The 5-HT receptor--G-protein--effector system complex in depression. I. 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 Gs/Gi mediates stimulation/inhibition of adenylate cyclase (AC system), which forms cyclic AMP as second messenger, while receptors stimulating phospholipase C do so through Go to produce two second messengers, inositol 1,4,5-triphosphate and diacylglycerol (PI system). Recent evidence suggests that GC increase Gs alpha-and decrease Gi alpha-protein subunit expression without affecting Go alpha. Activation of central pre- and postsynaptic 5-HT1A receptors which are linked to the Gi-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-Gi-AC complex function. Differential regulation of 5-HT1A and 5-HT2 function leading to a relative 5-HT2-Go-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 Gi (but not 5-HT2-coupled Go) 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.
Lesch
K P
KP
Department of Psychiatry, University of Würzburg, Federal Republic of Germany.
Lerer
B
B
D000262:Adenylyl Cyclases / Q000378:metabolism; D000302:Adrenal Cortex / Q000503:physiopathology; D000324:Adrenocorticotropic Hormone / Q000378:metabolism; D000928:Antidepressive Agents / Q000494:pharmacology; D001833:Body Temperature Regulation / Q000187:drug effects; D003346:Corticotropin-Releasing Hormone / Q000378:metabolism; D003866:Depressive Disorder / Q000175:diagnosis / Q000503:physiopathology*; D005246:Feedback; D019204:GTP-Binding Proteins / Q000502:physiology*; D005938:Glucocorticoids / Q000494:pharmacology*; D006801:Humans; D006854:Hydrocortisone / Q000378:metabolism; D007030:Hypothalamo-Hypophyseal System / Q000187:drug effects / Q000503:physiopathology; D011743:Pyrimidines; D011985:Receptors, Serotonin / Q000145:classification / Q000187:drug effects* / Q000502:physiology; D012701:Serotonin / Q000502:physiology; D015398:Signal Transduction / Q000187:drug effects*
D000928:Antidepressive Agents; D005938:Glucocorticoids; D011743:Pyrimidines; D011985:Receptors, Serotonin; D012701:Serotonin; C043077:ipsapirone; D000324:Adrenocorticotropic Hormone; D003346:Corticotropin-Releasing Hormone; D019204:GTP-Binding Proteins; D000262:Adenylyl Cyclases; D006854:Hydrocortisone