Evidence for a role of neurosteroids in modulation of diurnal changes and acute stress-induced corticosterone secretion in rats

Abstract

The neurosteroid allopregnanolone has been shown to be a potent ligand of gamma-aminobutyric acid (GABA)-A receptors and enhances its receptor-mediated inhibitory events. Since central GABA plays a major inhibitory role, via GABA-A receptors, in hypothalamic-pituitary-adrenal (HPA) function in rats, the present study has evaluated the effect of passive immunoneutralization of allopregnanolone on diurnal changes in corticosterone secretion and acute stress-induced corticosterone secretion in rats. In the first protocol, four groups of male rats (prepubertal, fertile, castrated adult and aged) and three groups of female rats (prepubertal, fertile at different phases of the estrous cycle and aged) were studied. Rats were injected intracerebroventricularly (i.c.v.) with 10 microliters anti-allopregnanolone serum or 10 microliters normal rabbit serum (control) 24 h before exposure to an acute cold swimming stress, and sacrificed either before stress or after 5 min stress. In the second protocol, fertile male or female rats at diestrus II were injected i.c.v. with anti-allopregnanolone serum or normal rabbit serum and sacrificed on the following day at 10.00 or 18.00. Truncal blood samples were collected for measuring plasma corticosterone. Our results showed that there was no significant difference in basal plasma corticosterone levels between antiserum-treated and control rats of both sexes. However, in male rats, central injection of antiserum to allopregnanolone significantly potentiated plasma corticosterone response to stress in prepubertal and adult fertile rats as well as in castrated rats. Likewise, in female rats, the stress response of plasma corticosterone was enhanced by passive immunoneutralization of allopregnanolone in prepubertal and fertile rats throughout the estrous cycle.(ABSTRACT TRUNCATED AT 250 WORDS)

Neurosteroids in the context of stress: Implications for depressive disorders

“…In contrast to the diminished neuroactive steroid concentrations seen in chronically stressed rats, and consistent with the role of the neuroactive steroids as endogenous negative modulators of the HPA axis (Guo et al, 1995;Patchev et al, 1996), plasma corticosterone concentrations are elevated in isolated animals compared with controls (Serra et al, 2000). Thus, this profile of diminished neurosteroid concentrations coupled with elevated glucocorticoids in socially isolated animals is strikingly similar to that seen in patients with melancholic depression, since many depressed patients are also hypercortisolimic relative to non-depressed controls (e.g., Nemeroff, 1998;Young et al, 2000aYoung et al, , 2000b.…”

“…Specifically, neurosteroids appear to serve as endogenous homeostatic mechanisms restoring both normal GABAergic and hypothalamic-pituitary-adrenal (HPA) function following acute stress (Guo et al, 1995;Patchev et al, 1996;Barbaccia et al, 1998;Strous et al, 2006). Animal models indicate that acute stress results in a rapid decrease in GABAergic neurotransmission and that this reduction in inhibitory neurotransmission with stress is mediated by the GABA A receptor (Concas et al, 1988;Drugan et al, 1989;Biggio et al, 1990).…”

Olanzapine and Clozapine Increase the GABAergic Neuroactive Steroid Allopregnanolone in Rodents

“…Interestingly, progesterone elevations in this study preceded allopregnanolone elevations by approximately 30 min, suggesting that CRF challenge may result in progesterone metabolism to allopregnanolone in the adrenal. This sequence of events may be highly relevant to the regulation of the stress response, since rodent data suggest that allopregnanolone negatively modulates the HPA axis (Guo et al, 1995;Patchev et al, 1994Patchev et al, , 1996. Recent evidence in human subjects demonstrating that allopregnanolone and cortisol levels are inversely related both at baseline and following mental stress also supports this possibility (Girdler et al, 2001).…”

“…It is therefore possible that antipsychotic-induced HPA axis alterations may be relevant to stress modulation in schizophrenia and antipsychotic treatment response. Accompanying elevations in cerebral cortical allopregnanolone may function to modulate this corticosterone response and ultimately suppress the HPA axis , since allopregnanolone inhibits corticosterone release in rodents (Patchev et al, 1996;Guo et al, 1995).…”

Aging is associated with changes in allopregnanolone concentrations in brain, endocrine glands and serum in male rats

“…A putative inhibitory role of allopregnanolone on the response of corticosterone to stress has been hypothesized. In fact, it has been reported that in aged rats treatment with antiserum raised against allopregnanolone failed to modify serum corticosterone levels following acute physical stress, as it does in adult rats (23). Therefore, it is possible that with advancing age neurosteroids lose part of their activity in the control of the hypothalamus-pituitary-adrenal axis (11).…”