INFLUENCE OF OLFACTORY BULBECTOMY AND SUBSEQUENT IMIPRAMINE TREATMENTON 5-HYDROXYTRYPTAMINERGIC PRESYNAPSES IN THE RAT FRONTAL-CORTEX - BEHAVIORAL-CORRELATES

1 Alterations of 5-hydroxytryptaminergic mechanisms are thought to pla y a special role in the pathogenesis of depression and antidepressant treatments are assumed to restore these changes. 2 We have used one of the most reliable models of depression, the olfactory bulbectomized r at to study the long term consequences of this manipulation and of sub chronic imipramine treatment on two parameters of 5-hydroxytryptaminer gic presynapses, 5-hydroxytryptamine (5-HT) transporter density and tr yptophan hydroxylase apoenzyme concentration, in the frontal cortex as well as on active avoidance learning several weeks after bulbectomy. 3 The B-max value of [H-3]-paroxetine binding and the concentration of the 5-HT synthesizing enzyme were both significantly elevated in the frontal cortex of bulbectomized rats compared to sham-operated control s. 4 Imipramine treatment, either by daily injections or by subcutaneo us implantation of slow release imipramine-containing polymers reduced the elevated tryptophan hydroxylase apoenzyme levels in the frontal c ortex of bulbectomized, but not of sham-operated control rats and rest ored the deficient learning performance of bulbectomized rats. 5 Both effects were more pronounced after continuous drug administration by i mipramine-releasing polymers compared to daily i.p. injections. 6 Thes e findings indicate that bulbectomy leads to a compensatory 5-hydroxyt ryptaminergic hyperinnervation of the frontal cortex. Chronic antidepr essant treatment seems to attenuate the increased output of the 5-hydr oxytryptaminergic projections in the frontal cortex through the destab ilization of the rate limiting enzyme of 5-HT synthesis of the 5-hydro xytryptaminergic nerve endings in this brain region.