Differential expression of c-fos and zif268 in rat striatum after haloperidol, clozapine, and amphetamine.
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Antipsychotic drugs are monoamine receptor antagonists. However, the mechanisms by which these direct actions are translated into therapeutic effects are unknown. Candidate mechanisms include receptor-mediated regulation of gene expression in target neurons. Inducible transcription factors, including certain immediate early genes (IEGs), may mediate between receptor-activated second messenger systems and expression of genes involved in the differentiated functions of neurons. We examined the specificity of induction of the IEGs c-fos and zif268 after acute administration of several antipsychotic drugs and, for comparison, the stimulant amphetamine, which has pharmacologic effects relatively opposite to those of antipsychotics. Antipsychotic drugs with potent dopamine D2 receptor antagonist properties, such as haloperidol, induced both c-fos and zif268 mRNA in the caudate-putamen; however, the atypical antipsychotic drug clozapine induced zif268 but not c-fos mRNA in that region. Similarly, haloperidol, but not clozapine, induced c-Fos-like immunoreactivity in the caudate-putamen. In contrast, both drugs induced c-Fos-like immunoreactivity in the nucleus accumbens. Like haloperidol, amphetamine induced both c-fos and zif268 mRNA in the caudate-putamen, but the anatomic patterns of induction of c-Fos-like immunoreactivity by the two drugs were dramatically different. Haloperidol and amphetamine induced AP-1 binding activity in cell extracts from the caudate-putamen, indicating that drug-induced IEG expression results in protein products that may function in the regulation of target gene expression. Thus these data demonstrate that inductions of IEG expression by haloperidol, clozapine, and amphetamine are specific, may be biologically relevant, and suggest avenues for further investigation. (+info)
Controlled observations on the single case.
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Valuable information can be gained from studies of a single case, provided bias on the part of physician and patient can be minimized. Use of the double-blind method achieves this. Some pitfalls in such studies are mentioned, and it is emphasized that skill, judgment and knowledge all play a part in the design and interpretation of investigations of this nature. As an example, a trial of three analeptics in the treatment of a narcoleptic patient, using a simple rating scale, is described. (+info)
d-Amphetamine-chlorpromazine antagonism in a food reinforced operant.
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Dose effect curves for d-amphetamine and chlorpromazine were obtained with rats on a milk reinforced FR 10 schedule. A dose of d-amphetamine (2.5 mg/kg, i.p.) which completely suppressed all responding for 60 min was administered simultaneously (concomitant with the pretreatment times) with various doses of chlorpromazine. The d-amphetamine-induced cessation of responding was removed by several of the doses of chlorpromazine with maximal antagonism occurring at a dose of 1.5 mg/kg i.p. This dose of chlorpromazine, when administered independently, produced no observable side effects and showed no effect on the FR 10 schedule. One animal appeared to develop tolerance to the repeated dosages of d-amphetamine. (+info)
Evidence for a competitive antagonism of guanethidine by dexamphetamine.
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After guanethidine had blocked the response of the cat nictitating membrane to sympathetic nerve stimulation, dexamphetamine restored the responses to all frequencies of stimulation. Dexamphetamine antagonized the sympathetic nerve block by guanethidine in the isolated sympathetically innervated rabbit ileum; the evidence suggests that the antagonism was competitive. Dexamphetamine antagonized the sympathetic nerve block by guanethidine in the isolated hypogastric nerve-vas deferens preparation of the guinea-pig. Doses of dexamphetamine, larger than those required to antagonize the blocking action of guanethidine, abolished the responses of the nictitating membrane, ileum and vas deferens to nerve stimulation. Dexamphetamine did not influence the depletion of noradrenaline by guanethidine in the heart and spleen of rabbits. The hypothesis is advanced that both dexamphetamine and guanethidine act on the store of noradrenaline at sympathetic nerve endings. (+info)
TACHYPHYLAXIS TO SOME SYMPATHOMIMETIC AMINES IN RELATION TO MONOAMINE OXIDASE.
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Tachyphylaxis to the effects of indirectly acting sympathomimetic amines has been studied on the blood pressure of the cat, rabbit and rat, on the cat spleen and nictitating membrane and on the rabbit heart. The pressor responses to tyramine and to phenethylamine declined slowly with repeated injection; the extent of tachyphylaxis induced by these amines depended on the dosage and on the frequency of injection. The pressor responses to alpha-methyltyramine and to dexamphetamine (alpha-methylphenethylamine) declined rapidly with successive injections. The tachyphylaxis induced by one indirectly acting sympathomimetic amine is crossed to others, but not to directly acting amines, such as noradrenaline. In animals treated with nialamide, a drug which inhibits monoamine oxidase, the tachyphylaxis induced by tyramine and by phenethylamine was similar to that produced by their alpha-methyl derivatives in normal animals. Similar results were obtained when the responses to indirectly acting sympathomimetic amines were studied on the cat spleen in situ and on the rabbit heart in vitro. Indirectly acting sympathomimetic amines impaired the responses of the cat nictitating membrane to sympathetic nerve stimulation; this effect was most evident with alpha-methylated amines. (+info)
MUTUAL POTENTIATION OF AMPHETAMINE AND AMYLOBARBITONE MEASURED BY ACTIVITY IN RATS.
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Dose/response relations have been analysed for the actions of amphetamine-barbiturate mixtures on exploratory activity and ataxia in rats. Amphetamine sulphate and amylobarbitone sodium were studied separately and together (in a constant ratio of 1:20) in doses which ranged from those producing no effect to those which incapacitated the animals. Dexamphetamine and amylobarbitone were similarly studied in a ratio of 1:6.5; this corresponds to the ratio of a commercial preparation, Drinamyl. The results showed that mixtures could stimulate exploratory activity and their maximal effects were much greater than the effects produced by any dose of the separate drugs. The maximal effect with the first dose-ratio included conspicuous ataxia, but the maximal effect with the second ratio did not. Further experiments in which the dose of one drug was held constant and that of the other was varied showed that maximal effects on activity could be obtained with mixtures of dexamphetamine and amylobarbitone. Equivalent effects could be obtained both with relatively small and with relatively large amounts of the two drugs, in varying ratios; some constituent doses of the individual drugs were found to be optimal; whether the mixture effect was accompanied by ataxia depended largely on the constituent amount of barbiturate. For practical purposes mixtures producing maximal effects on activity with the smallest amounts of both drugs and not accompanied by ataxia might be most desirable, and these can be approximately read off from an isobol plotted from the results. It was concluded that the marked stimulant effects of the amphetamine-barbiturate mixtures on activity of rats could be regarded as due to true potentiation. (+info)
ACTION OF DEXAMPHETAMINE ON 5-HYDROXYTRYPTAMINE RECEPTORS.
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Dexamphetamine contracted isolated preparations of rat stomach, dog retractor penis, rabbit aorta, rabbit uterus and all sections of guinea-pig ileum. Adrenaline inhibited rat stomach and all but the terminal 10 cm of guinea-pig ileum, but contracted dog retractor penis, rabbit aorta, rabbit uterus and the terminal portion of the guinea-pig ileum. 5-Hydroxytryptamine contracted all five preparations. Responses to dexamphetamine and 5-hydroxytryptamine were not blocked in preparations protected by a high concentration of either drug during exposure to phenoxybenzamine in a dose which usually caused block. Responses to dexamphetamine and 5-hydroxytryptamine were blocked in preparations protected by adrenaline. Responses to dexamphetamine in dog retractor penis, rabbit aorta and rabbit uterus were not reduced in preparations from animals treated with reserpine or after cocaine, indicating that the contraction is not mediated by released noradrenaline. It is concluded that dexamphetamine acts directly on 5-hydroxytryptamine receptors in these smooth muscles and therefore cannot be regarded as a true sympathomimetic amine. (+info)
PREGANGLIONIC AND POSTGANGLIONIC STIMULATION OF THE GUINEA-PIG ISOLATED VAS DEFERENS PREPARATION.
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The isolated vas deferens of the guinea-pig contracted when stimulated transmurally with parallel wire electrodes. These contractions persisted in concentrations of hexamethonium, pentolinium, nicotine and mecamylamine which at the same time abolished the responses to hypogastric nerve stimulation. Procaine and lignocaine in local anaesthetic concentrations abolished the responses to transmural stimulation but potentiated the contractions produced by added noradrenaline. Guanethidine and bretylium in concentrations specific for adrenergic neurone blockade abolished the contractions due to transmural stimulation without impairing the responses of the muscle to added noradrenaline or acetylcholine. In contrast, high concentrations of the adrenergic-blocking agents phentolamine and dihydroergotamine were needed to block the contractions due to transmural stimulation; these concentrations also blocked the response to added noradrenaline but simultaneously reduced the responses to added acetylcholine or potassium chloride. Preparations from guinea-pigs previously treated with reserpine at first responded normally to transmural stimulation; thereafter the contractions diminished progressively but were never abolished. Hyoscine and atropine produced a small decrease in the response to transmural stimulation when present in concentrations up to 1x10(-5) and a larger decrease only in concentrations of 1x10(-4) or greater. Hemicholinium produced a small decrease of the contractions due to transmural stimulation in concentrations up to 1x10(-4); concentrations of 5x10(-4) present for 1 hr produced only a slightly greater reduction in response. These experiments show that when the guinea-pig vas deferens is removed without the hypogastric nerve and stimulated transmurally by the method described, contractions are produced mainly by excitation of postganglionic adrenergic nerves. (+info)