THE 5-HT RECEPTOR G-PROTEIN EFFECTOR SYSTEM COMPLEX IN DEPRESSION .1. EFFECT OF GLUCOCORTICOIDS

Hormonal modulation of neurotransmission emerged as a concept from the recognition that adrenocortical steroids exert profound effects at the level of receptors, G-proteins and effector units. G-proteins, a family of guanine nucleotide binding regulatory components that couple neurotransmitter receptors to various types of intracellular effector systems, appear to be a key target of glucocorticoid (GC) action in the CNS. It is thought that G(s)/G(i) mediates stimulation/inhibition of adenylate cyclase (AC system), which forms cyclic AMP as second messenger, while receptors stimulating phospholipase C do so through G(o) to produce two second messengers, inositol 1,4,5-triphosphate and diacylglycerol (PI system). Recent evidence suggests that GC increase G(s-alpha)-and decrease G(i-alpha)-protein subunit expression without affecting G(o-alpha). Activation of central pre- and postsynaptic 5-HT1A receptors which are linked to the G(i) - AC complex, induces hypothermia and ACTH/cortisol release in rodents and humans. Compared with controls, patients with a major depressive disorder exhibit increased basal cortisol secretion associated with decreased hypothermic and ACTH/cortisol responses. The attenuated neuroendocrine and thermoregulatory response to 5-HT1A receptor activation may reflect a GC-dependent feedback inhibition of the hypothalamic-pituitary-adrenal (HPA) system and subsensitivity of the presynaptic 5-HT1A - G(i) - AC complex function. Differential regulation of 5-HT1A and 5-HT2 function leading to a relative 5-HT2 - G(o) - PI complex supersensitivity may maintain HPA hyperactivity during the course of depression. These findings corroborate recent reports that GC, via GC - GC receptor (GR) complex activated promotion of gene transcription, modify the expression 5-HT1A-coupled G(i) (but not 5-HT2-coupled G(o) resulting in altered sensitivity of 5-HT1A-mediated signal transduction and further support the hypothesis of a differential regulation of 5-HT1A and 5-HT2 receptor function and a GC - GR/5-HT1A - G-protein - effector system-related abnormality in depression.