PHARMACOLOGICAL STUDIES OF THE REGULATION OF CHRONIC FOS-RELATED ANTIGEN INDUCTION BY COCAINE IN THE STRIATUM AND NUCLEUS-ACCUMBENS

Previous work has demonstrated that chronic administration of cocaine induces apparently novel Fos-like transcription factors, termed chroni c Fras (Fos-related antigens), in the rat striatum and nucleus accumbe ns. induction of these proteins is associated with prolonged increases in AP-1 DNA binding activity that parallel the long half-life of the chronic Fras in brain. The goal of the present study was to characteri ze pharmacologically the regulation of chronic Fra induction by cocain e. Chronic Fra induction was examined with respect to the cocaine dose , time course and administration intervals used. Cocaine was found to induce the chronic Fras over widely differing treatment regimens in th e striatum and nucleus accumbens, although clear differences between t he two brain regions were observed. In general, maximal induction occu rred with moderate treatment conditions, with more or less intensive t reatments resulting in lower levels of chronic Fras. The pharmacologic al mechanisms underlying cocaine induction of the chronic Fras were al so investigated. Pretreatment with a DI receptor antagonist, which did not affect chronic Fra levels by itself, attenuated cocaine induction of the chronic Fras in striatum and nucleus accumbens. in contrast, t reatment with a D2 receptor antagonist alone greatly induced chronic F ra levels, with no further increase seen in response to combined treat ment with cocaine. Combined treatment with D1 and D2 receptor agonists , or with amphetamine, led to a strong induction of chronic Fras. Simi larly, repeated treatment with a specific dopamine transporter inhibit or increased chronic Fra levels, whereas treatment with a specific ser otonin or norepinephrine transporter inhibitor failed to produce this effect. These results support an important role for dopaminergic neuro transmission in the induction of chronic Fras by cocaine. Taken togeth er, the results of the present study provide a more complete understan ding of the pharmacological properties underlying cocaine regulation o f the chronic Fras, which will assist in identifying the functional ro le played by these proteins in cocaine action.