REPEATED ADMINISTRATION OF DESIPRAMINE AND A GABA(B) RECEPTOR ANTAGONIST, CGP-36742, DISCRETELY UP-REGULATES GABA(B) RECEPTOR-BINDING SITESIN RAT FRONTAL-CORTEX

1 GABA(B) receptor binding site densities within laminar regions of th e rat frontal cortex were examined autoradiographically following repe ated administration (21 days) of the antidepressants desipramine, paro xetine and amitriptyline in addition to the GABA(B) receptor antagonis ts, CGP 35348 and CGP 36742. Beta1-adrenoceptor autoradiography was st udied in parallel with that for GABA(B) receptor sites. 2 The effects of these compounds were examined concomitantly on the GABA(B) receptor -mediated inhibition of forskolin- and enhancement of noradrenaline-st imulated cyclic AMP production. 3 GABA(B) receptor binding was increas ed by both desipramine (20 mg kg-1, p.o. and 10 mg kg-1, i.p.) and CGP 36742 (100 mg kg-1, i.p.) in the outer laminar region of the frontal cortex by around 50% above control levels. Conversely, no significant changes were mediated by paroxetine, amitriptyline, CGP 35348 or the G ABA(B) receptor agonist, baclofen. 4 With the exception of paroxetine, all compounds down-regulated the total beta-adrenoceptor population t hroughout frontal cortical laminae which was attributable to the beta1 -adrenoceptor subtype. In contrast, the reduction in beta-adrenoceptor s mediated by CGP 35348 and CGP 36742 did not occur as a consequence o f reduced beta1-adrenoceptor numbers. 5 Protracted treatment with CGP 35348, failed to influence forskolin-stimulated cyclic AMP production; however, a significant increase in the accumulation of cyclic AMP pro duced in response to forskolin was seen after treatment with CGP 36742 . 6 Such discretely localized changes in GABA(B) receptor densities in duced by desipramine and CGP 36742 may provide an explanation for the discrepancies reported in membrane binding studies and possibly implic ate a role for GABA(B) receptor antagonists in antidepressant therapy.