Benzodiazepine withdrawal facilitates the subsequent onset of escape failures and anhedonia: influence of different antidepressant drugs

Abstract

The effect of benzodiazepine (BDZ) withdrawal on escape acquisition and on the behavioral response to two different reinforcing stimuli was investigated. In addition, the influence of antidepressant drugs (AD) differing in their mechanism of action on these behavioral outputs was also evaluated. Rats subjected to withdrawal from a chronic treatment with diazepam (DZM; 2 mg/kg per day, i.p.) during 21 days were subsequently exposed to a brief inescapable shock session (IS) and 48 h later to an active avoidance test. Only withdrawn animals exposed to the IS exhibited enhanced escape failures. In an additional experiment, withdrawn rats were repeatedly administered with vehicle (VEH), desipramine (DMI; 5 mg/kg, i.p.), fluoxetine (FLU; 5 mg/kg, i.p.) or phenelzine (PHEN; 5 mg/kg, i.p.) and subsequently exposed to IS and to active avoidance task. A significant reversal of escape deficit was only observed following DMI and PHEN but not after FLU. Furthermore, withdrawn rats showed a reduced preference for a sexually relevant olfactory cue, this reduced sensitivity was only normalized following DMI but not after the administration of FLU or PHEN. Finally, rats exposed to abrupt cessation of chronic BDZ administration did not exhibit preference for a context previously associated with amphetamine (AMP) under the conditioned place preference (CPP) procedure. All these findings are indicative that BDZ withdrawal facilitates the subsequent occurrence of behavioral changes-escape failures and reduced behavioral response to rewarding stimuli-suggested to parallel important symptoms of human depression. In addition, DMI seems to be much more effective in restoring such behavioral abnormalities as compared to a MAO inhibitor and to a inhibitor of 5-HT uptake.