Journal
EUROPEAN JOURNAL OF NEUROSCIENCE
Volume 28, Issue 8, Pages 1641-1653Publisher
WILEY
DOI: 10.1111/j.1460-9568.2008.06455.x
Keywords
ACTH; alcohol; corticosterone; corticotropin-releasing factor mRNA; self-administration; withdrawal
Categories
Funding
- Pearson Center for Alcoholism
- Addiction Research
- National Institutes of Health [AA06420, AA08459, AA12602]
- National Institute on Alcohol Abuse and Alcoholism
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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 similar to 0.4 mg/kg/session), and most blunted in dependent animals (averaging similar to 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.
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