DEFICITS IN D-FENFLURAMINE-SENSITIVE POOL OF BRAIN 5-HT FOLLOWING WITHDRAWAL FROM CHRONIC COCAINE EXPOSURE

Recent head-twitch response (HTR) studies in mice have indicated that withdrawal from chronic cocaine exposure produces deficits in CNS conv ersion of L-tryptophan to 5-HT. In the present study, the ability of 5 -HT releaser, d-fenfluramine, was utilized to induce the HTR in mice f ollowing abstinence from chronic cocaine exposure. d-Fentluramine-indu ced HTR, is a 5-HT2A receptor-mediated phenomenon and its induction fr equency can be regarded as an indirect but in vivo measure of basal br ain 5-HT concentration. Thus, different groups of mice were injected w ith cocaine twice daily (0, 0.1, 0.5, 2.5, 5 or 10 mg/kg, i.p.) for ei ther 7 or 13 days. At 24 h after last cocaine injection the treated mi ce received d-fenfluramine (5 mg/kg, i.p.) and the induced HTR (mean+/ -SEM) was recorded for the next 30 min. Cocaine attenuated the d-fenfl uramine-induced HTR frequency by 30-37% in the 13-day regimen and sign ificant effects were observed from 0.5 mg/kg dose. At 24 h withdrawal in the 7-day cocaine exposure group, the mean HTR frequencies were att enuated, however, they did not achieve statistical significance. Exten ded abstinence studies (i.e. 24, 48, 72 and 96 h postwithdrawal) from chronic cocaine exposure (0, 0.5 and 5 mg/kg/day for either 7 or 13 da ys) indicated that in the 7-day exposure group, significant reductions (26, 39 and 22%) in HTR frequency occurred at 48, 72 and 96 h followi ng withdrawal from 0.5 mg/kg cocaine, whereas its 5 mg/kg dose failed to induce a significant effect. In the 13-day exposure group significa nt reductions in HTR frequency were observed at 24 h abstinence (27%) for the 0.5 mg/kg cocaine dose and at 24 and 48 h for the 5 mg/kg. Ove rall, these results indicate that abstinence from chronic exposure to cocaine produces enduring deficits in basal 5-HT concentration. Lastly , serotonergic function appears to be uniquely sensitive to chronic ad ministration of low doses of cocaine.