Stimulatory effect of caffeine on the hypothalamo-pituitary-adrenocortical axis in the rat

Abstract

Intraperitoneal injection of caffeine (12.5-100 mg/kg) into rats caused a significant, dose-related increase in plasma corticosterone 2 h later, when the greatest response was measured. The corticosterone response to laparotomy stress or i.v. injection of ACTH(1-24) was unaffected by prior injection of caffeine. The response to stress or caffeine was unaffected by adrenal enucleation 28 days previously. In vitro, 10 mmol caffeine/l stimulated basal release of corticosterone from adrenal quarters and potentiated the response to a sub-maximal stimulatory concentration of cyclic AMP (cAMP). The drug had no effect on release stimulated by a sub-maximal concentration of ACTH(1-24). Release of ACTH from pituitary fragments incubated in vitro was stimulated in a dose-related manner by caffeine (0.01-10 mmol/l), and the responses to hypothalamic extract and sub-maximal concentrations of corticotrophin-releasing factor (CRF-41) or arginine vasopressin (AVP), but not cAMP, were significantly enhanced by 10 mmol caffeine/l. Release of immunoreactive CRF-41 (but not AVP) was significantly increased by caffeine (0.01-10 mmol/l) added to hypothalami incubated in vitro. The response to injection of caffeine in vivo was completely prevented by pharmacological blockade of endogenous CRF release. Taken together, these results show that caffeine at high concentrations can stimulate directly the release of the hormones of the hypothalamo-pituitary-adrenocortical axis in vitro, but the fact that these concentrations are unlikely to be reached after administration in vivo suggests that the effect of caffeine may be mediated centrally.

Pharmacological and Nonpharmacological Factors Influencing Hypothalamic–Pituitary–Adrenocortical Axis Reactivity in Acutely Depressed Psychiatric In-patients, Measured by the Dex-CRH Test

“…Caffeine intake is able to activate directly the HPA-axis (Nicholson, 1989;Nicholson et al, 1987;Holsboer-Trachsler et al, 1987) and could thus potentially influence the response in the Dex-CRH test. In this sample of acutely depressed patients, we did not observe an effect of caffeine.…”

Modulation of the hypothalamo–pituitary–adrenocortical axis by caffeine

“…Importantly, caffeine also elevates glucocorticoid levels in animals and humans. Acute caffeine increases plasma cortisol levels when injected into sleeping subjects (Lin et al, 1997) and elevates plasma corticosterone levels in rats (Nicholson, 1989).…”

“…In support of such a mechanism, only very high caffeine concentrations induced adrenocorticotropin hormone (ACTH) and corticosterone release from in vitro rat pituitary and adrenal gland tissues, respectively, as compared to effective systemic doses in vivo (Nicholson, 1989). In addition, blockade of corticotropin-releasing factor (CRF) release completely attenuated the caffeine-induced endocrine response in vivo, and only very high concentrations of caffeine induced CRF release from hypothalamic explants in vitro (Nicholson, 1989). Thus, caffeine likely activates the HPA axis via an interaction with centrally located adenosine receptors in hypothalamic afferent regions, eventually modulating CRF and HPA axis activity.…”

“…As mentioned above, high caffeine doses activate the HPA axis (Nicholson, 1989), but the effects of low to moderate doses of caffeine on HPA axis activation have not been studied systematically. In addition, although stressful stimuli were shown to attenuate some of the motor effects of caffeine (Meyer and Caston, 2005), the specific interactions of different doses of caffeine with neuroendocrine responses induced by stressful stimuli have not yet been reported.…”

Adenosine signalling pathways in the pituitary gland: one ligand, multiple receptors

“…The effects of xanthines, such as caffeine, theobromine and denbufylline, which act as adenosine receptor antagonists, have also been examined in the pituitary gland. These compounds have been shown to increase ACTH and corticosterone, while lowering TSH and GH concentrations (Spindel et al 1983, Nicholson 1989, Hadley et al 1996, Kumari et al 1997. Xanthines, however, also act as potent inhibitors of phosphodiesterases and it is likely that much of their activity in the pituitary gland relates as much to inhibition of these enzymes as to blockade of adenosine receptors (Hadley et al 1996, Kumari et al 1997.…”