Effect of chronic antidepressant treatment and subsequent withdrawal on [3H]-5-hydroxytryptamine and [3H]-spiperone binding in rat frontal cortex and serotonin receptor mediated behaviour

Abstract

Changes in [3H]-5HT and [3H]-spiperone binding in vitro and ex vivo following withdrawal from chronic administration of certain antidepressants and the 5HT antagonist metergoline were compared with changes in 5-methoxy-N′,N′-dimethyltryptamine (5MEODMT, 2.5 mg/kg) induced behaviour following acute, chronic and withdrawal from chronic treatment with the same drugs. In vitro metergoline, amitriptyline, imipramine and chlorimipramine displaced [3H]-5HT and [3H]-spiperone binding in that order of potency. Iprindole weakly blocked only [3H]-spiperone binding while fluoxetine had no effect on either ligand at concentrations up to 100 μm. Following 72h withdrawal from 14 days chronic treatment ex vivo [3H]-5HT binding was unaffected by any of the drugs, while fluoxetine (15 mg/kg), chlorimipramine (15 mg/kg) and iprindole (15 mg/kg) significantly reduced [3H]-spiperone binding. The 5MEODMT behavioural response was attenuated by metergoline (2 mg/kg) and amitriptyline (15 mg/kg) (Stolz and Marsden 1982) and by iprindole (15 mg/kg) and imipramine (15 mg/kg). Neither fluoxetine (2 mg/kg) nor chlorimiprmaine (15 mg/kg) altered the behavioural response. After 14 days chronic treatment metergoline, amitriptyline, chlorimipramine, fluoxetine and imipramine significantly reduced the 5MEODMT response while the reduction with iprindole did not reach significance. When further tested after 72h withdrawal from chronic treatment fluoxetine-and chlorimipramine-treated rats showed a significantly reduced response, imipramine-treated rats an increased response, while those given iprindole showed no significant change. The results suggest that decreased functional responsiveness observed following treatment with 5HT uptake blockers corresponds with changes in [3H]-spiperone but not [3H]-5HT binding. In contrast the enhanced functional response on withdrawal from metergoline, amitriptyline (Stolz and Marsden 1982) or imipramine does not correlate with changes in the binding of either ligand.