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 tricyclic antidepressant, imipramine, on radioligand binding to beta-adrenergic receptors and on beta-adrenergic agonist-stimulated adenylate cyclase 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 milnacipran up to 30 mg/kg/day did not modify either the maximum number of [3H]CGP-12177 binding sites (Bmax) or the equilibrium dissociation constant (Kd). On the other hand, treatment of the rats with 10 mg/kg/day imipramine induced a decrease (27%) in Bmax [3H]CGP-12177 binding sites without affecting the Kd value. Furthermore, milnacipran did not affect the stimulation of cAMP production induced by either 30 microM isoprenaline, 10 microM GTP gamma S or 10 microM 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, unlike imipramine, subacute administration of milnacipran does not produce any change in beta-adrenoceptor sensitivity in the rat brain cortex.