Alcohol self‐administration acutely stimulates the hypothalamic‐pituitary‐adrenal axis, but alcohol dependence leads to a dampened neuroendocrine state

Abstract

Clinical studies link disruption of the neuroendocrine stress system with alcoholism, but remaining unknown is whether functional differences in the hypothalamic-pituitary-adrenal (HPA) axis precede alcohol abuse and dependence or result from chronic exposure to this drug. Using an operant self-administration animal model of alcohol dependence and serial blood sampling, we show that long-term exposure to alcohol causes significant impairment of HPA function in adult male Wistar rats. Acute alcohol (voluntary self-administration or experimenter-administered) stimulated the release of corticosterone and its upstream regulator, adrenocorticotropic hormone, but chronic exposure sufficient to produce dependence led to a dampened neuroendocrine state. HPA responses to alcohol were most robust in ‘low-responding’ non-dependent animals (averaging < 0.2 mg/kg/session), intermediate in non-dependent animals (averaging ~0.4 mg/kg/session), and most blunted in dependent animals (averaging ~1.0 mg/kg/session) following several weeks of daily 30-min self-administration sessions, suggesting that neuroendocrine tolerance can be initiated prior to dependence and relates to the amount of alcohol consumed. Decreased expression of corticotropin-releasing factor (CRF) mRNA expression in the paraventricular nucleus of the hypothalamus and reduced sensitivity of the pituitary to CRF may contribute to, but do not completely explain, neuroendocrine tolerance. The present results, combined with previous studies, suggest that multiple adaptations to stress regulatory systems may be brought about by excessive drinking, including a compromised hormonal response and a sensitized brain stress response that together contribute to dependence.

Glucocorticoid receptor antagonism decreases alcohol seeking in alcohol-dependent individuals

“…Allostatic changes in brain reward and stress systems are thought to mediate many of these symptoms. We previously reported that dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis, the principal neuroendocrine stress system, and consequent alterations in brain glucocorticoid receptor (GR) expression accompany compulsive-like alcohol intake in rats (5,6). Despite these strong preclinical findings and evidence for dysregulation of the HPA axis in alcoholism (7,8), a role for GR signaling in humans who suffer from alcohol dependence has yet to be determined.…”

Ethanol Withdrawal-Induced Impaired Recognition Is Reversed by Chronic Exposure to Stress and the Acute Administration of Corticosterone in Mice

“…33) Glucocorticoid hormones are the final step in the activation of the HPA axis and are known to function in the biological response to stress. 34) In alcohol dependence, the HPA axis is dysregulated in both humans 35) and rodents, 8,36,37) but the effects of this dysregulation are still unclear. Here, we speculated that regulation of the HPA axis, such as by changes in the blood corticosterone level, may play an important role in the impaired recognition after the discontinuation of ethanol treatment.…”

“…7) Interestingly, the plasma concentration of corticosterone is increased by acute ethanol challenge, but this response is attenuated by chronic exposure. 8) It has been reported that corticosterone promotes learning and memory in non-stressed rodents, while the chronic administration of corticosterone has opposite effects. [9][10][11] Although there is increasing evidence that the stress hormone corticosterone may modulate learning and memory, the effects of chronic exposure to stress and acute administration of corticosterone on the impaired recognition after ethanol withdrawal are not sufficiently clear.…”

Neurobiology of Alcohol Dependence and Implications on Treatment

“…Akut alkol alımının dolaşımdaki adrenokortikotropik hormon (ACTH) ve kortizolü artırdığı bilinmektedir (Zhou ve ark. 2000, Richardson ve ark. 2008, Willey ve ark.…”