Long-Term Cortisol Treatment Impairs Behavioral and Neuroendocrine Responses to 5-HT₁ Agonists in the Rat

Abstract

The effects of chronic cortisol treatment on neuroendocrine and behavioral responses to serotonim (5-HT₁) receptor agonists were studied in conscious, freely moving rats. Seven-day cortisol treatment (25 mg/kg/day with osmotic minipumps) markedly suppressed basal plasma corticotropin (ACTH) and corticosterone concentrations, indicating a suppression of the hypothalamo-pituitary-adrenocortical axis. Cortisol also decreased body weight, food intake, plasma norepinephrine (NE), and epinephrine (E) levels. In the drug challenge studies, we used two 5-HTι agonists, the 5-HT_1B and 5-HT_1C agonist, m-chlorophenylpiperazine (m-CPP), and the 5-HT_1A agonist, 8-hydroxy-2-(di-n-propylamino) tetralin (8-OHDPAT), to examine the effect of cortisol on their behavioral and neuroendocrine effects. After 7-day cortisol treatment, plasma prolactin responses to both m-CPP and 8-OHDPAT were significantly decreased. While the plasma NE, E, and food intake responses to m-CPP were also significantly reduced by cortisol treatment, these same responses to 8-OHDPATwere unchanged. The effect of m-CPP on locomotor activity was also decreased. Since only the responses to m-CPP and 8-OHDPAT previously shown to be antagonized by pretreatment with the 5-HT₁/5-HT₂ antagonist, metergoline, were significantly attenuated after cortisol treatment, these changes may be specific to 5-FΓT receptors. These data indicate that chronic exposure to high glucocorticoid levels alters 5-HT₁ receptor-mediated functions and provides additional evidence relevant to the contribution of glucocorticoid elevation to the symptoms of depression.

Altered responsiveness of serotonin receptor subtypes following long-term cannabinoid treatment

“…This imbalance of 5-HT receptor responsiveness is reminiscent of changes that are seen following chronic stress or glucocorticoid administration (Bagdy et al, 1989 ;Berendsen et al, 1996 ;Takao et al, 1997). Glucocorticoids may be one of several mediating factors in the cannabinoidergic modulation of 5-HT receptor balance, as administration of CB 1 receptor agonists at doses comparable to those used in this study, elicit a robust adrenocortical response (Rodriguez de Fonseca et al, 1996.…”

Mineralocorticoid and glucocorticoid receptors in the brain. Implications for ion permeability and transmitter systems

“…However, chronic corticosterone per se down regulated 5HT1A receptors (Mendelsohn and McEwen, 1992b). Interestingly, chronic administration of corticosterone has also been shown to reduce 5HTl-dependent behavioural and endocrine responses (Bagdy et al, 1989), while repeated exposure to stressors resulted on the behavioural and neuroendocrine level in 5HTI supersensitive responses (Kenneth et al, 1985). These findings from behavioural pharmacology are consistent with the effects of steroid and stress at the level of 5HT1A receptors.…”

Adrenocorticotropin, Prolactin and Beta-Endorphin Stimulatory Actions of Alpha-2-Adrenoceptor Antagonists

“…These endocrine effects of yohimbine were reversed by the < X 2 -adrenoceptor agonist clonidine [3,4], suggesting that the a2-adrenoceptors might mediate the PRL and ACTH releasing actions of yohimbine. Recently, it has been sug gested that the ACTH stimulatory effect of yohimbine adrenoceptors, as has been demonstrated previously for some neurotransmitter systems [11][12][13], The model of chronic dexamethasone pretreatment has been employed. To further elucidate the sites and mechanisms by which yohimbine stimulates ACTH, P-endorphin (pE) and PRL secretion, we also studied the interaction between clonidine and yohimbine when clonidine was administered intracerebroventricular (i.c.v.)…”