Potential Role of 5HT1C and/or 5HT2 Receptors in the Mianserin-Induced Prevention of Anxiogenic Behaviors Occurring During Ethanol Withdrawal

A single dose of mianserin (a 5HT_1C/5HT₂ antagonist), administered 1 hr, 48 hr, or 7 days before testing, was evaluated for its efficacy in alleviating or preventing the occurrence of anxiogenic behaviors observed during ethanol withdrawal. Other behavioral experiments using selected drug interactions were conducted to examine whether the effect of mianserin was related to a long-term modification of 5-hydroxy-tryptamine (5HT) receptor function. Rats were fed a liquid diet containing 4.5% ethanol for 4 days. They were tested on the elevated plus-maze (EPM) 12 hr (acute withdrawal) and 5 days (protracted withdrawal) after the last ethanol dose. Ethanol withdrawal induced a pattern of “anxiogenic” behavior that consisted of reduced activity (total entries) and a reduced proportion of open arm activity. Mianserin, injected as a single dose given either 1 hr (0.16-5 mg/kg, ip) before testing or given (20 mg/kg, ip) on the morning of the 3rd day of ethanol administration, i.e., 48 hr and 7 days before testing, dose-dependently prevented or reversed the ethanol withdrawal induced reduction in open-arm activity. In contrast, the 5HT₁C/5HT₂ receptor agonist (±)-1-(2,5-dimethoxy-4-iodophenyl)-2-amino-propane HCI (DOI) did not affect behaviors in the EPM in ethanolnaive rats, nor in those undergoing ethanol withdrawal. However, although there was a marked tolerance to DOI-induced body shakes (a measure of 5HT₂ function) during withdrawal, DOI reversed the action of mianserin in the EPM. The 5HT₁ receptor agonist, 5HT₂ receptor antagonist 1-naphthyl-piperazine (1-NP) reduced open-arm activity in ethanol-naive rats and this action was enhanced during withdrawal. 1-NP reversed the effect of mianserin pretreatment and during ethanol withdrawal the dose-response curve of 1-NP was shifted to the left. The behavioral data indicated a reduced efficacy of 5HT₂ receptors during ethanol withdrawal while anxiogenic behaviors are present, whereas stimulation of 5HT_1C receptors appears anxiogenic. These data support the hypothesis that mianserin may alleviate withdrawal anxiety by direct blockade or down-regulation of 5HT_1C receptors.