Regulation of recognition and action function of the norepinephrine (NE) receptor-coupled adenylate cyclase system in brain: Implications for the therapy of depression

In this paper, the characteristics and the regulation of the norepinephrine (NE) receptor-coupled adenylate cyclase system with its β-adrenoceptor sub-population in brain are reviewed. While α-adrenoceptors in brain are not clearly coupled in an inhibitory fashion to adenylate cyclase, gb-adrenoceptors and a non-β-population of NE receptors in brain tissue are coupled to adenylate cyclase. The NE receptor-coupled adenylate cyclase system displays remarkable plasticity. Both supersensitivity and subsensitivity of the NE-sensitive adenylate cyclase system are of the "homologous" type. Most, if not all, clinically effective antidepressant treatments, including ECT, cause upon chronic administration subsensitivity of the system accompanied by a decrease in the density of β-adrenoceptors. The formation of the NE receptor complex is a prerequisite for the regulation of both the sensitivity of the system and the number of its β-adrenoceptor population. In addition, serotonergic neuronal input is co-required for the down-regulation of β-adrenoceptors by DMI-like drugs, but not for the up-regulation by propranolol. In the absence of serotonergie neuronal input, β-adrenoceptors display characteristics of "uncoupled" receptors. Steroid hormones (adrenocorticoids, sex steroids) have also been shown to alter the biological responsiveness of the system and/or the density of the β-adrenoceptor population, and β-adrenoceptor-mediated phospholipid methylation has been implicated in the regulation of the NE signal transfer through the membrane. The regulation of the number of NE membrane receptors and the efficacy of their coupling to adenylate cyclase represent physiologically important steps in the transfer of the NE signal through the membrane. Consequently, the changes induced by antidepressants at the level of membrane receptor regulation are altering the intensity of the signal transfer and appear to represent a therapeutically relevant biochemical action.