Stereospecific reversal of stress-induced anhedonia by mianserin and its (+)-enantiomer.

Chronic sequential exposure to a variety of mild unpredictable stressors has previously been found to depress the consumption of a dilute (1%) sucrose solution and to inhibit food-induced place preference conditioning. In the present study, using a simplified version of the mild stress procedure, the decreased sucrose intake was reversed by chronic (4 weeks) treatment with the atypical antidepressant mianserin. The racemic compound (+/-)-mianserin (5 mg/kg per day) and one of its enantiomers, (+)-mianserin (2.5 mg/kg) were effective in this model; a lower dose of (+/-)-mianserin (2.5 mg/kg), and the other enantiomer. (-)-mianserin (2.5 mg/kg), were ineffective. Vehicle-treated stressed animals were also subsensitive to food reward in the place conditioning procedure: normal place preference conditioning was reinstated by chronic treatment with (+/-)-mianserin (5 mg/kg) or (+)-mianserin, but not by the lower dose of (+/-)-mianserin (2.5 mg/kg) or by (-)-mianserin. Raclopride (100 micrograms/kg) reinstated the decrease in sucrose intake in stressed animals successfully treated with (+/-)- or (+)-mianserin. The results suggest that (+)-mianserin is the active enantiomer in reversing chronic mild stress-induced anhedonia, and further support the hypothesis of a dopaminergic mechanism of antidepressant action in this paradigm.