Withdrawal from chronic cocaine administration causes prolonged deficits in L-tryptophan-induced head-twitch response in mice.

Withdrawal from chronic cocaine exposure potentiates the ability of direct 5-HT2A agonists to induce the head-twitch response (HTR) in rodents. This supersensitivity is assumed to be a consequence of cocaine-induced deficits in presynaptic serotonin neurochemistry. The present study utilized the HTR produced by L-tryptophan (TP) to investigate the dose- and time-response effects of cocaine-induced 5-HT deficit. 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 procedure, at 24 h after last chronic injection, treated-mice received either: 1) no cocaine; 2) their corresponding daily dose; or 3) a 10 mg/kg dose. In paradigm 1, the frequency of TP-induced HTR was attenuated in a dose-dependent manner in both chronic cocaine regimens. In paradigm 2, small challenge doses (0.1-2.5 mg/kg) of cocaine in their respective pretreatment groups failed to alter HTR, but larger challenge doses (5 and 10 mg/kg) potentiated the behavior. In paradigm 3, the 10 mg/kg challenge dose potentiated the HTR to a similar degree in both chronically exposed vehicle and various cocaine-treated groups in both treatment regimens. Extended withdrawal studies from cocaine exposure (0, 0.5 and 5 mg/kg twice daily for 7 or 13 days) indicated attenuations in HTR persisted up to 96 h postcocaine abstinence in paradigm 1, whereas paradigm 2 revealed significant attenuations between 48-72 h for 0.5 mg/kg dose; and potentiations for the 5 mg/kg dose persisted throughout the 96 h abstinence. In paradigm 3, no significant effect was observed at 96 h abstinence, but the 10 mg/kg challenge dose significantly potentiated HTR in chronically exposed 10 mg/kg cocaine group 10 days following cocaine abstinence in both exposure regimens. Overall, these results support the notion that chronic cocaine exposure produces prolonged deficits in presynaptic serotonin neurochemistry. Furthermore, serotonergic mechanisms appear to be exquisitely sensitive to chronic administration of both low and high doses of cocaine.