CI-943, a potential antipsychotic agent. III. Evaluation of effects on dopamine neuronal activity.
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.(ABSTRACT TRUNCATED AT 250 WORDS)
Meltzer
L T
LT
Parke-Davis Pharmaceutical Research Division, Warner-Lambert Co., Ann Arbor, Michigan.
Christoffersen
C L
CL
Heffner
T G
TG
Freeman
A S
AS
Chiodo
L A
LA
D000200:Action Potentials / Q000187:drug effects; D000818:Animals; D014150:Antipsychotic Agents / Q000494:pharmacology*; D001921:Brain / Q000187:drug effects; D004298:Dopamine / Q000502:physiology*; D015259:Dopamine Agents / Q000494:pharmacology; D018492:Dopamine Antagonists; D007093:Imidazoles / Q000494:pharmacology*; D008297:Male; D009474:Neurons / Q000187:drug effects*; D011743:Pyrimidines / Q000494:pharmacology*; D051381:Rats; D011919:Rats, Inbred Strains
D014150:Antipsychotic Agents; D015259:Dopamine Agents; D018492:Dopamine Antagonists; D007093:Imidazoles; D011743:Pyrimidines; C061283:CI 943; D004298:Dopamine