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At least 91 records · Page 5Linked to original sources
PubMed1982

Pharmacological investigations of neurotransmitter involvement in passive avoidance responding: a review and some new results.

The roles of acetylcholine (ACh), noradrenaline (NA), dopamine (DA) and serotonin (5-HT) in passive avoidance responding are examined by reviewing previous studies of the effects on this task of drugs which alter the functioning of these neurotransmitter systems and also by presenting the results of a new study. This new study includes a number of drugs which do not seem to have been examined before, namely pilocarpine, pempidine, pentolinium, tetrabenazine, desipramine, clonidine, isoprenaline, pimozide, fluoxetine, L-tryptophan, methysergide and cyproheptadine. Because there is large variability in the effects of any one drug or class of drugs on passive avoidance responding, it is difficult to determine the exact involvement of the various neurotransmitter systems. There is also little good evidence that drug effects on performance of the passive avoidance response are caused by drug-induced changes in learning and memory processes or by state-dependent effects. Three other factors which may influence performance of the passive avoidance response-shock sensitivity, the biochemical response to stress and locomotor activity-are discussed and may be responsible for many of the drug-induced changes in passive avoidance responding.

Acetylcholine↗
PubMed1988

Mecamylamine is a selective non-competitive antagonist of N-methyl-D-aspartate- and aspartate-induced currents in horizontal cells dissociated from the catfish retina.

The nicotinic acetylcholine channel blockers mecamylamine (MECA) and pempidine (PEMP) blocked voltage-clamped isolated catfish retina cone horizontal responses to aspartate (Asp) and N-methyl-D-aspartate (NMDA) but had little effect on currents induced by kainate and quisqualate. Concentration response curves for NMDA and Asp in the presence of MECA suggested that MECA was a non-competitive inhibitor of NMDA and Asp responses. Further, the MECA and PEMP block of NMDA and Asp-induced currents was highly voltage-sensitive. The non-competitive and voltage-sensitive block of NMDA and Asp-induced currents by MECA suggest that MECA (and PEMP) block the NMDA receptor ion channel.

Animals↗
PubMed1996

N- and C-terminal substance P fragments modulate striatal dopamine outflow through a cholinergic link mediated by muscarinic receptors.

The present study investigated whether the modulatory effects of substance P and substance P fragments on striatal dopamine release involve a cholinergic link. Rat striatal slices were incubated with substance P, substance P(1-4), substance P(1-7), substance P(5-11) and substance P(8-11) in the absence or presence of various agents which modify cholinergic transmissions, and endogenous dopamine outflow was measured using high-performance liquid chromatography. The incubation of striatal slices with substance P and its N- and C-terminal fragments (1 nM) induced a significant overflow of endogenous dopamine. Neostigmine (150 nM) potentiated the effects of substance P and its fragments, whereas the incubation with hemicholinium-3 (50 microM) abolished the effects of the peptides on dopamine outflow. The acetylcholinesterase inhibitor and the inhibitor of choline uptake did not have intrinsic effects on dopamine outflow. The muscarinic antagonist atropine (1 microM) reversed completely the effects of substance P and its fragments, whereas the nicotinic antagonists dihydro-beta-erythroidine (0.5 microM) and pempidine (10 microM) were devoid of effects. None of the cholinergic antagonists modified dopamine outflow. The results suggest that substance P and several N- and C-terminal substance P fragments activate cholinergic neurons in striatal slices. The released acetylcholine induces an increased dopamine outflow, mediated by muscarinic receptors. These observations represent additional evidence which supports the functional interactions between substance P, acetylcholine and dopamine in the striatum. Furthermore, they show that substance P fragments may exert neuromodulatory effects through mechanisms similar to those underlying the effects of the parent peptide.

Animals↗
PubMed1998

Substance P fragments and striatal endogenous dopamine outflow: interaction with substance P.

Accumulating evidence shows that N- and C-terminal substance P fragments have significant biological activity. Substance P(1-9) and substance P(6-11) have been reported to be major substance P metabolites in rat striatum. We investigated the effects of these fragments on endogenous dopamine outflow in rat striatal slices. Substance P-(1-9) and substance P-(6-11) induced a significant increase in dopamine outflow at 0.1 and 1 nM. The effects of substance P-(6-11) (1 nM) were reversed by the tachykinin NK1 antagonist WIN 51,708 (17beta-hydroxy-17alpha-ethynyl-5alpha-androstano[3,2- b]pyrimido[1,2-a]benzimidazole) (2.5 nM), whereas the effects of substance P-(1-9) were not modified by the antagonist. Substance P-(1-9) and substance P-(6-11) (1 nM) did not increase the dopamine overflow induced by 25 mM KCI. The effects of the two fragments were reversed by the muscarinic antagonist atropine (1 microM) but not by nicotinic antagonists dihydro-beta-erythroidine (0.5 microM) and pempidine (10 microM). The co-incubation of tissue with substance P and each fragment in a 1/1 or 10/1 ratio of substance P to metabolite revealed a negative interaction between parent and fragments. A similar pattern was observed when substance P was co-administered with the active fragments substance P(1-4), substance P(1-7), substance P(5-11) and substance P(8-11). The data show that substance P-(1-9) and substance P-(6-11) have modulatory effects similar to substance P. However, the presence of active substance P metabolites does not appear to amplify the signal mediated by the parent peptide.

Animals↗
PubMed2000

Practical and highly enantioselective ring opening of cyclic meso-anhydrides mediated by cinchona alkaloids.

The cinchona alkaloid-mediated opening of prochiral cyclic anhydrides in the presence of methanol leading to optically active hemiesters is described. Very structurally diverse anhydrides are converted into their corresponding methyl monoesters, and either enantiomer can be obtained with up to 99% ee by using quinine or quinidine as directing additive. After the reaction, the alkaloids can be recovered almost quantitatively and reused without loss of enantioselectivity. Additionally, a catalytic protocol which permits the substoichiometric use of quinidine in the presence of easily accessible pentamethylpiperidine (pempidine) is presented.

Anhydrides↗
PubMed1990

Nicotinic modulation of [3H]dopamine release from striatal synaptosomes: pharmacological characterisation.

Presynaptic nicotinic acetylcholine receptors on striatal nerve terminals modulate the release of dopamine. We have compared the effects of a number of nicotinic agonists and antagonists on a perfused synaptosome preparation preloaded with [3H]dopamine. (-)-Nicotine, acetylcholine, and the nicotinic agonists cytisine and 1,1-dimethyl-4-phenylpiperazinium iodide (DMPP), at micromolar concentrations, stimulated the release of [3H]dopamine from striatal nerve terminals. Carbamylcholine was a much weaker agonist. The actions of (-)-nicotine, cytisine, and DMPP were inhibited by low concentrations of the nicotinic antagonists dihydro-beta-erythroidine, mecamylamine, pempidine, and neosurugatoxin; alpha-bungarotoxin was without effect, and extending the time of exposure to this toxin resulted in only very modest inhibition. This pharmacology points to a specific nicotinic receptor mechanism that is clearly distinct from that at the neuromuscular junction. Atropine failed to antagonise the effects of acetylcholine and carbamylcholine, suggesting that no muscarinic component is involved. The nicotinic receptor ligands (-)-[3H]nicotine and 125I-alpha-bungarotoxin bound to specific sites enriched in the synaptosome preparation. Drugs tested on the perfused synaptosomes were examined for their ability to interact with these two ligand binding sites in brain membranes. The differential sensitivity to the neurotoxins alpha-bungarotoxin and neosurugatoxin of the 125I-alpha-bungarotoxin and (-)-[3H]nicotine binding sites, respectively, leads to a tentative correlation of the (-)-[3H]nicotine site with the presynaptic nicotinic receptor on striatal nerve terminals.

Animals↗
PubMed1974

The innervation of the rat cervix and its pharmacology in vitro and in vivo.

1 Contractions of the rat cervix and uterine horns were measured both in vitro and in vivo as changes in luminal perfusion pressure during perfusion at constant flow.2 Spontaneous cervical and uterine horn contractions in vitro were reduced from rats pre-treated with 17beta-oestradiol compared to those ovariectomized only or those pre-treated with 17beta-oestradiol plus progesterone.3 The rat cervix exhibited similar in vitro sensitivities to methacholine, oxytocin, isoprenaline and phenylephrine as did the uterine horns.4 Transmural stimulation produced cervical and uterine horn contractions, which were blocked by hyoscine or tetrodotoxin, suggesting a cholinergic motor innervation. This was supported by histological findings.5In vivo, the injections of propranolol (1.9 x 10(-7) mol/kg) or pempidine (3.2 or 6.4 x 10(-6) mol/kg) were followed by large cervical and smaller uterine horn contractions, suggesting an adrenergic inhibitory tone mediated by beta-adrenoceptors.6 The evidence for a cervical sphincter is discussed.

Acetylcholinesterase↗
PubMed1978

Effect of mecamylamine on the fate of dopamine in striatal and mesolimbic areas of rat brain; interaction with morphine and haloperidol.

1 The effects of the nicotinic cholinoceptor blocking drug, mecamylamine (alone or in combination with morphine or haloperidol) were investigated on the striatal homovanillic acid (HVA) concentration and on the alpha-methyl-p-tyrosine (AMPT)-induced depletion of striatal or mesolimbic dopamine content in the brain of rats. 2 Mecamylamine (2 mg/kg) alone did not alter the striatal HVA concentration, but it reduced the probenecid-induced accumulation of HVA. Mecamylamine pretreatment reduced the morphine- and haloperidol-induced elevation of striatal HVA concentrations. Hexamethonium did not alter the striatal HVA concentration when given alone or in probenecid- or morphine-treated rats, whereas pempidine (8 mg/kg) clearly reduced the probenecid-induced accumulation of HVA in the striatum. 3 Mecamylamine (2 and 8 mg/kg) slowed the rate of AMPT-induced depletion of dopamine from the striatum and mesolimbic area both in the brain of control rats treated with morphine or haloperidol. 4 Mecamylamine slightly prolonged the cataleptic effect of morphine. 5 The results indicate that mecamylamine inhibits the release of dopamine both from the striatal and mesolimbic dopaminergic neurones.

Animals↗
PubMed1981

Effect of nicotinic and muscarinic drugs on amphetamine- and apomorphine-induced circling behaviour in rats.

The effect of drugs modulating the activity of nicotinic or muscarinic cholinergic receptors on the circling behaviour induced by amphetamine and apomorphine in rats with unilateral 6-hydroxydopamine lesion of nigrostriatal dopaminergic pathway was studied. Nicotine (0.2 mg/kg subcutaneously) significantly increased amphetamine-induced circling behaviour and tended to inhibit apomorphine-induced circling behaviour. Mecamylamine and pempidine (both 2 mg/kg intraperitoneally) slightly but significantly depressed the intensity of circling behaviour induced by amphetamine, but failed to modify the induced by apomorphine. Pilocarpine (10 mg/kg intraperitoneally) clearly inhibited both amphetamine- and apomorphine-induced circling behaviour. Unlike pilocarpine, atropine (10 mg/kg intraperitoneally significantly increases the intensity of the circling behaviour induced by amphetamine and also to some extent that induced by apomorphine. Neither hexamethonium (5 mg/kg intraperitoneally) nor methylatropine (1 mg/kg subcutaneously) modified the circling behaviour induced by either amphetamine or apomorphine. The results show that stimulation of central nicotinic and muscarinic receptors may have some opposite effects on the dopamine dependent circling behaviour. The presynaptic nicotinic cholinergic receptors on the terminals of the nigrostriatal dopaminergic neurones, stimulation of which may increase the release of dopamine, might be involved in the action of nicotinic drugs. The muscarinic cholinergic receptors in the striatum and/or in the substantia nigra might be involved in the action of muscarinic drugs.

Amphetamine↗
PubMed1983

Different types of blockade of crustacean acetylcholine-induced currents.

The voltage dependence, concentration dependence, and agonist dependence of blocking and unblocking produced by anticholinergic agents on the ionophoretically activated cholinergic currents of the lobster gastric mill 1 (g.m.1) muscle were examined. Although the ionophoretic technique provides only qualitative information as to blocking mechanisms it is useful in revealing slow components of the blocking action of some drugs. At least two qualitatively different types of voltage-dependent block of the crustacean cholinergic currents were observed. For pempidine, mecamylamine and decamethonium (also chlorisondamine: Lingle, 1983), a slowly developing voltage-dependent block was produced that led to the formation of a stable-blocked state. Recovery from this stable-blocked state is largely dependent on subsequent application of agonist. In contrast, recovery from the voltage-dependent block produced by QX-222, atropine, procaine and curare either proceeds independently of agonist application or occurs too rapidly to be observed by the present methods. Blockade by hexamethonium reveals anomalous voltage dependence, being enhanced over some voltages and relieved with additional hyperpolarization. Blockade by trimetaphan is largely independent of membrane potential except at higher concentrations.

Animals↗
PubMed1983

Evidence for a cholinergic inhibitory feed-back mechanism in the rabbit retina.

The effects of muscarine, atropine and nicotinic antagonists on the light-evoked release of radioactivity from rabbit retinas previously exposed to [3H]choline (Ch) was studied. On the basis of previous experiments, this light-evoked release of total radioactivity was taken as a measure of the light-evoked release of [3H]acetylcholine (ACh) from the cholinergic amacrine cells. Atropine (1 microM) in the presence, but not the absence, of eserine more than doubled the light-evoked release of [3H]ACh. Eserine (30 microM) itself had no significant effect on either the spontaneous resting release or the light-evoked release of [3H]ACh. Muscarine (10 microM) in the presence or absence of eserine reduced the light-evoked release of [3H]ACh from the retina by 50%. This effect of muscarine was blocked by atropine used in the absence of eserine. The nicotinic antagonists pempidine, hexamethonium and gallamine had no significant effect on retinal [3H]ACh release. Strychnine (20 microM), which alone had no effect on retinal [3H]ACh release, abolished the effects of both muscarine and atropine on the light-evoked release of [3H]ACh. Bicuculline (5 microM) did not affect the actions of muscarine or atropine on the light-evoked release of [3H]ACh. Previous experiments had shown that glycine and gamma-aminobutyric acid (GABA) reduce the light-evoked release of [3H]ACh from the retina and that these inhibitory effects are selectively blocked by strychnine (20 microM) and bicuculline (5 microM) respectively. These results suggest the presence in the retina of a cholinergic inhibitory feed-back mechanism which involves a neuronal loop, rather than presynaptic or post-synaptic inhibitory muscarinic receptors on the cholinergic amacrine cells themselves. Our experiments do not provide evidence on the nature of the proposed inhibitory loop, except that it apparently includes a glycinergic or taurinergic (amacrine) cell.

Acetylcholine↗
PubMed1980

The pharmacological profile of the acetylcholine response of a crustacean muscle.

A pharmacological analysis was made of the depolarizing acetylcholine (ACh) response found on the gastric mill I muscles of the crabs Cancer pagurus, Cancer irroratus and Cancer borealis. Acetylcholine, carbamylcholine, trimethylammonium, nicotine, and dimethyl-4-phenyl-piperazinium were effective in producing contractures and depolarizations in these muscles. No response to decamethonium, suberyldicholine, acetyl-beta-methylcholine, carbamyl-beta-methylcholine, pilocarpine and oxotremorine could be detected. High concentrations of muscarinic agonists (10(-4) to 10(-3) M) potentiated and prolonged the ACh iontophoretic response. When the acetylcholinesterase activity was inhibited with neostigmine, or when the response was elicited with carbamylcholine, muscarinic agonists partially inhibited the response. ACh responses were most effectively blocked by vertebrate nicotinic ganglionic antagonists, including dihydro-beta-erythroidine, pempidine, and mecamylamine. alpha-Bungarotoxin was without effect on the ACh response.

Acetylcholine↗
PubMed1980

Ganglionic effect of beta adrenergic receptor blocking agents.

When tested on the isolated sympathetic ganglion of the rat and frog, beta adrenergic blocking agents were found to inhibit synaptic transmission. This effect can be attributed, in some cases, to the aspecific membrane-stabilizing effect of the drugs, and in other instances to a specific ganglionic blocking property of the agents tested. Beta blockers proved to be more potent ganglioplegics than hexamethonium, their effect was in turn surpassed by pempidine and d-tubocurarine. In some cases the duration of the transmission block induced by beta blockers was longer than that of the reference compounds. On basis of the obtained results, it might not be excluded that the antihypertensive effect of beta adrenergic blocking agents involves a ganglionic component.

Action Potentials↗
PubMed1984

Binding of the nicotinic cholinergic antagonist, dihydro-beta-erythroidine, to rat brain tissue.

The nicotinic cholinergic antagonist, dihydro-beta-erythroidine, binds to two sites in rat cortical membranes with dissociation constants of 4 and 22 nM and respective apparent Bmax values of 52 and 164 fmol/mg of protein. Binding to the higher affinity site, defined by the use of 2 nM [3H]dihydro-beta-erythroidine, was saturable, reversible, and susceptible to protein denaturation. Binding was highest in the thalamus and lowest in the spinal cord and showed preferential enrichment in a synaptosomal subfraction of rat brain. Nicotine displaced [3H]dihydro-beta-erythroidine in a stereospecific manner, the (-)-isomer being approximately 6 times more potent than the (+)-isomer. The alkaloid nicotinic agonists, cytisine and lobeline, were potent inhibitors of binding, while acetylcholine in the presence of the cholinesterase inhibitor di-isopropylfluorophosphate was equipotent with (+)-nicotine. Binding was also inhibited by the muscarinic ligands, arecoline, atropine, and oxotremorine. The nicotinic antagonists mecamylamine, hexamethonium, and pempidine were essentially inactive in displacing [3H]dihydro-beta-erythroidine. These findings indicate that dihydro-beta-erythroidine binds to a nicotinic recognition site in rat brain which is neuromuscular, rather than ganglionic, in nature and that such binding is similar in several respects to that seen with nicotinic agonists. Whether such binding is to a nicotinic, as opposed to nicotinic cholinergic, recognition site or to a "common" nicotinic/muscarinic site is an issue that requires further study.

Alkaloids↗