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PubMed1993

Homomeric and native alpha 7 acetylcholine receptors exhibit remarkably similar but non-identical pharmacological properties, suggesting that the native receptor is a heteromeric protein complex.

Sucrose gradient analysis of chick acetylcholine receptor (AChR) alpha 7 subunits expressed in oocytes indicates that they form pharmacologically active homomers of the same size as native alpha 7 AChRs, a size compatible with a complex of five alpha 7 subunits. By immunoisolating the [35S]methionine-labeled alpha 7 subunits we also demonstrate that they do not appear to assemble with endogenous Xenopus AChR subunits. Pharmacological characterization of detergent-solubilized brain alpha 7 AChRs and alpha 7 homomers reveals that they have similar but nonidentical properties. The pharmacological difference is most accentuated for cytisine (approximately 50-fold). Thus, at least in E18 chicken brain, most or all of the native alpha 7 AChRs do not appear to be homomeric.

Animals↗

PubMed1994

The human serotonin 5-HT2B receptor: pharmacological link between 5-HT2 and 5-HT1D receptors.

The human serotonin 5-HT2B receptor, isolated from a human liver cDNA library, was transfected in COS-1 cells. Its pharmacological profile shows divergence with serotonin 5-HT2B receptors of other species. In particular, although strong correlation is observed between the human and the rat 5-HT2B receptor pharmacology, the correlation is almost as significant for the mouse 5-HT2B and the human 5-HT1D receptor agonists. The major sites of expression of its mRNA are in the human liver and kidney, with detectable expression in lung and heart. Therefore, this human 5-HT2B receptor could account for functions attributed to the peripheral 5-HT1D/5-HT2-like receptors, especially in the cardiovascular system. Thus, its detailed original pharmacology is of prime importance for therapeutic drug development.

Amino Acid Sequence↗

PubMed1982

Specific binding and pharmacological interactions of apamin, the neurotoxin from bee venom, with guinea pig colon.

This paper describes the interaction of apamin, the bee venom neurotoxin, with its receptor in the guinea pig colon. The pharmacological activity of the toxin was assayed by measuring its contracting effect on guinea pig colon preparations that had been previously relaxed by neurotensin. The IC50 value of apamin in this in vitro bioassay is 7 nM. These pharmacological data are compared to the binding properties of apamin to smooth muscle membranes prepared from guinea pig colon. The highly radiolabeled monoiododerivative of apamin binds to its colon receptor with a dissociation constant Kd* = 36 pM. The maximal binding capacity of colonic membranes is 30dfmol/mg of protein. The dissociation constant of the unmodified toxin is 23 pM. The difference between the toxin concentrations that produce half-maximal effects in the binding and pharmacological studies arises from the different experimental conditions used for the two assays.

Animals↗

PubMed1982

High performance liquid chromatography of pharmacologically active amines and peptides in biological materials.

Precise and quantitative reversed-phase high performance liquid chromatographic (HPLC) procedures are described which can be used in biogenic amine and neuropeptide research. The amine procedure was applied to various pharmacological matrices including plasma, heart tissue and brain. The use of peptide HPLC as an analytical tool for various neuropeptides is illustrated by studies on des-tyrosine-gamma-endorphin (DT gamma E) metabolism in the brain and the stability of an ACTH (ORG-2766) analogue during a chronic infusion in rats. The power of HPLC as a research tool in peptide pharmacology is described, discussed and demonstrated as an aid in the understanding of the pharmacological effects of exogenous peptides and the function of the brain.

Adrenocorticotropic Hormone↗

PubMed1988

The Paw test: an animal model for neuroleptic drugs which fulfils the criteria for pharmacological isomorphism.

Recently we have developed an animal model which could discriminate between classical and atypical neuroleptic drugs: the PAW TEST. This test measures the ability of rats to spontaneously withdraw its force- and hindlimbs. It was found that the ability of drugs to affect the rat's forelimb retraction time was associated with the liability of the drug to induce so-called extra-pyramidal side-effects in man. Likewise the ability of drugs to affect the rat's hindlimb retraction time was associated with the antipsychotic efficacy of the drug. These data open the perspective that the forelimb retraction time (FRT) is an animal analogue of parkinsonian side-effects, and that the hindlimb retraction time (HRT) is an animal analogue of antipsychotic effects In the present series of experiments we further evaluated the validity of these notions by applying the criteria of "pharmacological isomorphism" as proposed by Matthysse (1). Thus HRT had to fulfil the criteria of pharmacological isomorphism for the therapeutic effects of neuroleptics, whereas FRT had to fulfil these criteria for the parkinsonian side-effects. The results of the present study show that both FRT and HRT met these criteria. Thus both classical and atypical neuroleptics were effective in prolonging HRT, whereas only the classical neuroleptics prolonged FRT (criterion 1); the nonneuroleptic phenothiazine promethazine (as well as the narcotic morphine, the muscle relaxant diazepam and the antidepressant desipramine) were ineffective in this respect (criterion 2); the acetylcholinergic antagonist scopolamine blocked the FRT, but not the HRT (criterion 3); chronic neuroleptic treatment reduced the FRT, but not the HRT (criterion 4). In conclusion the paw test, an animal model for testing antipsychotic drugs, was found to fulfil the criteria for "pharmacological isomorphism". Although the exact mechanism underlying the paw test is as yet unknown, the present data improve its validity as an animal model.

Animals↗

PubMed1988

Clip-induced analgesia and immobility in the mouse: pharmacological characterization.

A pinch to the nape of the neck of mice, by application of a noxious clip, produces analgesia and immobility. Because both opiate and dopaminergic systems are usually implicated in analgesia and immobility, the pharmacological profile of clip-induced effects was compared to those elicited by the dopamine antagonist haloperidol, and by morphine. In addition, the effects of a series of pharmacological agents on clip-induced effects was examined. Haloperidol, but not morphine, produced immobility similar to that seen after application of the clip to the neck. Application of clip completely inhibited righting in all tests utilized. Haloperidol inhibited righting in all tests, except for inversion from a supine position. Righting from this position could also be inhibited in mice treated with haloperidol when a mild pinch, ineffective in a naive animal, was applied. Clip-induced immobility, but not analgesia, was reversed by amphetamine. Administration of the cholinergic antagonist scopolamine, but not methylscopolamine, reversed both the analgesia and immobility. Pinch-induced analgesia was as marked as that elicited by morphine but could not be reversed by the opiate antagonist naloxone. It is proposed that pinch-induced immobility is mediated by both dopaminergic and cholinergic systems. Additional unidentified systems are also involved. Analgesia, induced by a noxious pinch, can be dissociated pharmacologically from the immobilizing effect, is non-opiate in nature, and involves activation of central cholinergic synapses.

Analgesia↗

PubMed1993

Distinctive pharmacology and kinetics of cloned neuronal Ca2+ channels and their possible counterparts in mammalian CNS neurons.

This paper provides a brief overview of the diversity of voltage-gated Ca2+ channels and our recent work on neuronal Ca2+ channels with novel pharmacological and biophysical properties that distinguish them from L, N, P or T-type channels. The Ca2+ channel alpha 1 subunit known as alpha 1A or BI [Mori Y., Friedrich T., Kim M.-S., Mikami A., Nakai J., Ruth P., Bosse E., Hofmann F., Flockerzi V., Furuichi T., Mikoshiba K., Imoto K., Tanabe T. and Numa S. (1991) Nature 350, 398-402] is generally assumed to encode the P-type Ca2+ channel. However, we find that alpha 1A expressed in Xenopus oocytes differs from P-type channels in its kinetics of inactivation and its degree of sensitivity to block by the peptide toxins omega-Aga-IVA and omega-CTx-MVIIC [Sather W. A., Tanabe T., Zhang J.-F., Mori Y., Adams M. E. and Tsien R. W. (1993) Neuron 11, 291-303]. Thus, alpha 1A is capable of generating a Ca2+ channel with characteristics quite distinct from P-type channels. Doe-1, recently cloned from the forebrain of a marine ray, is another alpha 1 subunit which exemplifies a different branch of the Ca2+ channel family tree [Horne W. A., Ellinor P. T., Inman I., Zhou M., Tsien R. W. and Schwarz T. L. (1993) Proc. Natn. Acad. Sci. U.S.A. 90, 3787-3791]. When expressed in Xenopus oocytes, doe-1 forms a high voltage-activated (HVA) Ca2+ channel [Ellinor P. T., Zhang J.-F., Randall A. D., Zhou M., Schwarz T. L., Tsien R. W. and Horne W. (1993) Nature 363, 455-458]. It inactivates more rapidly than any previously expressed calcium channel and is not blocked by dihydropyridine antagonists or omega-Aga-IVA. Doe-1 current is reduced by omega-CTx-GVIA, but the inhibition is readily reversible and requires micromolar toxin, in contrast to this toxin's potent and irreversible block of N-type channels. Doe-1 shows considerable sensitivity to block by Ni2+ or Cd2+. We have identified components of Ca2+ channel current in rat cerebellar granule neurons with kinetic and pharmacological features similar to alpha 1A and doe-1 in oocytes [Randall A. D., Wendland B., Schweizer F., Miljanich G., Adams M. E. and Tsien R. W. (1993) Soc. Neurosci. Abstr. 19, 1478]. The doe-1-like component (R-type current) inactivates much more quickly than L, N or P-type channels, and also differs significantly in its pharmacology.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗

PubMed1984

Pharmacological activity of the basic fraction of marihuana whole smoke condensate alone and in combination with delta-9-tetrahydrocannabinol in mice.

This basic fraction (BF) of marihuana whole smoke condensate was subjected to pharmacological testing in males, Swiss-Webster mice. In a general pharmacological activity screen looking at behavioral, neurologic, and autonomic parameters, BF, at iv doses of 5, 10, and 20 mg/kg, caused impairment of visual placing, increase in tail pinch response, decrease in tail elevation, and induction of piloerection. These effects, although statistically significant, were slight and not consistently dose dependent. In a second study with doses ranging from 10 to 29 mg/kg, BF caused a decrease in spatial locomotion, rearing behavior, and urination incidence. In a third study, body temperatures of mice were measured periodically for 2 hr following administration of BF (1.2, 2.4, and 4.8 mg/kg) alone or in combination with 1.0 mg/kg delta-9-tetrahydrocannabinol (THC). BF did not alter body temperature, nor did it affect THC-induced hypothermia. These results, although suggesting that the basic fraction of marihuana whole smoke condensate has pharmacological activity in mice, offers little evidence for the presence of highly active compounds.

Animals↗

PubMed1995

Percutaneous transluminal angioplasty in a canine model of cerebral vasospasm: angiographic, histologic, and pharmacologic evaluation.

BACKGROUND: Cerebral vasospasm following subarachnoid hemorrhage (SAH) is one of the leading factors that deteriorate the clinical outcome after aneurysmal surgery. Percutaneous transluminal angioplasty (PTA) is a method to directly dilate the constricted vessel using the intravascular neurosurgical technique. METHODS: Angiographic, histologic, and pharmacologic evaluations related to PTA are presented, using a canine double-injection model of SAH. In angiographic evaluation, we studied the effect of PTA performed on day 1, 4, or 7 of SAH. We performed sequential histologic study by light microscopy using the same for the angiographic evaluation. In pharmacologic evaluation, we measured in vitro isotonic constrictive force using two vasoconstrictors immediately after PTA on normal basilar arteries (control group) and basilar arteries on day 7 of SAH. RESULTS: In angiographic evaluation, we observed the effective dilation of spastic artery immediately after PTA and saw no recurrence of vessel constriction when PTA was performed on day 7 of SAH. However, the preventive effect of PTA was inconsistent when it was performed earlier after SAH (days 1, 4). In histologic evaluation, PTA segments immediately after PTA showed denuding of endothelial cells and stretching of the internal elastic lamina without disruption of the muscle layer. In pharmacologic evaluation, there was no difference in isotonic constrictive force created by vasoconstrictors between the PTA and non-PTA segments without SAH. However, there was a statistically significant reduction of isotonic constrictive force on the PTA segment with SAH. CONCLUSIONS: We suggest that the mechanism of PTA vasodilation in vasospasm after SAH may result from mild functional changes in the vascular wall when PTA was applied on day 7 of SAH. The functional changes would not be adequately induced to prevent recurrence of vasoconstriction when PTA was applied soon after SAH.

Angioplasty↗

PubMed1996

Cisternal talc injection in dog can induce delayed and prolonged arterial constriction resembling cerebral vasospasm morphologically and pharmacologically.

BACKGROUND: The possible role of inflammation in the pathogenesis of cerebral vasospasm has been noted in recent studies. In order to examine the role of inflammation, we examined the vasocontractile activity of talc, which is known to cause severe inflammation, using a canine cisternal talc injection model. METHODS: Under general anesthesia, a sterile talc powder suspended in saline was injected into the cisterna magna of the dog. Serial vertebral angiography and postmortem histologic changes of the harvested basilar artery were examined. The morphologic and pharmacologic features of talc-induced vessel spasm were compared with the usual autologous blood-induced artery spasm. RESULTS: Cisternal injection of sterile talc powder caused no early spasm, but induced definite basilar arterial constriction 2 days after injection. This vascular constriction was observed to continue up to 7 days after injection. Ultrastructural study of the constricted vessel revealed several morphologic changes, such as corrugation of the elastic lamina, subintimal proliferation, migration of smooth muscle cells, detachment of endothelial cells, etc.; findings that are compatible with the changes observed in vasospasm. Pharmacologic study showed a moderate decrease in the maximal contraction to KCl and UTP. Endothelium-dependent relaxation was markedly disturbed, while endothelium-independent relaxation was preserved. These pharmacologic properties were also similar to those reported in vasospasm. CONCLUSIONS: Our present study indicates that the several changes of vascular properties, which had been considered to be specific to cerebral vasospasm, can be regarded as a nonspecific biologic defense reaction against the foreign body. The analysis of the common pathway from talc and autologous blood to vasospasm may lead to the pathogenesis of cerebral vasospasm.

Animals↗

PubMed1984

Pharmacological and toxicological investigations of cesium.

Cesium, a mineral resource abundantly present in Manitoba with important existing and potential industrial applications was investigated to study its effects on biological systems. Several rodent models of pharmacological activities were utilized. The profile that emerged indicated that cesium is only moderately toxic and exerts salubrious effects which could be gainfully investigated for application in the treatment of certain psychological disorders and some tumors. Its conjunction with existing pharmacological agents for these two types of disorders could yield a pharmacologically active yet less toxic therapeutic combination.

Animals↗

PubMed1986

Learned and pharmacologically-induced tolerance to ethanol and cross-tolerance to morphine and clonidine.

The development of tolerance to the inhibitory effect of ethanol on the tail-flick reflex was studied in the spinal rat. This preparation was used in order to avoid uncontrolled learning effects. Tolerance due to intoxicated practice (learned tolerance) and tolerance due to mere ethanol exposure (pharmacologically-induced tolerance) were studied in separate experiments. It was found that that learned tolerance to ethanol also caused tolerance to morphine and clonidine, whereas pharmacologically-induced tolerance did not have the same effect. The results challenge the concept of "behaviorally augmented tolerance" and suggest that learned and pharmacologically-induced tolerance involve different basal mechanisms in the CNS.

Animals↗

PubMed1988

Pharmacological treatment of tobacco dependence.

Pharmacologically based approaches for the treatment of tobacco dependence are reviewed. The rational basis for pharmacologic treatment approaches is that tobacco dependence is partially, and critically, mediated by the actions of tobacco-delivered nicotine to the central nervous system. These actions include direct reinforcing properties of nicotine itself, tolerance and physiologic dependence, possible beneficial effects of nicotine in the alleviation of anxiety and control of weight, and neurohormonal regulation which can become important to the maintenance of emotional well-being and performance at work. Insofar as tobacco abstinence leads to negative consequences, via these biobehavioral mechanisms, pharmacologic intervention should be able to assist in initial tobacco detoxification and help tobacco abstinent persons to avoid subsequent relapse. The purpose of this review is to survey some of the efforts to develop such interventions, as well as to elucidate some of the issues relevant to such development. Four distinct approaches are discussed: (1) Nicotine replacement, in which physiologic dependence is transferred to a safer and more therapeutically manageable nicotine delivering formulation; this category includes nicotine polacrilex gum; (2) Blockade therapy, in which a drug is taken that blocks the reinforcing properties of nicotine should relapse occur; (3) Nonspecific pharmacotherapy, in which the biobehaviorally mediated correlates of tobacco abstinence are treated on a symptomatic basis; (4) Deterrent therapy, in which a drug is taken prior to smoking such that any tobacco use would produce reliable aversive effects.

Affect↗

PubMed1993

Pharmacological nature of soman-induced hypothermia in mice.

The object of the study was to determine the pharmacological nature of pinacolyl methylphosphonofluoridate (soman)-induced hypothermia in mice. This was accomplished by examining the soman hypothermia dose response and the effect of various pharmacological antagonists in comparison to the hypothermia responses of muscarinic and nicotinic cholinergic agonists such as oxotremorine and nicotine and another anticholinesterase, physostigmine. Core temperature in mice was monitored by telemetry. In general, atropine antagonized oxotremorine, physostigmine, and soman hypothermia but not nicotine hypothermia whereas mecamylamine antagonized nicotine hypothermia but not that produced by the other agonists. Soman hypothermia was not affected significantly by various pharmacological antagonists, suggesting that other neurotransmitters were not involved in the expression of soman hypothermia. Soman hypothermia appears to be due to muscarinic receptor stimulation and can be effectively antagonized, but not completely, by the use of atropine. Acetylcholinesterase oxime reactivators, such as HI-6 and toxogonin, were ineffective in antagonizing soman-induced hypothermia and reactivating hypothalamic acetylcholinesterase, whereas HI-6 was effective in reactivating soman-inhibited diaphragm acetylcholinesterase when administered up to 10 min after soman, indicating that aging of the soman-inhibited acetylcholinesterase had not occurred. Soman hypothermia appears to be primarily a muscarinic receptor-related event.

Acetylcholinesterase↗

PubMed1993

Pharmacological evaluation of iodo and nitro analogs of delta 8-THC and delta 9-THC.

One aspect of cannabinoid structure-activity relationships (SARs) that has not been thoroughly investigated is the aromatic (A) ring. Although halogenation of the side chain enhances potency, our recent observation that iodination of the A ring also enhanced activity was surprising. The purpose of this investigation was to establish the steric and electrostatic requirements at these sites of the cannabinoid molecule via molecular modeling, while determining pharmacological activity. Molecular modeling was performed using the Tripos molecular mechanics force field and the semiempirical quantum mechanical package AM1. The Ki values for novel cannabinoids were determined in a [3H]CP-55,940 binding assay and ED50 values generated from four different evaluations in a mouse model. The present studies underscore the increase in potency produced by a dimethylheptyl (DMH) side chain. Trifluoro substitutions on the pentyl side chain, or bromination of the DMH side chain, had little effect on the pharmacological activity. Any substitution at the C4 position of the aryl ring resulted in a loss of activity, which appears to be due to steric hindrances. Nitro, but not iodo, substitution at the C2 position essentially produces an inactive analog, and the drastic alteration of the electrostatic potential appears to be responsible. The altered pharmacological profile of the 2-iodo analog seems to be related to an alteration in the highest occupied molecular orbital because there is no alteration in the electron density map compared to delta 8-tetrahydrocannibinol.

Analgesics↗

PubMed1981

Amphetamine and tranylcypromine in an animal model of depression: pharmacological specificity of the reversal effect.

Amphetamine and tranylcypromine are structurally related chemical isomers with pharmacologically distinctive activity profiles. Since they are equimolar and structurally similar they may be used to assess the pharmacologically distinctive activity profiles. Since they are equimolar and structurally similar they may be used to assess the pharmacological specificity of a proposed animal model of depression. Adult male Sprague-Dawley rats were exposed to a chronic stress regimen or remained undisturbed. They were then acutely stressed with white noise. The monoamine oxidase inhibitor tranylcypromine was effective in restoring otherwise reduced stress elicited open field activity in chronically stressed rats. Amphetamine did not resemble tranylcypromine or other antidepressants, and produced a variety of effects at least some of which indicated a potential increase rather than reduction in depression consequent to chronic administration.

Amphetamine↗

PubMed1981

Behavior analysis and experimental pharmacology.

This paper provides an introduction to the field of behavioral pharmacology. A brief description of the main characteristics of behavior analysis is followed by a review of the contributions of experimental pharmacology to behavior analysis and vice versa. Finally, a section on new procedures in behavioral pharmacology outlines experimental situations in which complex kinds of behavior can to studied. These include: (a) temporal discrimination; (b) preference to be free and informed; (c) commitment, choice and self-control; and (d) high-order concept formation.

Animals↗

PubMed1994

Recent developments in the behavioral pharmacology of benzodiazepine (omega) receptors: evidence for the functional significance of receptor subtypes.

Recent research in molecular biology has demonstrated the complexity of GABAA receptors and shown that benzodiazepine (BZ-omega) receptor subtypes have a structural reality. It is therefore appropriate to ask whether the different pharmacological effects produced by benzodiazepines (anticonvulsant activity, anxiety reduction, motor incoordination, learning deficits, characteristic discriminative stimulus effects, tolerance and dependence) are associated with activity at different receptor subtypes. The present paper reviews the literature dealing with the behavioral effects of novel BZ (omega) receptor ligands relevant to the question of the functional significance of the BZ1 (omega 1) and BZ2 (omega 2) receptor subtypes. The only drugs currently available with a considerable degree of selectivity are alpidem and zolpidem. These compounds have relatively high affinity for GABAA receptors containing the alpha 1 subunit (corresponding to the BZ1 (omega 1) subtype) and very low affinity for receptors with the alpha 5 subunit (corresponding to one type of BZ2 (omega 2) receptor). Pharmacological effects observed with these, and other, less selective compounds allow several tentative conclusions to be drawn: (a) Little is known of the role of subtype selectivity in anxiolytic or amnestic effects but compounds with low intrinsic activity may reduce anxiety without giving rise to sedation or motor incoordination and BZ1 (omega 1) selective drugs appear to disrupt memory only at sedative doses; (b) Selectivity for BZ1 (omega 1) receptors may be associated with sleep-inducing activity but not with motor incoordination, suggesting that BZ2 (omega 2) receptors may be of particular importance in mechanisms of muscle relaxation; (c) The discriminative stimulus effects of different BZ (omega) receptor ligands are not identical and differences may be related to receptor selectivity; (d) Compounds with BZ1 (omega 1) selectivity and compounds with low intrinsic activity produce little or no tolerance and dependence. A wider range of selective compounds will be necessary to investigate these factors in detail and many different pharmacological profiles can be expected from drugs with selectivity and different levels of intrinsic activity.

Animals↗