Functional interaction between serotonin-S2 and dopamine-D2 neurotransmission as revealed by selective antagonism of hyper- reactivity to tryptamine and apomorphine

F Awouters, CJ Niemegeers, AA Megens and PA Janssen

Janssen Research Foundation, Beerse, Belgium.

The functional significance of the interaction between serotonergic and dopaminergic neurotransmission is still uncertain. To document this interaction further, specific behavioral responses of rats to tryptamine and apomorphine were studied. The sequential injection of these agonists, at time intervals with minimal direct behavioral interference, was used to observe response changes with respect to a single challenge. The antagonists haloperidol, ritanserin and risperidone, with known actions on serotonin-S2 (5-HT2) and dopamine-D2 (D2) receptors were used to evaluate effective antagonism of single and sequential challenges. When tryptamine was preceded by an apomorphine challenge the effective doses of the 5-HT2 antagonists ritanserin and risperidone for 50% inhibition of the seizures increased by a factor of 2.5. The dose-response curve of haloperidol remained virtually unchanged, apparently because of the potent dopamine-D2 antagonism associated with these doses which may block the potentiating effect of apomorphine. When apomorphine was preceded by a tryptamine challenge, the total agitation score of the control animals increased by 59% on the average. Haloperidol was equally effective against the enhanced as against the unenhanced apomorphine response. Ritanserin reduced agitation only by the part corresponding to the tryptamine enhancement. Risperidone's activity against the enhanced agitation started at very low doses and was complete at a dose still about 2.5 times lower than that required against the single apomorphine challenge. Mutual enhancement of tryptamine and apomorphine appears to occur even at a time when the behavioral effects of the first agonist are no longer manifest. The enhanced agitation remains largely dopamine-D2-specific and the enhanced seizures serotonin 5-HT2-specific.(ABSTRACT TRUNCATED AT 250 WORDS)

Volume 254, Issue 3, pp. 945-951, 09/01/1990
Copyright © 1990 by American Society for Pharmacology and Experimental Therapeutics