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The 5-HT receptor — G-protein — effector system complex in depression I. Effect of glucocorticoids

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Summary

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 Gsα-and decrease Giα-protein subunit expression without affecting Goα.

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) systemand 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.

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  1. K. P. Lesch

    Present address: Laboratory of Clinical Science, NIMH, NIH Clinical Center, Bethesda, MD, USA

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  1. Department of Psychiatry, University of Würzburg, Federal Republic of Germany

    K. P. Lesch

  2. Yaacov Herzog Center for Brain and Psychiatry Research, Ezrath Nashim, Jerusalem, Israel

    B. Lerer

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K. P. L. is recipient of an International Fogarty Fellowship.

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Lesch, K.P., Lerer, B. The 5-HT receptor — G-protein — effector system complex in depression I. Effect of glucocorticoids. J. Neural Transmission 84, 3–18 (1991). https://doi.org/10.1007/BF01249105

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