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 µg/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.These data were presented at the joint meeting of the British Association for Psychopharmacology and the European Behavioural Pharmacology Society held in Cambridge, UK in July 1992 (Cheeta et al. 1992).