Effects of ICI 169,369, a selective serotonin2 antagonist, in electrophysiological tests predictive of antipsychotic activity

JM Goldstein, LC Litwin, EB Sutton and JB Malick

Department of Pharmacology, ICI Americas Inc., Wilmington, Delaware.

Extracellular single unit recording techniques were used to compare the effects of ICI 169,369, a selective serotonin2 receptor antagonist, with the reference antipsychotic (AP) agents clozapine and haloperidol, in electrophysiological tests that may predict AP activity. ICI 169,369 was found to reverse the inhibitory actions of amphetamine on A9 and A10 dopamine (DA) neurons, a common property shared by other AP drugs, and was comparable in potency to clozapine. In cell population studies, acute treatment with ICI 169,369 (at a low dose only) and clozapine selectively increased the number of spontaneously active A10 DA cells, which was found to correlate with the ability of both these drugs to cause depolarization inactivation (DI) of A10 DA cells after chronic administration. Interestingly, chronic treatment with ICI 169,369 also caused a significant increase in the number of actively discharging A9 DA cells, an effect not predicted on the basis of the acute data. A similar effect was noted for clozapine, although the magnitude did not reach statistical significance. This profile of activity was unlike that of haloperidol, which acutely caused a nonselective increase in the number of active A9 and A10 DA cells, associated with the ability of this agent to cause DI of both A9 and A10 DA cells after chronic treatment. Inasmuch as DI of A10 DA cells may be correlated with AP efficacy whereas DI of A9 DA cells may predict the ability of an AP to cause extrapyramidal side effects, ICI 169,369, like clozapine, may be a potential AP with a reduced likelihood for producing extrapyramidal side effects.

Volume 249, Issue 3, pp. 673-680, 06/01/1989
Copyright © 1989 by American Society for Pharmacology and Experimental Therapeutics