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 conversion 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 following abstinence from chronic cocaine exposure. d-Fenfluramine-induced HTR, is a 5-HT2A receptor-mediated phenomenon and its induction frequency can be regarded as an indirect but in vivo measure of basal brain 5-HT concentration. 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 either 7 or 13 days. At 24 h after last cocaine injection, the treated mice 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-fenfluramine-induced HTR frequency by 30-37% in the 13-day regimen and significant 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 attenuated, however, they did not achieve statistical significance. Extended 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 days) indicated that in the 7-day exposure group, significant reductions (26, 39 and 22%) in HTR frequency occurred at 48, 72 and 96 h following 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 significant 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. Overall, 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 administration of low doses of cocaine.
Darmani
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Department of Pharmacology, Kirksville College of Osteopathic Medicine, MO 63501, USA.
D000818:Animals; D001921:Brain / Q000378:metabolism*; D003042:Cocaine / Q000008:administration & dosage*; D005277:Fenfluramine / Q000494:pharmacology*; D019416:Head Movements / Q000187:drug effects; D007700:Kinetics; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D012701:Serotonin / Q000172:deficiency*; D018490:Serotonin Agents / Q000494:pharmacology*; D013375:Substance Withdrawal Syndrome / Q000150:complications*
D018490:Serotonin Agents; D005277:Fenfluramine; D012701:Serotonin; D003042:Cocaine