Progressive effects of cocaine on behavior and central amine metabolism in rhesus monkeys: relationship to kindling and psychosis.
Chronic administration of the same dose of cocaine to rhesus monkeys for up to 6 months was associated with progressive alterations in pathological behavior and increased susceptibility to seizures. Monkeys initially displaying prominent hyperactive stereotypic responses for up to 2 months began to demonstrate increasing amounts of inhibitory behavior, consisting of catalepsy, motor inhibition, and abnormal visual tracking and staring. Four of 13 animals developed increasing intensities of lingual-buccal dyskinesias after 10 weeks of chronic cocaine. Animals initially showing no convulsions to a given dose of cocaine eventually developed convulsions to the same dose, and then displayed an increased frequency of convulsions following subsequent injections. Levels of the dopamine metabolite, homovanillic acid (HVA), in the cisternal cerebrospinal fluid were significantly elevated during both excitatory stereotypic and inhibitory syndromes; a similar trend was observed for HVA after probenecid administration. Only the probenecid-induced accumulations of the serotonin metabolite 5-hydroxyindoleacetic acid, following acute cocaine administration, were significantly elevated. The progressive increases in convulsions, dyskinesias, and the inhibitory syndrome did not appear related to alterations in peak levels of cocaine in plasma or CSF, and a pharmacological kindling model is suggested as an alternate explanation of the data. The study extends the current models of stimulant-induced psychoses by highlighting the progressive alterations in behavior and neurological sequelae and in suggesting that this progressive mechanism may also be important in the development of psychosis in man.