Effects of Chronic Antidepressants in an Operant Conflict Procedure of Anxiety in the Rat

Abstract

The effects of chronic antidepressants were investigated in an animal procedure for the study of anxiety and anxiolytics, the conditioned suppression of operant behavior in rats. In daily 18-min sessions, three periods of nonpunished lever pressing for food alternated with two 4-min periods signaled by a light-on conditioned stimulus during which 50% of the responses were randomly punished by electric foot shocks. Antidepressants were administered once daily for 7–8 weeks to trained, food-restricted rats. Desipramine (dose regimen increase from 4 to 16 mg/kg/day) induced a gradual (4–5-week latency) release of response suppression during punished periods over the course of several weeks of testing. This anxiolytic-like effect was still present 3 weeks following drug discontinuation. In contrast, chronic imipramine (dose regimen increase from 4 to 16 mg/kg/day), maprotiline (4 to 16 mg/kg/day), phenelzine (2 to 4 mg/kg/day), and fluoxetine (1 or 8 mg/kg/day; constant dose), resulted in no change in punished responding, suggesting that no anxiolytic-like effect developed in the course of chronic treatment with these compounds. The largest dose of all antidepressants studied (except fluoxetine) induced a moderate to marked reduction of nonpunished performance that disappeared within 1 week after the last injection. A transient release of conditioned response suppression emerged during the week that followed discontinuation of imipramine, maprotiline, and fluoxetine (8 mg/kg/day). This apparent anxiolytic-like activity might be due to a reduction of some adverse effect induced by the high doses used, and/or might have resulted from a new dynamic equilibrium between monoamine release, reuptake processes, and sensitivity of postsynaptic receptors. In conclusion, operant conflict procedures in rats seem not particularly able to model human anxiety sensitive to chronic antidepressant treatments.