Desensitization by Antidepressants of Central Norepinephrine Receptor Systems Coupled to Adenylate Cyclasea

The experimental results discussed in this paper provide evidence that antidepressant-induced attenuation of the NE receptor-coupled adenylate cyclase system in brain and the down-regulation of its beta adrenoceptor subpopulation result in a net deamplification of the NE signal. The desensitization of the NE receptor system requires an unhindered occupancy of the receptor by the agonist NE. Following adrenalectomy, the non-beta population of NE receptors coupled to adenylate cyclase shows an enhanced response to NE without changes in the activity of adenylate cyclase or phosphodiesterase. This supersensitivity to NE can be prevented by corticosterone. The synaptic availability of 5HT is co-required for the down-regulation by DMI-like drugs of the density of beta adrenoceptors. Moreover, beta adrenoceptors from tissue deprived of serotonergic neuronal input display a marked decrease in agonist affinity as determined from competition binding of (-)-isoproterenol for [3H]dihydroalprenolol. Using NE as an agonist, competition binding curves with membrane preparations from cortical tissue lacking 5HT input show low affinity binding of the receptor for NE that cannot be further modified by guanine nucleotides. The reduction in beta adrenoceptor agonist affinity following reduction of the synaptic availability of 5HT is accentuated by chronic administration of DMI or zimelidine. The new experimental data on the biomolecular linkage between serotonergic and noradrenergic neurons, expressed functionally at the level of NE receptors, provide the scientific basis for a "serotonin-norepinephrine link hypothesis" of affective disorders. The pursuit of studies on the molecular mechanisms of the action of steroid hormones on central NE receptor systems and on mechanisms underlying the functional 5HT-NE linkage and its modification by antidepressants should generate a deeper understanding of neuronal signal processing in brain.