New perspectives on the molecular pharmacology of affective disorders.

Research with antidepressants has emphasized the importance of a delayed deamplification of the linked serotonin (5HT)/norepinephrine (NE) receptor coupled adenylate cyclase system in brain. The basic phenomena of regulation of receptor number and function of the beta adrenoceptor linked adenylate cyclase system in brain are well established, with NE regulating beta adrenoceptors in the high agonist affinity conformation (linked to adenylate cyclase and down-regulated by antidepressants), and with 5HT regulating those receptors in the low agonist affinity conformation. The biochemical effector systems of NE and 5HT are discussed and it is concluded that the final common pathway of signal transduction is protein kinase mediated phosphorylation of cellular proteins. Glucocorticoid receptors are located in the perikarya of aminergic cell bodies and may exert their effects by modifying the genomic expression of the diffusely projecting stress-responsive monoamine systems. The molecular neurobiology of beta adrenoceptors, with its implication for genetic and immunologic investigations, is briefly discussed and further research on stimulus-transcription coupling and regulation of gene expression in brain is suggested as an exciting new direction in central receptor research relevant to the psychopharmacology of affective and other disorders.