Comparison of the effects of d-para-methoxyamphetamine (d-PMA) and chlorimipramine on the uptake and release of [3H]5-hydroxytryptamine ([3H]5-HT) in brain tissues slices in vitro revealed that d-PMA was equipotent to chlorimipramine in inhibiting the uptake of [3H]5-HT and was much more potent than chlorimipramine in increasing the release of radioactivity from slices preloaded with [3H]5-HT. The results indicate that the increased release of [3H]5-HT by d-PMA is not due to the inhibition of reuptake of [3H]5-HT. Intraventricular injection of [3H]5-HT was given 30 min before the beginning of ventricular perfusion with artificial cerebrospinal fluid in anesthetized rats. dPMA, 2 and 4 mg/kg i.v., increased the 3H-radioactivity in the perfusate after injection. Higher doses of d-amphetamine (5 and 10 mg/kg i.v.) also increased the release of 3H-radioactivity. Addition of d-PMA and d-amphetamine into the artificial cerebrospinal fluid during the perfusion also increased the release of radioactivity into the perfusate and d-PMA was found to be more potent than d-amphetamine. Thin-layer chromatographic analysis of the perfusate taken before and after the administration of d-PMA and d-amphetamine revealed increased amounts of radioactivity in 5-HT and the ratio of [3H]5-HT to [3H]5-hydroxyindole-acetic acid was increased after d-PMA and d-amphetamine. d-PMA was much more effective than d-amphetamine in this respect. Chlorimipramine injected 20 min before the injection of d-PMA completely blocked the increased release of 3H-radioactivity and [3H]5-HT induced by d-PMA. With perfused brain slices which were preincubated with [3H]5-HT, chlorimipramine also prevented the release of radioactivity produced by d-PMA. In behavioral studies, chlorimipramine reduced the disruption of fixed-ratio responding induced by d-PMA but not by d-amphetamine. In addition, the increased locomotor activity and myoclonic twitch activity of suprahyoideal muscle induced by PMA were also blocked by pretreatment with chlorimipramine. Since these behavioral and pharmacological effects induced by PMA have previously been suggested to involve the serotonergic system, it is proposed that chlorimipramine blocks the effects of PMA by preventing the PMA-induced release of 5-HT in the central nervous system.
|Original language||English (US)|
|Number of pages||12|
|Journal||Journal of Pharmacology and Experimental Therapeutics|
|State||Published - Jan 1 1978|