Evidence for alterations in presynaptic serotonergic function during withdrawal from chronic cocaine in rats

The effects of repeated cocaine administration on serotonin (5-hydroxytryptamine, 5-HT) function were investigated by comparing the corticosterone response to 5-HT receptor agonists in cocaine-treated and vehicle-treated rats. Male rats were fitted with indwelling jugular catheters and received cocaine (15 mg/kg i.p., b.i.d.) or saline for 7 days. Rats were challenged with either saline, the 5-HT releaser fenfluramine (1.2 mg/kg i.v.), the 5-HT1A receptor agonist 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT; 50 micrograms/kg i.v.), or the 5-HT2A/2C receptor agonist 1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI; 100 micrograms/kg i.v.) 42 h and 8 days after the final chronic treatment. Repeated blood samples were withdrawn immediately before and at 15, 30 and 60 min after acute challenge injections. All 5-HT receptor agonists increased plasma corticosterone, but the fenfluramine-induced rise in corticosterone was significantly attenuated in cocaine-treated rats withdrawn for 42 h. This blunted response to fenfluramine exhibited only partial recovery when examined at 8 days postchronic treatment. Corticosterone responses to 8-OH-DPAT and DOI were not affected by cocaine exposure. Our data suggest that chronic cocaine produces deficits in presynaptic 5-HT function, and alterations in 5-HT neurotransmission may underlie the dysphoria experienced by abstinent cocaine users. Neuroendocrine challenge tests should be performed in human addicts to evaluate potential 5-HT dysfunction associated with cocaine abuse.