LACK OF EFFECT OF REPEATED ADMINISTRATION OF MILNACIPRAN, A DOUBLE NORADRENALINE AND SEROTONIN REUPTAKE INHIBITOR, ON THE BETA-ADRENOCEPTOR-LINKED ADENYLATE-CYCLASE SYSTEM IN THE RAT CEREBRAL-CORTEX

The effects of subacute administration of the double noradrenaline and serotonin uptake inhibitor antidepressant, milnacipran, and the tricy clic antidepressant, imipramine, on radioligand binding to beta-adrene rgic receptors and on beta-adrenergic agonist-stimulated adenylate cyc lase activity, in the rat cerebral cortex, have been determined. Rats were injected intraperitoneally for 21 days with milnacipran (3, 10 or 30 mg/kg/day) or imipramine (10 mg/kg/day). The treatment with milnac ipran up to 30 mg/kg/day did not modify either the maximum number of [ H-3]CGP-12177 binding sites (B-max) or the equilibrium dissociation co nstant (K-d) On the other hand, treatment of the rats with 10 mg/kg/da y imipramine induced a decrease (27%) in B-max [H-3]CGP-12177 binding sites without affecting the K-d value. Furthermore, milnacipran did no t affect the stimulation of cAMP production induced by either 30 mu M isoprenaline, 10 mu M GTP gamma S or 10 mu M forskolin. Under similar conditions, treatment with imipramine reduced by 70% the isoprenaline- induced stimulation of cAMP production without affecting that induced by either GTP gamma S or forskolin. These results demonstrate that, un like imipramine, subacute administration of milnacipran does not produ ce any change in beta-adrenoceptor sensitivity in the rat brain cortex . Copyright (C) 1996 Elsevier Science Ltd.