Sensitization to 5-HT1C receptor agonist in rats observed following withdrawal from chronic ethanol

Anxiogenic action of m-chlorophenylpiperazine (mCPP), a 5-HT1C receptor agonist, was studied in naive rats and in ethanol-tolerant rats following withdrawal from chronic ethanol administration. The purpose of this investigation was to determine whether a sensitization to mCPP develops during withdrawal from chronic ethanol. Male Long-Evans hooded rats were fed a liquid diet containing 4.5% ethanol or dextrin (as control) for four days. Twelve hours (acute withdrawal) or 4 days (protracted withdrawal) after the last dose of ethanol, rats were injected with saline or mCPP (0.08-5.0 mg/kg) and were tested in the elevated plus-maze 15 min postinjection. A reduction in percent open-arm activity, indicative of anxiogenic behavior, was observed in ethanol-treated rats injected with saline. Administration of mCPP further reduced the percent open-arm entries and time in ethanol-withdrawn rats. An eightfold reduction in maximum effective dose of mCPP was observed during acute ethanol withdrawal as compared to that in naive rats. During protracted ethanol withdrawal the maximum effective dose of mCPP was reduced by 75%. A shift of the mCPP dose-response curve to the left following withdrawal from chronic ethanol may indicate that 5-HT1C receptor sites are more sensitive to the activation by an agonist. This effect may be exploited in developing specific 5-HT1C receptor antagonists for the treatment of ethanol withdrawal symptoms.