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 deficits occur in brain 5-HT neurochemistry during cocaine withdrawal. The purpose of the present study was to utilize the head-twitch response (HTR) produced by 5-hydroxytryptophan (5-HTP) to investigate the dose- and time-response effects of this deficit. The HTR is considered to be a sensitive model for activation of central postsynaptic 5-HT2A receptors 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 24 h following last injection, the treated mice received either 1) no cocaine; 2) their corresponding daily dose as challenge injection; or 3) a 10 mg/kg challenge dose. In a second series of experiments, extended abstinence studies were performed under the conditions of experimental protocols 1 and 2 for both 7- and 13-day cocaine (0, 0.5 and 5 mg/kg, twice daily) exposure regimens at 24, 48, 72 and 96 h following last cocaine injection. In protocol 3, the effects of a 10 mg/kg challenge dose of cocaine were studied following 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 24 h abstinence in the 7 day exposure group, only lower doses of cocaine (0.5-2.5 mg/kg) significantly attenuated the 5-HTP-induced HTR. The deficit in 0.5 mg/kg group persisted up to 72 h abstinence. Although in the 13 day cocaine exposure groups (experimental paradigm 1) mean HTRs were generally reduced, they however failed to attain statistical significance throughout the 96 h abstinence. In protocol 2 very low challenge doses of cocaine (0.1-0.5 mg/kg) in their corresponding pretreatment groups significantly reduced the behavior 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 stimulant potentiated the HTR score at various abstinence periods. However, the degree of the potentiations are considerably less than the ability of acute cocaine administration in enhancing the 5-HTP-induced HTR. The 10 mg/kg challenge injection in experimental protocol 3 at 24 h abstinence in the 7-day exposed mice attenuated the 5-HTP-induced HTR in 0.5, 5 and 10 mg/kg cocaine-treated groups relative to their chronic vehicle-treated controls receiving a 10 mg/kg challenge cocaine injection. The deficit in chronic 10 mg/kg cocaine-exposed mice persisted up to 240 h postcocaine abstinence. On the other hand, in the 13-day regimen, the challenge 10 mg/kg dose exhibited significant potentiations at 24 h and at 96 h for 5 and 0.5 mg/kg chronic cocaine doses respectively, but it also produced significant deficits in 0.5 and 10 mg/kg chronic doses of cocaine at 240 h abstinence. Overall, the present results suggest that enduring deficits occur in presynaptic serotonin neurochemistry and serotonergic adaptive mechanisms are exquisitely sensitive to chronic administration of low- and high-doses of cocaine.
Darmani
N A
NA
Department of Pharmacology, Kirksville College of Osteopathic Medicine, MO, USA.
Shaddy
J
J
Elder
E L
EL
D006916:5-Hydroxytryptophan / Q000494:pharmacology*; D000818:Animals; D003042:Cocaine / Q000009:adverse effects*; D018765:Dopamine Uptake Inhibitors / Q000009:adverse effects*; D004305:Dose-Response Relationship, Drug; D019416:Head Movements / Q000187:drug effects*; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D017661:Receptors, Presynaptic / Q000502:physiology*; D012701:Serotonin / Q000502:physiology*; D013375:Substance Withdrawal Syndrome / Q000503:physiopathology*
D018765:Dopamine Uptake Inhibitors; D017661:Receptors, Presynaptic; D012701:Serotonin; D006916:5-Hydroxytryptophan; D003042:Cocaine