International journal of neuropharmacology最新文献

Ten isomers of known central nervous system stimulants were examined for ability to lower chenaoconvulsive threshold. In addition, the involvement of endogenous brain catecholamines in the central activity of these compounds was investigated. The drugs evaluated were d(+) amphetamine,l(−) amphetamine,d(+) pipradrol,l(−) pipradrol,d(−) ephedrine,l(+) ephedrine,d(−)pseudophedrine,l(+)pseudophedrine,d(−) norephedrine, andl(+) norpseudophedrine. All compounds exceptl(−) pipradrol andd(−)pseudoephedrine demonstrated significant effects on chemoconvulsive threshold. The active isomers of amphetamine and ephedrine were shown to possess large indirect components of activity in that central stimulation with these agents was dependent upon small stores of readily available catecholamines. However,d(+) pipradrol and the isomers of norephedrine appeared to have a considerable amount of direct effect on central receptors. No structure-activity relationship for central stimulation was readily apparent.

Lesions were electrolytically placed in the septal area and/or hypothalamus of male albino rats using a stereotaxic instrument and well-defined co-ordinates. The effect of various types of pharmacological agents on the induced hyper-reactivity has been determined. All classes of compounds tested reduced to varying degrees the hyper-reactivity produced by septal lesions. Chlorpromazine and morphine also reduced the hyper-reactivity of rats with hypothalamic and hypothalamic-septal lesions, though only to a limited extent. Possible mechanisms and sites of action are discussed.

The relationship between brain monoanunes and the behavioral effect ofp-chlorophenylalanine in mice and rats was investigated. When brain serotonin was depleted byp-chlorophenylalanine spontaneous motor activity was decreased only in rats. Administration ofp-chlorophenylalanine changed neither the brain levels of catecholamines in both species nor the turnover rate of brain norepinephrine and dopamine in rats. These results suggest that the decrease of spontaneous motor activity afterp chlorophenylalanine administration is probably not mediated through serotonin or the catecholamines and that another mode ofp-chlorophenylalanine action must be supposed.

Ethanol was administered i.p, to rats 1 hr prior to sacrifice and 5-HTP-¹⁴C was administered i.p. 30 min prior to sacrifice. Multiple doses of ethanol increased 5-HTP-¹⁴C found in the brain, possibly due to decreased efflux. Multiple doses of ethanol also increased the ratio of 5-hydroxyindoleacetaldehyde and/or 5-hydroxytryptophol to 5-HIAA. The possibility was considered that the increased neutral fraction and decreased acid fraction was due to inhibition of aldehyde dehydrogenase and activation of alcohol dehydrogenase by virtue of an ethanol-induced increase in brain NADPH/NADP ratio. High doses of ethanol, 6 lg/kg, slightly inhibited decar☐ylase and monoamine oxidase. The possibility was considered that inhibition of decar☐ylase and monoamine oxidase was due to acetaldehyde derived from ethanol

Microinjections ofd-tubocurarine chloride (d-Tc) were made into the hypothalamus of cats through a stereotaxically implanted cannula-electrode to reproduce the effects of intraventricular doses (100–200 μg/kg) ofd-Tc. Single intrahypothalamic injections of 3–6 μg caused rise of blood pressure, stimulation of respiration and enhancement of knee jerk and produced tremor and jerks in most of the experiments. After a delay of 10–15 min the electrical activity of the injected site changed with the appearance of high voltage waves and spikes which were found to spread to other areas recorded. The effects of similarly low intraventricular doses were comparatively much less in incidence and intensity. Thus the hypothalamus appeared to be the site of origin ofd-Tc-induced autonomic and motor effects, and abnormal electrical activity. The effects of intrahypothalamic doses ofd-Tc were poorly counteracted by Prostigmin.

Administration of α-MT (four separate doses of 50 mg/kg with 4 hr interval between each injection) lowered the body temperature of rats. Hyperthermic effects induced by CPZ injection into the anterior part of hypothalamus persist in animals pretreated with α-MT. It is suggested therefore that the mechanism for the hyperthermic action of CPZ is more likely to be due to a direct effect of CPZ than with its interaction with NA.

The effect of stereotaxic administration of tremorine and oxotremorine into four brain areas has been investigated using rats. Tremorine produced tremor significantly higher than control after administration into the globus pallidus, caudate nucleus, and substantia nigra. Oxotremorine produced tremor significantly higher than control only after injection into the substantia nigra. Dyflos injected into the caudate nucleus produced tremor. No change in the tremorgenic action of tremorine was observed after the simultaneous intracaudate injections of atropine and tremorine, and dyflos and tremorine. Intraperitoneal atropine reduced the tremorgenic action of an intracaudate injection of tremorine.

The rate of disappearance of amphetamine is faster in male adult Sprague-Dawley rats than in adult females. Estradiol (0·8 mg/kg s.c. for 16 days) slow down the rate ofd-amphetamine disappearance in adult male rats. The half-life (T12) ofd-amphetamine in young male rats is greater than in adult male or female rats. Pretreatment of rats with either phenobarbital or 3-methylcholanthrene in doses sufficient to decrease theT₁₂ of hexobarbital and zoxazolamine does not change the tissue levels ofd-amphetamine. Diphenylhydantoin, another inducer of liver microsomal aromatic hydroxylase, does not increase and actually decreases the rate ofd-amphetamine disappearance.

Chicks (1–5 day-old) were made hyperactive and aggressive with the tricyclic antidepressant, imipramine hydrochloride. Norepinephrine (NE), which crosses the bloodbrain barrier to produce behavioral depression in the chick (in a monotonic, dose-response manner) antagonized the behavioral effects of imipramine. Associated with this behavioral antagonism was a relative decrease in the radioactivity of brain normetanephrine and 3-methoxy-4-hydroxymandelic acid when isotopic NE was infused following imipramine pretreatment. This suggests that imipramine may block the access of NE to the post-synaptic membrane as well as interfering with other aspects of NE inter- and intracellular mobility. The differences from the previous literature shown in this study may be due to species differences or the failure of other studies to achieve behavioral activation with imipramine before doing biochemical studies.

Levels of 5HIAA and HVA have been measured in the lumbar CSF of psychiatric patients. Pre-treatment values for CSF 5HIAA were lower in a combined group of psychiatric patients age matched with neurologic patients as controls. CSF 5HIAA was lower than in age matched neurologic controls in each psychiatric diagnostic sub-group; however, these differences were significant prior to treatment in the schizophrenic group only. Depressives treated with amitriptyline showed significant decreases in CSF 5HIAA. There were no significant correlations between degree of improvement in depression (as rated with the BPRS) and CSF 5HIAA levels while patients were improved and continuing on the drug. Further, no correlations were noted between values or changes in either CSF amine metabolite and initial ratings or changes in BPRS ratings as a result of treatment. Values for HVA tended to be higher in schizophrenics and lower in manics and depressives than for a combined psychiatric group, although this difference was significant only for depressives vs. schizophrenics while on drug therapy. Groups of patients scoring above the median on total sleep ratings were also found to have significantly above median HVA scores prior to treatment.