's ability to learn a new discrimination. Tolerance to drug discriminative control has four important characteristics: the dose of drug required to evoke stimulus control is increased, the requirement for an increased dose is limited to the period of supplemental drug treatment, the change in potency is pharmacologically specific, and the change may require suspension of discrimination training.
The effects of chronic cocaine administration on brain neurotransmitter receptors
Authors: Goeders Nick E.
Published: January 2005

The nonmedical use of cocaine has continued to increase during the past decade, resulting in considerable interest in the clinical and neurobiological implications of this behavior. A better understanding of the complex neurobiological changes associated with chronic cocaine intoxication may assist in the search for improved methods of treatment in the clinic. In this investigation, chronic daily injections of cocaine for 15 days resulted in opposite effects on dopamine receptor number measured with [3H]sulpiride in the striatum and nucleus accumbens of rats. Binding was increased in the nucleus accumbens but decreased in the striatum. By contrast, benzodiazepine receptors measured with [3H]Ro 15‐1788 were increased in the striatum and cerebellum but decreased in the frontal cortex. Intraventricular injections of 6‐hydroxydopamine resulted in a decrease in the number of benzodiazepine receptors measured in the striatum and reduced the effects of cocaine on these receptors. These data suggest that while chronic cocaine administration may induce changes in dopaminergic activity and dopaminergic receptors, opposite effects may be observed in benzodiazepine receptor number induced either directly by cocaine or indirectly through changes in dopaminergic neuronal activity. Although the significance of these findings is not clear, the results of this investigation suggest a different noncatecholaminergicavenue for future studies to follow.
Noradrenergic processes in the behavioral actions of psychomotor stimulants
Authors: Tessel Richard E.
Published: January 2005

Although psychomotor stimulants such as cocaine and amphetamine are known to release both norepinephrine and dopamine in brain, most evidence indicates that it is the release of central dopamine rather than that of norepinephrine that mediates the reinforcing, discriminative, and eliciting properties of psychomotor stimulants, i.e., that drug‐induced dopamine release is a necessary and sufficient factor to account for these properties, while drug‐induced norepinephrine release is neither necessary nor sufficient. However, this generally accepted conclusion may not be completely accurate. Evidence is available indicating that psychomotor‐stimulant‐induced increases in norepinephrine release, while possibly not necessary, are sufficient to account at least for the eliciting and discriminative‐stimulus properties of amphetamine‐like drugs. The data supporting this contention are reviewed.
Electroencephalographic and evoked potential methods in human marihuana research: Historical review and future trends
Authors: Struve Frederick A. , Straumanis John J.
Published: January 2005

The sensitivity of electroencephalographic (EEG) signals to variables affecting brain neurophysiological substrate is briefly reviewed. Because this sensitivity extends to numerous pharmacological compounds with central nervous system (CNS) effect, it is suggested that EEG methods may also be useful in studies of human marihuana exposure. EEG investigations of marihuana are grouped by the type of research strategy employed and, within each grouping, the review summarizes salient reported findings as well as methodological issues of concern. The value of using quantitative methods of EEG analyses under blind conditions is stressed. Recent technological developments permitting topographic brain mapping of quantitative EEG variables are described as offering promise for marihuana research and some examples are given. Finally, evoked potential findings in studies of marihuana exposure are reviewed.