PROLONGED DEFICITS IN PRESYNAPTIC SEROTONIN FUNCTION FOLLOWING WITHDRAWAL FROM CHRONIC COCAINE EXPOSURE AS REVEALED BY 5-HTP-INDUCED HEAD-TWITCH RESPONSE IN MICE

Recent in vivo microdialysis studies have indicated that presynaptic d eficits occur in brain 5-HT neurochemistry during cocaine withdrawal. The purpose of the present study was to utilize the head-twitch respon se (HTR) produced by 5-hydroxytryptophan (5-HTP) to investigate the do se- and time-response effects of this deficit. The HTR is considered t o be a sensitive model for activation of central postsynaptic 5-HT2A r eceptors in rodents. Thus, different groups of mice were injected with cocaine twice daily (0, 0.1, 0.5, 2.5, 5 or 10 mg/kg, i.p.) for 7 or 13 days. During HTR testing, at 24h following last injection, the trea ted mice received either 1) no cocaine; 2) their corresponding daily d ose as challenge injection; or 3) a 10 mg/kg challenge dose. In a seco nd series of experiments, extended abstinence studies were performed u nder the conditions of experimental protocols 1 and 2 for both 7 and 1 3-day cocaine (0, 0.5 and 5 mg/kg, twice daily) exposure regimens at 2 4, 48, 72 and 96h following last cocaine injection. In protocol 3, the effects of a 10 mg/kg challenge dose of cocaine were studied followin g prolonged withdrawal from chronic cocaine exposure (0, 0.5, 5 and 10 mg/kg, twice daily for 7 and 13 days) at 24, 96 and 240 h abstinence. In experimental protocol 1 at 24h abstinence in the 7 day exposure gr oup, only lower doses of cocaine (0.5-2.5 mg/kg) significantly attenua ted the 5-HTP-induced HTR. The deficit in 0.5 mg/kg group persisted up to 72h abstinence. Although in the 13 day cocaine exposure groups (ex perimental paradigm 1) mean HTRs were generally reduced, they however failed to attain statistical significance throughout the 96h abstinenc e. In protocol 2 very low challenge doses of cocaine (0.1-0.5 mg/kg) i n their corresponding pretreatment groups significantly reduced the be havior at diverse abstinence intervals in both 7- and 13-day exposure regimens relative to their chronically vehicle-treated controls which had received a vehicle challenge injection during HTR testing. Unlike small doses of cocaine, larger challenge doses (5-10 mg/kg) of the sti mulant potentiated the HTR score at various abstinence periods. Howeve r, the degree of the potentiations are considerably less than the abil ity of acute cocaine administration in enhancing the 5-HTP-induced HTR . The 10 mg/kg challenge injection in experimental protocol 3 at 24h a bstinence in the 7-day exposed mice attenuated the 5-HTP-induced HTR i n 0.5, 5 and 10 mg/kg cocaine-treated groups relative to their chronic vehicle-treated controls receiving a 10 mg/kg challenge cocaine injec tion. The deficit in chronic 10 mg/kg cocaine-exposed mice persisted u p to 240 h postcocaine abstinence. On the other hand, in the 13-day re gimen, the challenge 10 mg/kg dose exhibited significant potentiations at 24h and at 96h for 5 and 0.5 mg/kg chronic cocaine doses respectiv ely, but-it also produced significant deficits in 0.5 and 10 mg/kg chr onic doses of cocaine at 240 h abstinence. Overall, the present result s suggest that enduring deficits occur in presynaptic serotonin neuroc hemistry and serotonergic adaptive mechanisms are exquisitely sensitiv e to chronic administration of low-and high-doses of cocaine.