bluuebunny/crossref_metadata_2025 huggingface dataset:
Embryonic development of central nervous system myelination in a reptilian species, Eumeces fasciatus
Authors: Nadon Nancy L. , Crotzer David R. , Stewart James R.
Published: January 2005

The myelin proteolipid proteins are a vital component of the vertebrate central nervous system (CNS), contributing essential functions to the development of the myelinating cells of the CNS and to the structure of CNS myelin. Alternative splicing of the proteolipid protein (PLP) gene to produce two related isoforms occurs in Mammalia, Ayes, and Reptilia, but not Amphibia. As part of a long‐term investigation into the function of the different isoforms of PLP, embryonic development, myelination, and PLP gene expression in reptilian CNS were examined. PLP gene expression was already substantial by day 19 (stage 39) of the 27‐day Eumeces fasciatus egg incubation period. By day 21 of incubation, also stage 39, PLP mRNA was at peak levels; there was a significant amount of CNS myelination as demonstrated by electron microscopy of the spinal cord; and the reflexive motor response was evident. Although most axons were myelinated by the time of hatching, myelin sheaths continued to increase in size and compactness after hatching. The correlation of physiological development, CNS myelination, and expression of the PLP gene in the lizard corresponded well with the developmental pattern seen in mammals. © 1995 Wiley‐Liss Inc.
Amygdala efferents form inhibitory‐type synapses with a subpopulation of catecholaminergic neurons in the rat nucleus tractus solitarius
Authors: Pickel V. M. , Van Bockstaele E. J. , Chan J. , Cestari D. M.
Published: January 2005

The central nucleus of the amygdala (CNA) integrates visceral responses to stress partially through efferent projections to portions of the medial nuclei of the solitary tracts (mNTS) containing catecholaminergic neurons. To determine anatomical sites for CNA modulation of these neurons, immunoperoxidase detection of anterogradely transported Phaseolus vulgaris leucoagglutinin (PHA‐ L) or biotinylated dextran amine (BDA) was combined with immunogold silver labeling of the catecholamine‐synthesizing enzyme, tyrosine hydroxylase, in adult rat mNTS. From 350 anterogradely labeled terminals identified within the intermediate mNTS, 30% formed symmetric, inhibitory‐type synapses and the remainder lacked recognized junctions as seen within a single plane of section. Of the terminals forming symmetric synapses, 16% were presynaptic to tyrosine hydroxylase immunoreactive dendrites and the remainder to unlabeled dendrites. The level of tyrosine hydroxylase immunoreactivity as assessed by density of gold‐silver particles was significantly lower in dendrites receiving synaptic input from CNA efferents as compared with dendrites of the same sizes (2. 0 μm2 in mean area) which received synapses from unlabeled terminals or lacked recognizable synaptic inputs. When separately examined without regard to afferent input, the medium‐ and larger‐sized dendrites having mean cross‐sectional areas of 1–3 μ2m also contained significantly less tyrosine hydroxylase immunoreactivity than small (<1 μ2m) dendrites. These results suggest that CNA efferents to the mNTS inhibit non‐catecholamine‐containing neurons and a subpopulation of catecholamin ergic neurons distinguished by their low levels of tyrosine hydroxylase. The findings also indicate that small, presumably more distal, dendrites in the intermediate mNTS may synthesize and/or release catecholamines. © 1995 Wiley‐Liss Inc.
Nucleus medialis‐nucleus interpositus interface: Its olivary and cerebellocortical projections in the rat
Authors: Yatim N. , Buisseret‐Delmas Catherine , Buisseret P. , Compoint C. , Angaut P.
Published: January 2005

The nuclear target of the X zone of the cerebellar cortex was identified in rats as clusters of neurons scattered at the interface between the nuclei medialis (NM) and interpositus (NI). In a previous study, we had outlined these target neurons and termed them “interstitial cell groups” (icg). In order to determine whether the icg should be considered as part of either the NM or the medial NI, we analyzed two efferent pathways from the icg: their nucleocortical and nucleoolivary projections. These were compared to their homologues from the NM and the NI. This analysis is based on mapping retrograde cell labeling and anterograde terminal labeling following microinjections of tracers in either the cerebellar cortex, the cerebellar nuclei, or the inferior olive.

Nucleocortical projections originating from the icg are of the three types described previously: a “reciprocal” projection to the ipsilateral X zone, a “nonreciprocal” projection to the ipsilateral A zone, and a “symmetrical” projection to the contralateral X zone. These features can be considered as the summed characteristics of the nucleocortical projections from the NM and from the medial NI. Nucleoolivary projections from the icg target the lateral‐rostral portion of the dorsal accessory olive as well as the centrocaudal part of the medial accessory olive. These pathways converge with the nucleoolivary projections from the medial NI and from the NM, respectively. The icg receives olivary afferents from both the regions of the dorsal and medial accessory olives to which it projects.

On the basis of similarities shown here between the two types of efferents originating from the icg and those from the NM as well as the medial NI, the icg may be regarded as a “mosaic” of neuron clusters alternately belonging to the NM and the medial NI. Therefore, the icg would be reciprocally connected with the inferior olive. © 1995 Wiley‐Liss, Inc.
Development of the spinocerebellar projection in the prenatal mouse
Authors: Grishkat Holly L. , Eisenman Leonard M.
Published: January 2005

An abundance of information is available concerning the spinocerebellar projection in adult mammals. However, only a few studies have attempted a developmental analysis of this important projection system in early postnatal and/or prenatal animals. The present study provides an analysis of the development of the projection from the spinal cord to the cerebellum in fetal mice using anterograde tracing techniques in an in vitro preparation. After applications of biocytin to the caudal cervical spinal cord, anterogradely labelled fibers were present in the brainstem of embryonic day 12 (E12/13) mice, however, there was no indication of label in the cerebellum. At E13/14, labelled fibers were evident in the rostrolateral portions of the cerebellum/isthmus region. By E15/16, labelled spinocerebellar fibers had progressed farther into the cerebellum and were seen crossing the midline in a very superficial position. At older ages, the number of crossing fibers increased, and they became more ventrally positioned within the cerebellum. At E17/18 and E18/19, labelled spinocerebellar fibers were observed to branch and invade deeper portions of the cerebellum including the cerebellar nuclei. However, at E18/19, there was no indication of the parasagittal organization characteristic of this projection in the adult animal. The results of this study indicate that spinocerebellar fibers are present within the cerebellum significantly earlier than the development and differentiation of their primary targets, the granule cells. Furthermore, these data suggest that spinocerebellar fibers may form associations with cerebellar nuclear cells during fetal development. © 1995 Wiley‐Liss, Inc.
Morphologically heterogeneous met‐enkephalin terminals form synapses with tyrosine hydroxylase‐containing dendrites in the rat nucleus locus coeruleus
Authors: Van Bockstaele Elisabeth J. , Branchereau Pascal , Pickel Virginia M.
Published: January 2005

Physiological and anatomical studies have suggested that the endogenous opioid peptide, methionine‐enkephalin (ENK), may directly modulate noradrenergic neurons. Additionally, chronic opiate administration has been shown to increase the levels of a number of G‐proteins and phosphoproteins including the catecholamine synthesizing enzyme, tyrosine hydroxylase (TH). We combined immunogold‐silver localization of tyrosine hydroxylase and immunoperoxidase labeling for ENK in single sections through the nucleus locus coeruleus (LC) in the rostral pons to determine potential substrates for the divergent actions of this opioid peptide. Light microscopic analysis of ENK immunoreactivity in the LC area indicated that ENK fibers are dense and highly varicose. In coronal sections, ENK‐immunoreactive processes were punctate and appeared to envelop LC cell bodies. More rostrally, in the region of catecholamine immunoreactive extranuclear dendrites, ENK‐immunoreactive varicose processes were inter digitated with TH‐labeled processes. Electron microscopy of this rostral region revealed that ENK‐immunoreactive axon terminals contained small clear as well as large dense core vesicles. The large dense core vesicles (1‐10/terminal) were consistently the most immunoreactive and were identified toward the periphery of the axon terminal distal to the active zone of the synapse. Unlabeled axon terminals and glial processes were the most commonly observed elements located adjacent to the plasmalemma of axons containing the labeled dense core vesicles. Axon terminals containing ENK immunoreactivity varied in size (0.3 μm to 2.0 μm) as well as formation of synaptic specializations (i. e., asymmetric versus symmetric). The ENK labeled terminals formed synapses with dendrites with and without detectable TH immunoreactivity. These results provide the first direct ultrastructural evidence that morphologically heterogeneous terminals containing ENK immunoreactivity form synapses with catecholamine dendrites within the LC. The formation of asymmetric and symmetric synaptic specializations suggests that the opioid peptide, ENK, may be colocalized with other neurotransmitters. Furthermore, the distribution of ENK immunoreactivity in axon terminals apposed to other unlabeled afferents or astrocytic processes suggests that actions of ENK may also include presynaptic modulation of other transmitters and/or effects on astrocytes. © 1995 Wiley‐Liss, Inc.
Connections between the reticular nucleus of the thalamus and pulvinar‐lateralis posterior complex: A WGA‐HRP study
Authors: Fitzgibbon T. , Tevah L. V. , Sefton A. Jervie
Published: January 2005

The present study utilises the capacity of wheat germ agglutinin‐conjugated horseradish peroxidase to label both afferent and efferent projections from selected regions of the thalamic reticular nucleus (TRN) to the pulvinar lateralis‐posterior complex (Pul‐LP) of the cat. Fourteen injections into the TRN located between anterior‐posterior levels 8.5 and 4.5 were analysed. The projection of the TEN to the Pul‐LP complex is roughly organised in a topographic manner and is not widespread within the thalamus. Anterograde labelling in the Pul‐LP extended rostrocaudally with a slight oblique dorsoventral orientation. Projections to the medial LP were predominantly but not exclusively from rostral areas of TRN, while projections to the lateral LP were largely from caudal areas of the TRN. Projections to other areas of the Pul‐LP were sparse. The connections between TRN and Pul‐LP were reciprocal, although the distribution of labelled cells and anterograde labelling was not completely overlapping. Reciprocal connections with the dorsal lateral geniculate nucleus were largely with the C‐laminae and the medial interlaminar nucleus. The results are discussed with reference to the corticothalamic projections and the visuotopy of the Pul‐LP. © 1995 Wiley‐Liss, Inc.
Observations on the weight and length of the central nervous system and of the legs, in bull‐frogs of different sizes
Authors: Donaldson Henry H.
Published: January 2005

In the Bull‐frog the relative weight of the brain compared to that of the spinal cord decreases as the frog increases in size. The relative weight of the brain is temporarily increased in frogs kept dry for twenty‐four hours before death.

The weight of the leg muscles compared with the weight of the entire frog, slightly decreases as the frog increases in size. In frogs of all sizes, the muscles of the thight weight 1.8 times as much as those of the rest of the leg.

In frogs of all sizes, the sum of the lengths of the leg bones is a nearly constant fraction of the length of the entire frog. The proportional lengths of the several bones are also nearly constant.
The total number of functional cells in the cerebral cortex of man, and the percentage of the total volume of the cortex composed of nerve cell bodies, calculated from Karl Hammarberg's data; together with a comparison of the number of giant cells with the number of pyramidal fibers
Authors: Thompson Helen Bradford
Published: January 2005

The total number of functional nerve cells in the cerebral cortex of the adult man is, in round numbers, 9200 million.

The proportion of the total volume of the cerebral cortex of the adult man composed of functional nerve cell bodies, is 1.37%.

The number of giant cells in the cerebral cortex of man is almost the same as the number of pyramidal fibers passing to the spinal cord.
Excitatory effects of hydergine on intracranial self‐stimulation
Authors: Poschel B. P. H. , Ninteman F. W.
Published: January 2005

The effect of Hydergine on intracranial self‐stimulation was tested in male albino Holtzman rats. The rats had monopolar electrodes implanted in the medial forebrain bundle of the posterior hypothalamus. Hydergine was given orally at 40 and 80 mg/kg. A dose‐dependent excitatory effect occurred which was rapid in onset, large, long‐lasting, and evidenced in acute trials of the drug. The results suggest that a major portion of Hydergine's action in aged patients is stimulatory and antidepressant in nature.
Effects of morphine, fentanyl, sufentanil, and the short‐acting morphine‐like analgesic alfentanil on the EEG in dogs
Authors: Wauquier A. , Van Den Broeck W. A. E. , Niemegees C. J. E. , Janssen P. A. J.
Published: January 2005

Visual and computerized methods were used to analyze the effects of intravenously injected narcotic analgesics on the EEG of dogs implanted with cortical and subcortical electrodes. The drugs were morphine (1.6 mg/kg), fentanyl (0.004 mg/kg), sufentanil (0.0004 mg/kg), and a new potent and very short‐acting compound under clinical trial in anaesthesia, alfentanil (0.04, 0.16 and 0.63 mg/kg). All compounds increased the amplitude of the EEG, decreased the frequency of the EEG, and produced spindle‐like bursts of biphasic waves. These bursts were more frequent and of a higher amplitude following alfentanil than after the other compounds. A computerized on‐line power spectral analysis was applied to three derivations (frontal‐occipital cortex, dorsal hippocampus, amygdala). The power of the total band width (0–40 Hz) increased following all narcotic analgesics. The duration of this increase was coincident with the period of loss of righting. Spectral analysis of various frequency bands revealed significant differences between the compounds, specifically with regard to fentanyl and alfentanil as compared to morphine and sufentanil. Sleep‐wake patterns of the night following injection of alfentanil were studied. This compound did not produce significant post‐drug effects.
Effects of viloxazine with and without alcohol on performance tests related to driving in normal volunteers
Authors: Wilson William H. , Petrie William M. , Ban Thomas A.
Published: January 2005

The effects of single doses of 50 mg of viloxazine, 100 mg of viloxazine, 50 mg of imipramine, and placebo given alone and in combination with alcohol on perceptual‐motor performance potentially related to driving were studied in eight normal subjects. The study design permitted testing of visual reaction time, pursuit rotor performance, and depth perception when blood levels of the active drugs and alcohol were at or near peak. Analyses revealed that the effects of alcohol increased visual reaction time and decreased pursuit rotor performance. None of the drugs produced statistically significant changes on any of the measures. None of the effects of the combined drug and alcohol conditions differed significantly from the effects of alcohol alone.
Synthesis of biologically active proteins by recombinant DNA technology
Authors: Miller Walter L. , Baxter John D.
Published: January 2005

DNA from a variety of sources may be inserted into the DNA of bacteria (cloned) by means of bacteriophage or plasmid vectors. DNA to be cloned may originate from the genome of another organism (genomic DNA), it may be copied enzymatically from messenger RNA (complementary DNA), or it may be synthesized by purely chemical means. In general, cloning of genomic DNA is useful for studying gene structure, but not useful for inducing bacteria to synthesize the proteins coded by the DNA. This is because the genes of higher organisms usually consist of stretches of DNA coding for parts of a protein which are separated from one another by other DNA (intervening sequences) which does not code for protein. Bacterial genes are not interrupted by intervening sequences, hence bacteria cannot make protein accurately from genes containing such interruptions. The use of complementary DNA or chemically synthesized DNA circumvents this problem. These sources of DNA have been used successfully to produce an increasing number of pharmacologically useful proteins. The bacterial synthesis of insulin, growth hormone, and endorphin are reviewed as examples of the applications of this technology.
A neurochemical differentiation between exposure to stress and the development of learned helplessness
Authors: Petty Frederick , Sherman Arnold Dr.
Published: January 2005

Both learned helplessness and stress produce deficits in escape/avoidance behavior. The yoked control paradigm was used to compare these two phenomena, with pairs of animals exposed to the same amount of shock—in one case controllable (stress) and in the other uncontrollable (learned helplessness). Stressed animals demonstrated a transient (one day) elevation in serotonin levels in the septal synaptosomal pellet. On the other hand, animals subjected to uncontrollable footshock sustained a significant decrease in septal synaptosomal serotonin for five days. Similar differences were found in the anterior cortex, but not in the posterior cortex or hippocampus. This work demonstrates the importance of using appropriate controls in neurochemical and pharmacologic research with learned helplessness.
Lack of Na+ ‐independent binding of [3H]GABA or [3H]Muscimol to subcellular particles of C6 glioma cells
Authors: Ossola L. , DeFeudis F. V. , Rebel G. , Varga V. , Prasad C. R. , Mandel P.
Published: January 2005

Using several different experimental conditions, centrifugation assays revealed that no “specific” high‐affinity Na+‐independent binding of [3H]GABA (3–15 nM) or [3H]muscimol (6–92 nM) occurred to subcellular particles prepared from C6 glioma cells. Therefore, like the membranes of glial cells grown in primary culture and like the modified oligodendroglial membranes of myelin, the transformed glial membranes of C6 cells do not appear to possess GABA‐receptors. These results provide further evidence that the depolarizing actions of GABA on glia that have been recorded in electrophysiological studies occur indirectly rather than by activation of glial GABA‐receptors.
A three‐day study with miconazole gelatin capsules in vaginal candidosis
Authors: Akbar M. R. , Ahmadi S. M. , Hedayati A. H. , Khami M. A.
Published: January 2005

One hundred (50 pregnant) women with vaginal candidosis (age range: 14–60 years) inserted 1 gelatin capsule, containing 400 mg of miconazole, into the vagina on 3 consecutive evenings. Excellent results (90–100% cure) were obtained for clinical symptoms (vaginal discharge, pruritus vulvae, dysuria, dyspareunia, eczematous aspect of vulva), microscopic examinations, and Nickerson's cultures. No adverse reactions were reported.
Anticonvulsant activity of (+)‐5‐methyl‐10, 11‐dihydro‐5H‐dibenzo[a, d]cyclohepten‐5, 10‐imine (MK‐801), a substance with potent anticonvulsant, central sympathomimetic, and apparent anxiolytic properties
Authors: Clineschmidt Bradley V. , Martin Gregory E. , Bunting Patricia R.
Published: January 2005

MK‐801 prevented tonic extensor seizures in the rat induced by bicuclline with the ED50 being 23 μg/kg p.o. Clonazepam, phenobarbital, diazepam, phenytoin, γ‐acetylenic GABA, sodium valproate, and trimethadione were all less potent. In mice, MK‐801 was likewise the most potent (ED50 = 0.35 mg/kg p.o.) compound in protecting against tonic seizures induced by electroshock. Clonazepam (ED50 = 0.41 mg/kg p.o.) and MK‐801 (ED50 = 0.67 mg/kg p.o.) were by far more potent than any of the other anticonvulsants tested versus bicuculline‐elicited seizures in mice. Besides being a potent anticonvulsant, MK‐801 demonstrated selectivity, since much higher doses were required in mice to block clonic convulsions produced by pentylenetetrazol (ED50 = 11 mg/kg p.o.) and tonic seizures caused by strychnine (ED50 > 15 mg/kg p.o.) than were needed against electroshock or bicuculline.

The anticonvulsant (electroshock) effect of MK‐801 in mice was unaffected by pretreating the animals with various receptor antagonists (atropine, mecamylamine, chlorpheniramine, tripelennamine, cyproheptadine, cinanserin, methysergide, cimetidine, and propranolol). MK‐801 was slightly, but significantly, antagonized by methergoline, naloxone, and theophylline, whereas haloperidol and especially α‐adrenoceptor blockers (prazosin, HEAT, phenoxybenzamine) markedly reduced the anticonvulsant effect of MK‐801. Haloperidol was selective for MK‐801, not affecting the anticonvulsant actions of phenytoin or phenobarbital. Prazosin antagonized phenytoin and phenobarbital, but to a much lesser extent than it antagonized MK‐801.

MK‐801 is an extremely potent and selective anticonvulsant acting at least partly via a catecholaminergic mechanism.
Restoration of shock‐suppressed behavior by treatment with (+)‐5‐methyl‐10,11‐dihydro‐5H‐dibenzo[a, d]cyclohepten‐5, 10‐imine (MK‐801), a substance with potent anticonvulsant, central sympathomimetic, and apparent anxiolytic properties
Authors: Clineschmidt Bradley V. , Williams Michael , Witoslawski John J. , Bunting Patricia R. , Risley Edwin A. , Totaro James A.
Published: January 2005

MK‐801 was evaluated in rats for “antipunishment” and “anticonflict” activity in two procedures: (1) A conditioned emotional response (CER) test involving the suppression of lever‐pressing by unaviodable shock and (2) a simple conflict test in water‐deprived animals that were shocked for licking water. The effect of MK‐801 in both procedures was qualitatively similar to the benzodiazepines. Lever‐pressing in the CER test was increased by MK‐801 at doses ranging from 50–400 μg/kg administered orally (p.o.) at either 0.5 or 2 hours prior to testing. The number of shocks received in the “thirsty rat” conflict procedure was increased by MK‐801 at doses from 110–1,000 μg/kg p.o., providing the compound was given 2 or more hours before test. MK‐801 was without anticonflict activity when administered 1 hour prior to study.

In squirrel monkeys trained in a response‐contingent conflict paradigm, a specific anticonflict effect for MK‐801 (50–400 μ/kg p.o.) was not demonstrable. As assessed by observing the overt behavior of squirrel monkeys, MK‐801 at doses greater than 100 μg/kg p.o. caused apparent “taming” or “tranquilization.” Chlordizepoxide and diazepam given, respectively, at doses above 1 and 2 mg/kg p.o. had a similar “taming” action. The benzodiazepines possessed a greater separation between doses producing “taming” and those causing ataxia than did MK‐801.

The mode of action for the antipunishment effect of MK‐801 in rats is not known, but it was found that naloxone (2 or 5 mg/kg SC) antagonized the anticonflict actions of both MK‐801 and chlordiazepoxide. In vitro, MK‐801 was inactive (IC50 > 2 μM) with respect to competing for binding to rat brain tissue by various radioligands (diazepam, muscimol, apomorphine, spiroperidol, serotonin, LSD, WB‐4101, dihydroalprenolol, QNB, and 2‐chloroadenosine). An increase in 3H‐diazepam binding in vitro in rat brain tissue was detected following acute, but not chronic, treatment in vivo with MK‐801.
Viloxazine and amitriptyline in endogenous depression
Authors: Petrie William M. , Wilson William H. , Jamieson Robert C. , Ban Thomas A.
Published: January 2005

In a double‐blind clinical trial carried out on 20 outpatients with the diagnosis of endogenous depression, amitriptyline (75–225 mg) was found to be somewhat faster in its therapeutic effects on depression than viloxazine (150–450 mg), whereas viloxazine was somewhat faster in its therapeutic effect on anxiety. Cardiovascular adverse effects were only encountered with amitriptyline, whereas gastrointestinal side effects were present with viloxazine.
The role of brain acetylcholine in cardiovascular regulation and hypertension: A minireview and therapeutic implications
Authors: Brezenoff Henry E. , Coram Willie Mae
Published: January 2005

Acetylcholine in the central nervous system exerts a significant influence on cardiovascular parameters and appears to be involved in some aspects of hypertension. Stimulation of central muscarinic receptors with direct‐acting cholinomimetics or with acetylcholinesterase inhibitors evokes a rise in blood pressure in unanesthetized cats, dogs, rats, and humans. Anesthetics may significantly modify this response. Concomitant with the pressor response is a potentiation of reflex bradycardia, inhibition of reflex tachycardia, and enhancement of the pressor reflex to carotid artery occlusion. Administration of atropine or intracerebroventricular injection of hemicholinium‐3 reduces blood pressure in spontaneously hypertensive rats (SHR) but not in normotensive rats. Preliminary results are presented showing that systemic or central injection of N‐(4‐diethyl‐2‐butynyl)‐ succinimide, a muscarinic receptor antagonist specific for central receptors, also reduces blood pressure in SHR but not in normotensive animals.
Successful treatment of ballism with diazepam
Authors: Becker Robert E. , Lal Harbans , Alexander Paul , Karkalas John , Kucharski Thomas
Published: January 2005

Two patients with ballism were treated successfully with diazepam. It is suggested that diazepam acted as an indirect GABAmimetic drug to correct a functional GABA deficiency secondary to hyperactivity of the dopamine system in the subthalamic nucleus as a cause for ballism.
Physical dependence liability of TR5379, a novel narcotic antagonist analgesic
Authors: Howes John F. , Bousquet Ann R.
Published: January 2005

TR5379 is a novel morphinan with potent antinociceptive activity in the mouse abdominal constriction procedure. It is a narcotic antagonist with a potency similar to that of butorphanol. In rats and monkeys, TR5379 does not appear to induce any physical dependence. Following a 6‐day chronic administration of TR5379 to rats, no indications of withdrawal were observed. TR5379 did not substitute for morphine in either the physically dependent rat or the physically dependent monkey. In the chronically morphinized rat, an acute dose of TR5379 caused the rapid onset of a marked withdrawal syndrome.
The in vivo pharmacological profile of histamine (H1) antagonists in the rat
Authors: Niemegeers C. J. E. , Awouters F. H. L. , Janssen P. A. J.
Published: January 2005

Thirteen known H1‐antagonists were studied in a series of pharmacological in vivo tests in rats. Antihistamine activity, oral absorption, and duration of action were determined in the compound 48/80 test. The dissociation between the activity in the compound 48/80 test and in the other tests was used as a measured of antihistaminic specificity. Properties common to several H1‐antagonists were: antimuscarinic (diphenhydramine, promethazine, mequitazine, azatadine, cyproheptadine, chlorphenriamine, clemastine, pyrilamine) and anti‐serotonin activity (mianserin, pizotifen, cyproheptadine, prometazine, diphenhydramine, pyrilamine). Sedative effects of H1‐antagonists were not detected by the pharmacological tests used here. Astemizole, ketotifen, and terfenadine were found to be very specific H1‐antagonists. For ketotifen and terfenadine, oral activity (1/5 and 1/25 of astemizole, respectively) and oral absorption (1/50 and 1/7 respectively) were poor, and the duration of action (4 and 6 hr, respectively) was relatively short. Astemizole was as potent orally as it was subcutaneously (ED50 = 0.11 mg/kg) and appeared to have a duration of action as long as 24 hr.
Comparison of the minimal lethal doses, cardiac toxicities, and cardiodepressor effects of tricyclic antidepressants and UP 614‐04, a potential antidepressant
Authors: Cazes M. , Witchitz S. , Provost D. , Versigny A. , Renard M. , Sebe B.
Published: January 2005

The cardiotoxic and hemodynamic effects of intravenously administered UP 614‐04, imipramine, clomipramine, and amitriptyline were compared using guinea pigs and dogs. In guinea pigs, determinations of minimal lethal dose and electrocardioraphic changes indicated that UP 614‐04 was much less cardiotoxic than the three tricyclic antidepressants tested. In dogs, both imipramine and clomipramine exerted more pronounced effects than UP 614‐04 on hemodynamic parameters. However, all three agents had qualitatively similar dose–response characteristics in that low doses produced slight increases in systolic blood pressure and heart rate, intermediate doses did not alter haemodynamic parameters, and high doses produced marked cardiodepressor effects. Imipramine and clomipramine were also much more potent than UP 614‐04 in potentiating the pressor action of intravenously administered norepinephrine. Taken together, these results have indicated that UP 614‐04 is about five times less cardiotoxic and about four to eight times less potent as a cardiodepressor than imipramine or clomipramine.
Comparative toxicity of oral all‐trans‐retinoic acid and the aromatic retinoids Ro 10‐9359 and Ro 12‐7554 in rats: Hematologic and biochemical studies
Authors: Teelmann Kampe
Published: January 2005

Reduced bodyweight gains and bone fractures are the most obvious effects in rats after repeated ingestion of high doses of vitamin A derivatives. These effects are dose dependent and well reproducible. Doses of different retinoids causing similar reductions of bodyweight gain and comparable frequencies of bone fractures can be called equitoxic in this respect. The following study was performed with approximately equitoxic doses of all‐trans‐retinoic acid (15 mg/kg/d) and the aromatic retinoids Ro 10‐9359, etretinate (7.5 mg/kg/d), and Ro 12‐7554 (2 mg/kg/d) administered as dietary admix to 18 rats/sex/group for 4 weeks. An additional group of 18 rats/sex remained untreated and served as controls. The aim of this experiment was to investigate and compare the toxic effect of these retinoids on additional parameters such as red blood counts, hemoglobin, alkaline phosphatase, cholesterol, and serum proteins known to be altered in rats exposed to this class of compounds. Under the conditions of this study, using doses which were approximately equitoxic as regards weight gain and bone fractures, the most pronounced changes on the additional parameters mentioned above were caused by retinoic acid. Less influence was shown by etretinate. The degree of compound‐related effects was lowest in the rats treated with the newly developed aromatic retinoid Ro 12‐7554.
Effects of punishment‐attenuating drugs on deprivation‐induced drinking: Implications for conflict procedures
Authors: Leander J. David
Published: January 2005

Various drugs which increase the rates of punished operant responding were studied for their effects on deprivation‐induced drinking of water. Chlordiazepoxide, diazepam, lorazepam, pentobarbital, amobarbital, phenobarbital, and SQ‐20,009 increased deprivationinduced drinking. Drugs which did not increase drinking include ethanol, cyproheptadine, methysergide, and baclofen. This grouping of drugs as to their effects on deprivation‐induced drinking is similar to the grouping of drugs on punishment procedures using deprivationinduced drinking, rather than punishment procedures using operant responding. This suggests that the effects of drugs on punished drinking reveal more about the effects of drugs on deprivation‐induced drinking than they do about the effects of drugs on punished behavior in general.
Tissue blood flow and cephalic arteriovenous shunting in cats following administration of indalpine, a selective inhibitor of 5‐hydroxytryptamine uptake
Authors: Saxena Pramod R. , Tangri Krishna K.
Published: January 2005

A number of observations indicate that a decrease in plasma 5‐hydroxytryptamine (5‐HT) level may lead to a diminished tissue perfusion and an opening of arteriovenous (AV) anastomoses in the head during migraine headaches. Indeed, some antimigraine drugs and the amine itself decrease the shunting of radioactive microspheres over the cephalic circulation in the experimental animals. Since indalpine selectively inhibits 5‐HT uptake mechanisms and increases plasma 5‐HT level, we have investigated the effects of the drug (1, 2, and 4 mg·kg−1) on tissue blood flow and on AV shunting using the radioactive microsphere method in anesthetized cats. Indalpine caused minimal systemic hemodynamic effects; only a moderate (14%) hypotension resulted with the highest dose. Regionally, the drug increased blood flow to brain, intestines, mesentery + pancreas, and skeletal muscles. Both total peripheral AV‐shunting (as indicated by the microsphere content of the lungs) and jugular venous AV‐shunting (as measured by microspheres in the jugular venous blood) were decreased by the drug. These hemodynamic changes resemble those occurring during 5‐Ht infusions. It is suggested that indalpine may be of therapeutic value in migraine since it decreased AV‐shunting across the cephalic circulation.
The effect of pirenzepine (LS 519), a specific antimuscarinic drug, on cortisol levels in man
Authors: Alagna Sergio , Masala Antonio , Satta Andrea , Faedda Rossana , Devilla Luisa , Rassu Sergio , Rovasio Pier Paolo
Published: January 2005

The authors investigated the effect of a single 75‐mg oral dose of pirenzepine, a drug which selectively blocks the muscarinic receptors and does not cross the blood‐brain barrier, on the function of the HPA axis. A significant decrease in basal cortisol values following the administration of the drug was observed in comparison with a placebo test. Moreover, the adrenal response to exogenous adrenocorticotropin (ACTH) administration was unchanged following a 5‐day course of the drug, ruling out direct action of pirenzepine at the adrenal level. These data suggest that cholinergic muscarinic hypothalamic and/or pituitary systems may be involved in the regulation of ACTH‐cortisol secretion.
Treatment with antidepressants and down regulation of beta‐adrenergic receptors
Authors: Pandey Ghanshyam N. , Davis John M.
Published: January 2005

The effect of chronic and acute treatment with several antidepressant drugs and electroconvulsive shock (ECS) on the responsiveness of norepinephrine (NE) receptor coupled adenylate cyclase and beta‐adrenergic receptor binding sites in rat brain has been studied by several groups of investigators. It has been consistently reported that chronic administration (2 to 4 weeks of treatment) of antidepressant drugs or ECS causes a decreased accumulation of NE stimulated cyclic AMP accumulation in rat brain. It has also been reported that chronic treatment with antidepressant drugs or ECS causes decreased binding of [3H]dihydroalprenolol (DHA) or [125I]hydroxybenzylpindolol (I‐HYP) (ligands used for studies of beta‐adrenergic receptors) in rat brain. However, such effects are not observed after acute or single administration of these drugs or ECS. Since there appears to be a close correlation between the time course of the effects of these drugs on NE receptor coupled adenylate cyclase and beta‐adrenergic receptor binding, and since most of the antidepressant drugs tested thus far produce such effects, it has been suggested that down regulation or decreased responsiveness of beta‐adrenergic receptors may be related to the therapeutic effects manifested by antidepressant drugs. These observations offer the possibility that determination of beta‐adrenergic receptor responsiveness after chronic treatment with drugs may prove useful in the preclinical screening of potential antidepressant drugs. In this paper, studies related to down regulation of beta‐adrenergic receptors, including our own, are reviewed.
Enhancement of benzodiazepine binding by a diaryltriazine, LY81067
Authors: Wong David T. , Bymaster Franklin P. , Lacefield William B.
Published: January 2005

Ly81067, a diaryltriazine, represents a new class of compounds to enhance [3H]flunitrazepam binding to membranes of rat cerebral cortex. The enhancement induced by LY81067 exceeds that induced by γ‐aminobutyric acid (GABA) and is partially abolished by the GABA antagonists bicuculline and picrotoxin. Scatchard analysis on the saturable binding of [3H]flunitrazepam reveals that LY81067 at 10 μM increases mainly the affinity for the [3H]ligand, due to a reduced rate of dissociation of the receptor‐bound [3H]flunitrazepam. A dependence on chloride anions was demonstrated in the enhancement of [3H]flunitrazepam binding by LY81067. These findings suggest that the diaryltriazine LY81067 enhances [3H]flunitrazepam binding by exerting its effect at or near the picrotoxinsensitive anion recognition sites of the GABA/benzodiazepine receptor complex.
The use of a microcomputer for collecting screening data and for conducting range finding experiments on muscle relaxant drugs
Authors: Thut Paul D. , Polansky Gregg , Rudo Frieda G.
Published: January 2005

This report describes a method that has been developed to use an Apple II Plus microcomputer in data collection, data analysis, and transfer of raw and summary data to a data base that is maintained on a larger computer. The compounds being screened are potential skeletal muscle relaxants acting at the neuromuscular junction. The microcomputer produces a CRT (cathode ray tube) display resembling the data sheets previously used in a drug screening project. It prompts the user to enter the following data through the keyboard: compound number, date, drug solution, animal weight, desired compound dose. From the entered data, the microcomputer calculates and displays the appropriate injection volume so that a technician will be shown the exact dose that is to be injected into the test animal. Following injection, the mouse is immediately placed on an inclined screen as described by Pradham and De [1953]. Times to onset and offset of muscle paralysis are entered and displayed on the CRT. For lower doses, the effects of the drug on respiration are recorded. After these primary data are recorded, all other relevant data are elicited by a menu of appropriate pharmacological questions. Data from each animal are stored in a random access file on a 5.25‐in. floppy disk. From these files tabular and narrative reports of the drug's effects can be automatically generated. The data are also sent by telephone modem to a data base that is maintained on a larger computer for access by chemists in structure–activity studies. This method has greatly increased the speed and efficiency of data collection and report generation. Furthermore, it has allowed the raw data to be easily searched and reviewed in subsequent structure–activity studies. Because this data collection system is small and self‐contained, it may be mobed easily to different testing sites.
Comparative anticholinergic activity of oxaprotiline and amitriptyline
Authors: Roffman Mark , Gould Eugene , Brewer Samuel , Lau Helen , Sachais Barry , Dixon Nina , Kaczmarek Linda , Le Sher Anne
Published: January 2005

As part of a double‐blind multicenter trial comparing oxaprotiline with amitriptyline and placebo in 308 outpatients with moderate depression, objective (salivary flow) and subjective (dry mouth, blurred vision/visual disorder, and constipation) determinants of anticholinergic activity were assessed. Both active treatments, but not placebo, induced approximately a 40% reduction in salivary flow after one week of treatment with 75 mg/day h.s. Whereas amitriptyline caused a further reduction (26%) in salivary flow by the end of the trial (week 5), no such reduction was noted with oxaprotiline. With regards to subjective complaints, more patients experienced dry mouth and blurred vision/visual degree of sedation is related to the degree of anticholinergic effects per se. Rather, the sedation may be related to a specific anticholinergic effect, such as changes in salivary flow.
Putative endogenous ligands to the benzodiazepine receptor: What can they tell us?
Authors: Davis Leonard G. , Manning Robert W. , Dawson William E.
Published: January 2005

The endogenous ligand for the benzodiazepine receptor has not been convincingly demonstrated, nor is it clear what role this drug receptor actually plays in brain function. A number of putative endogenous ligands for the benzodiazepine receptor have been identified and reported in the literature. These putative ligands, at various stages of purification, have been typically identified by their ability to displace 3H‐diazepam in a radioreceptor binding assay. Taken together, these studies provide useful information on the role that the benzodiazepine receptor and its ligand might play in brain function. The purpose of this paper is to review this area of research and attempt to provide a unifying hypothesis. In summary, calling this bioactive site the benzodiazepine receptor may be a misnomer, as it appears to effect both anxiogenic and anxiolytic activities involved in the maintenance of homeostatic levels of vigilance. Moreover, it can be suggested that endogenous ligands of reciprocal action could exist, mediating each function (relaxation and vigilance) and, thereby, maintain a balance of neural activity.
The action of structural analogues of γ‐aminobutyric acid on binding sites in mouse brain
Authors: Tunnicliff Godfrey , Welborn Kathy L.
Published: January 2005

Nineteen structural analogues of γ‐aminobutyric acid (GABA) and the anxiolytics buspirone and diazepam were tested for their ability to modify GABA function in vitro. Each compound was added to the GABA receptor binding assay, the flunitrazepam receptor binding assay, the sodium‐dependent GABA binding assay, and the assay for GABA aminotransferase. It was anticipated that some of these analogues would substantially affect several of these assays. The most interesting compound to emerge was phenylthiohydantoic acid. This not only inhibited GABA receptor binding (Ki = 121 μM) but also stimulated flunitrazepam binding and inhibited the activity of GABA aminotransferase. In light of the evidence that a reduced GABA function can be a factor in anxiety, phenylthiohydantoic acid has the potential to be a GABA‐mimetic and thus be useful in the treatment of anxiety.
Tracazolate: A novel nonsedative anxiolytic
Authors: Malick Jeffrey B. , Patel J. B. , Salama A. I. , Meiners B. A. , Giles R. E. , Goldberg M. E.
Published: January 2005

Tracazolate (ICI 136,753; 4‐butylamino‐1‐ethyl‐6‐methyl‐1H‐pyrazolo [3,4‐b] pyridine‐5‐carboxylic acid ethyl ester) exhibited dose‐related anticonflict activity in mice, rats, and squirrel monkeys. The potency of tracazolate appears to be one‐quarter to one‐half that of chlordiazepoxide, and their durations of activity are similar in rats. No tolerance to the anticonflict activity of either chlordiazepoxide or tracazolate was evident following 12 consecutive days of treatment. Tracazolate exhibits a much greater separation between sedative and therapeutic doses than does chlordiazepoxide; thus, it is predicted that tracazolate will not be sedative at anxiolytic doses in man. Furthermore, based upon studies in rodents, tracazolate should be much less likely than the benzodiazepines to potentiate the actions of barbiturates and ethanol in man. Although tracazolate is an anticonvulsant in rodents, it is considerably less potent in this respect than chlordiazepoxide. In contrast to benzodiazepine anxiolytics, tracazolate enhances the binding of 3H‐benzodiazepines to their binding sites in brain. Consistent with this finding, tracazolate potentiated both the anticonvulsant and anxiolytic effects of chlordiazepoxide in rodents. Although the benzodiazepine antagonists (RO 15‐1788 and CGS 8216) clearly antagonize the anticonflict activity of chlordiazepoxide, the activity of tracazolate was not significantly altered by either antagonist. Both chlordiazepoxide and tracazolate significantly enhanced 3H‐γ‐aminobutyric acid (GABA) binding. These results suggest that tracazolate is a novel psychoactive agent that should be a useful anxiolytic drug in man.
Lack of antinociceptive activity of clonidine in two pain models: Comparison with other analgesics and CNS active drugs
Authors: Spaulding Theodore C. , Ma Minh G. , Dunn Robert W. , Fielding Stuart
Published: January 2005

The antinociceptive activity of clonidine was investigated in two models of pain using the modified Haffner tail clip test (MHA) in mice and the formalin test (FT) in rats. Morphine was used as a positive control for comparison. Clonidine at does from 0.5 mg/kg to 8 mg/kg SC was not effective in MHA while morphine administration resulted in a dose‐dependent increase in the latency to bite the clip and an ED50 of 1.2 mg/kg SC. No antinociceptive activity was observed for clonidine using the FT up to a dose of 4 mg/kg SC which causes severe behavioral depression. The ED50 for morphine in FT was 1.7 mg/kg SC. From these studies we conclude that clonidine is not active in all tests used to predict analgesic efficacy in man. Additional analgesic and centrally acting drugs were also included for comparative purposes. Of the compounds tested only the opiates active in FT and MHA and cholinesterase inhibitors (active in MHA only) showed analgesic effects.
κ‐Agonist analogesics: Evidence for μ2 and δ opioid receptor antagonism
Authors: Wood Paul L.
Published: January 2005

Despite a unique in vivo pharmacology, K agonists possess moderate to high affinities for μ, δ, and κ binding sites in vitro. By monitoring the antagonist activity of κ agents on morphine‐ and DADLE‐dependent changes in dopamine and acetylcholine metabolism we were able to demonstrate a specific μ2 and δ receptor antagonism for κ analgesics. Furthermore, this antagonism was probably directly at the receptor level and not physiological.
Antidepressants in states of cognitive dysfunction
Authors: Cohen Robert M. , Sunderland Trey , Aulakh Charanjit S.
Published: January 2005

Several approaches are described for the design of pharmacologic strategies for the manipulation of cognition. By a variety of criteria, it is concluded that antidepressants deserve a trial in some patients with cognitive dysfunction. Depression is an illness with prominent cognitive dysfunction that shares, to some extent, cognitive and biochemical impairments similar to those observed in cognitive dysfunction of organic etiology. Antidepressants appear to produce their beneficial effect on cognition in depression by inducing slow adaptive changes in catecholamine and indoleamine pathways, therein promoting alterations in the individual's central motivational state. Animal data supporting these ideas are reported. As reviewed, few satisfactory studies of antidepressants in cognitive dysfunction of organic etiology appear in the literature, perhaps as the result of the potent anticholinergic properties of the most popular antidepressant drugs.