Psychopharmacology communications最新文献

The diurnal light-dark cycle, grouping of animals and spatial organization of the environment may affect the behavioral responses of animals to psychoactive drugs. A method of working with these factors experimentally is described, using a residential maze equipped with photocells for recording activity of groups of animals. Preliminary results show reliable activity measurements are produced which are sensitive to modification by drugs.

The effects of the two enantiomers of butaclamol and of several neuroleptics on the apomorphine-elicited inhibition of synaptosomal tyrosine hydroxylase activity was investigated. The (+) but not the (-) enantiomer of butaclamol reverses the apomorphine-elicited enzyme inhibition. (+) Butaclamol is more potent than the other tested neuroleptics. All the tested neuroleptics reverse the apomorphine-elicited enzyme inhibition but their relative potency differs. Using two criteria, namely the concentrations of neuroleptics required to reverse enzyme inhibition maximally or by 25%, the order of decreasing potency is as follows: (+) butaclamol, fluphenazine, haloperidol, pimozide, chlorpromazine. The results suggest that the reversal of apomorphine-elicited inhibition of synaptosomal tyrosine hydroxylase activity is a valid test model for screening antipsychotic drugs.

Inbred mouse strains exhibit differences in brain cyclic AMP concentrations. In two mouse strains, we have shown that both the tendency for aggressive attack and high brain cyclic AMP content are inherited as recessive traits and that these traits maintain a close association in segregating generations.

Previously, d-lysergic acid diethylamide was found to have a more powerful inhibitory action upon serotonergic (raphe) neurons than upon neurons in areas receiving an identified serotonergic input (e. g., amygdala, ventral lateral geniculate). In the present studies, using microiontophoretic techniques, the relative potencies of 3 indoleamine hallucinogens, psilocin, DMT, and bufotenine were tested upon 5HT neurons in the raphe (presynaptic neurons) and postsynaptic neurons in the ventral lateral geniculate and amygdala of the rat. Psilocin showed the greatest preferential inhibitory effect upon raphe as compared to postsynaptic neurons. DMT was intermdeiate and bufotenine had the least differential activity. This rank ordering correlates with the relative hallucinogenic potencies of these compounds: psilocin greater than DMT greater than bufotenine. The results support the hypothesis that low doses of indoleamine halluciogens act preferentially upon presynaptic serotonin receptors to inhibit raphe neurons, thus releasing postsynaptic neurons from a tonic inhibitory serotonergic influence.

A potent benzodiazepin derivative, clonazepam, was studied over a range of single doses to determine tolerance for the drug. The best tolerated doses were 0.5 and 1 mg. Higher doses were associated with considerable evidence of sedation, more easily detected by clinical questioning and observation than by commonly used self-reporting scales or motor tests.

Nisoxetine, 3-(o-methoxyphenoxy)-3-phenyl-N-methyl-propyl-amine, is a new inhibitor of norepinephrine uptake. Nisoxetine antagonized 6-hydroxydopamine-induced depletion of norepinephrine in mouse heart with an ED50 of 0.9 mg/kg but had no effect on p-chloroamphetamine-induced depletion of serotonin in mouse brain at doses up to 32 mg/kg. Using the antagonism of these depleting agents to estimate inhibition of uptake into noradrenergic and serotoninergic neurons, we compared nisoxetine to several known amine uptake inhibitors. The order of effectiveness in antagonizing 6-hydroxydopamine action was protriptyline greater than desmethylimipramine greater than EXP 561 greater than nisoxetine greater than nortriptyline greater than chlorpheniramine greater than desmethylchlorimipramine greater than imipramine greater than doxepin greater than amitriptyline greater than chlorimipramine, with fluoxetine and its N-demethylated metabolite (103947) having no effect. In blocking p-chloroamphetamine, the order of effectiveness was EXP 561 greater than fluoxetine greater than 103947 greater than chlorpheniramine greater than chlorimipramine, with desmethylchlorimipramine, protriptyline, and nortriptyline having marginal effects and nisoxetine and the other drugs no effect at the highest dose tested, 32 mg/kg. Nisoxetine is thus one of the more potent and specific inhibitors of norepinephrine uptake, differing remarkably from fluoxetine to which it is related structurally.

Preliminary observations in a small animal sample reveal that chronic lithium treatment in rats produced significant changes in the microvillous processes on the cell surface of the choroid plexus. These alterations may be associated with increased intracellular choroidal volume. The type of changes noted by SEM suggest an alteration in movement of water into the extracellular areas of the brain. This basic alteration produced by lithium in the secretory/absorptive capacity of the chorid plexus is probably reversible.

Behavior and whole brain acetylcholine and choline levels were studied in rats following intraventricular administration of hemicholinium-3. There was an 80% decrease in the content of acetylcholine after 2 hours. The depletion was associated with a decreased turnover of acetylcholine and aggressive behavior. The acetylcholine level did not return to control values until 72 hours after injection, when hemicholinium was still detectable as determined by fluorescence assay. Endogenous choline levels as determined by microwave fixation were 22.7 +/- 1.1 nmol g-1 and were unaffected by hemicholinium; however, hemicholinium caused a significant reduction in the postmortem increase in choline.

Racemic methadone hydrochloride was administered to male rats in daily subcutaneous injections of 10-30 mg/kg. Dependence, when assessed by naloxone challenge after 26 days, was quantitatively and qualitatively similar to that previously reported by us for rats implanted with a 75 mg morphine pellet for 72 hours. Abstinence scores in animals pretreated acutely with 10 mg/kg delta 9-THC one hour before naloxone were significantly less than those of a vehicle control group, and wet shakes and gastrointestinal signs of abstinence were blocked. These results extend previous observations of morphine abstinence attenuating properties of delta 9-THC to effects on animals dependent on methadone.