Serotonergic Stimulation of Pituitary-Adrenocortical Function in Rats

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Abstract
Various pharmacologic studies have supported a stimulatory role of brain serotonin neurons in the hypothalamic regulation of pituitary-adrenocortical function in rats. The serotonin precursor L-5-hydroxytryptophan (L-5HTP), serotonin uptake inhibitors, serotonin releasers, and direct-acting serotonin agonists all elevate serum corticosterone levels in rats. The elevation of serum corticosterone by L-5HTP is stereospecific and is potentiated by monoamine oxidase inhibition or by inhibition of serotonin uptake. Elevation of serum corticosterone by direct-acting receptor agonists is not altered by uptake inhibition or by depletion of serotonin stores. The elevation of serum corticosterone by p-chloroamphetamine, a serotonin-releasing drug, is antagonized by prevention of its uptake into serotonin neurons or by prior depletion of serotonin stores. The elevation of serum corticosterone by fluoxetine (an uptake inhibitor), by 1-m-trifluoromethylphenyl)piperazine (a direct agonist), and by p-chloroamphetamine (a serotonin releaser) does not occur with close structural analogs of those compounds lacking their specific effects on serotonin neurons. Pretreatment of rats with fluoxetine potentiates the elevation of corticosterone by L-5HTP, antagonizes the elevation of corticosterone by p-chloroamphetamine (which requires active transport into the serotonin neuron in order to release serotonin) and does not alter elevation of corticosterone by quipazine or 1-m-trifluoromethylphenyl)piperazine (direct-acting serotonin agonists) or by swim stress or insulin-induced hypoglycemia. Serotonin depletion in some cases leads to enhanced responsiveness to direct-acting drugs not requiring serotonin stores. Some serotonin receptor antagonists prevent corticosterone elevation by agents that enhance serotonergic function, but the differences among antagonists with regard to their ability to block the actions of particular agonists suggests that subpopulations of serotonin receptors may be involved. Thus most in vivo studies support the postulate developed from in vitro studies that serotonin neurons stimulate the release of corticotrophin-releasing factor from the hypothalamus, leading to enhanced secretion of adrenocorticotrophin from the pituitary gland and corticosterone from the adrenal glands. The physiological role of this postulated stimulatory serotonergic pathway is unknown, but some evidence suggests it may play a part in the diurnal rhythmicity of adrenocortical function.

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