CI-943, a potential antipsychotic agent. III. Evaluation of effects on dopamine neuronal activity

• Published in: The Journal of pharmacology and experimental therapeutics Vol. 251; no. 1; pp. 123 - 130
• Main Authors: Meltzer, L T, Christoffersen, C L, Heffner, T G, Freeman, A S, Chiodo, L A
• Format: Journal Article
• Language: English
• Published: United States American Society for Pharmacology and Experimental Therapeutics 01.10.1989
• Subjects: Action Potentials - drug effects; Animals; Antipsychotic Agents - pharmacology; Brain - drug effects; Dopamine - physiology; Dopamine Agents - pharmacology; Dopamine Antagonists; Imidazoles - pharmacology; Male; Neurons - drug effects; Pyrimidines - pharmacology; Rats; Rats, Inbred Strains
• ISSN: 0022-3565; 1521-0103

CI-943 (8-ethyl-7,8-dihydro-1,3,5-trimethyl-1H-imidazo[1,2- c]pyrazolo[3,4-e]pyrimidine) has been identified as a novel potential antipsychotic agent that does not bind to dopamine (DA) receptors. In the present studies, the effects of acute and chronic administration of CI-943 on the electrophysiological activity of A9 and A10 DA neurons were assessed and compared to the effects of DA antagonist antipsychotic drugs. Acute administration of CI-943 did not increase the base-line firing rate (10-20 mg/kg i.p.), did not increase the number of spontaneously active DA neurons (40 mg/kg p.o.) and did not antagonize the effects of apomorphine or amphetamine on A9 or A10 DA neurons (20-40 mg/kg i.p.). A high dose of CI-943 (40 mg/kg i.p.) decreased the firing rate of A9 and A10 DA neurons, an effect that was not antagonized by haloperidol. In contrast, haloperidol increased the base-line firing rate (0.5 mg/kg i.p.), increased the number of spontaneously active DA neurons (0.5 mg/kg p.o.) and antagonized the effects of apomorphine and d-amphetamine on A9 and A10 DA neurons (0.1 mg/kg i.p.). Repeated (21 days) administration of CI-943 (36 mg/kg/day p.o.) did not alter the number of spontaneously active A9 DA neurons but increased the number of active A10 DA neurons. In contrast, repeated administration of haloperidol (0.4 mg/kg/day p.o.) decreased the number of spontaneously active DA neurons in A9 and A10, whereas repeated administration of clozapine (19 mg/kg/day p.o.) decreased the number of active A10 DA neurons but increased the number of active A9 DA neurons.