Serotonin-norepinephrine receptor interactions in the brain: implications for the pharmacology and pathophysiology of...

When chronically administered, most clinically effective antidepressant treatments (pharmacotherapy and ECT) reduce the sensitivity of the norepinephrine-sensitive adenylate cyclase in brain which, in turn, is associated with a down-regulation of the beta-adrenoceptor subpopulation. Because this norepinephrine receptor system is linked to an amplifier system, small changes in the number of receptors or in the accumulation of the second messenger cyclic AMP will be amplified. Results of the studies discussed in this paper demonstrate that an intact serotonergic neuronal input is required for the proper functioning of beta-adrenoceptors and for the down-regulation of the density of these receptors by antidepressant treatments. Under conditions of impaired serotonergic activity, beta-adrenoceptors display profound decreases in agonist but not in antagonist affinity. The changes are reminiscent of "uncoupled" receptors. While beta-adrenoceptors are coupled in a stimulatory fashion to adenylate cyclase, resulting in the formation of the second messenger cyclic AMP, serotonin (5-HT) receptors are linked to phosphatidylinositol hydrolysis (5-HT2 receptors in cortex, 5-HT1C receptors in choroid plexus) generating two second messengers, diacylglycerol and inositol-1,4,5-trisphosphate. The final common pathway of aminergic receptor activation seems to be protein-kinase-mediated protein phosphorylation leading to changes in cellular activity. Evidence is presented suggesting that the delayed down-regulation of the linked 5-HT/norepinephrine beta-adrenoceptor system by antidepressant treatment reflects a therapeutically relevant biochemical action and prompts the generation of the "5-HT/norepinephrine link hypothesis" of affective disorders.