Roles of the locus coeruleus and adrenergic receptors in brain-mediated hypothalamic-pituitary-adrenal axis responses to intracerebroventricular alcohol.

BACKGROUND: Alcohol activates the hypothalamic-pituitary-adrenal (HPA) axis through its actions in both the periphery and the central nervous system (CNS). The studies presented here were designed to test the CNS-specific noradrenergic mechanisms by which alcohol stimulates HPA activity in the male rat. METHODS: We used an experimental paradigm in which a small, nontoxic amount (5 µl) of alcohol was slowly microinfused intracerebroventricularly (icv). Alcohol was administered icv to animals with lesions of the locus coeruleus (LC) or in animals pretreated with α- or ß-adrenergic receptor antagonists. Hormonal HPA activation was determined by measuring secretion of the pituitary stress hormone adrenocorticotropin (ACTH). Neuronal activation was determined by quantification of the expression of the transcription factor c-fos (Fos). RESULTS: As expected, icv alcohol stimulated ACTH secretion from the pituitary and Fos expression in the paraventricular nucleus of the hypothalamus (PVN). Bilateral electrolytic LC lesions blocked the ability of icv alcohol to stimulate ACTH secretion. Pretreatment with icv propranolol increased basal ACTH secretion levels, but icv alcohol did not increase this effect. Propranolol also blunted icv alcohol-induced PVN Fos expression. A low dose of phenoxybenzamine, an α-adrenergic receptor antagonist, did not affect the ability of icv alcohol to stimulate ACTH release. However, a higher dose of the drug was able to block the ACTH response to icv alcohol. Despite this, phenoxybenzamine did not inhibit alcohol-induced Fos expression. Icv pretreatment with corynanthine, a selective α-1 adrenergic receptor antagonist, modestly raised basal ACTH levels and blocked the icv alcohol-induced secretion of this hormone. CONCLUSIONS: These results indicate that the LC and norepinephrine play important roles in HPA activation caused by icv alcohol administration, but that the specific adrenergic receptor subtypes involved in this phenomenon still need to be identified.

Impact of the hormonal milieu on the neurobiology of alcohol dependence and withdrawal.

Alcoholism, or alcohol dependence, is a complex disorder with withdrawal symptoms that are often problematic for those trying to recover from their dependence. As researchers attempt to elucidate the neurobiological underpinnings of alcohol dependence and withdrawal, it is becoming clear that numerous factors, including the hormonal environment, impact the manifestations of this disorder. Of particular interest is the observation that women have fewer and less severe withdrawal symptoms than do men even though they tend to suffer greater physiological harm from excessive alcohol consumption. In this article, the authors present an overview of their understanding of how gonadal and stress hormones interact with alcohol, which results in differential neurobiological responses between males and females. Thus far, data generated from representative animal models have shown significant differences between the sexes in behavioral responses and neuroadaptations to chronic alcohol consumption and withdrawal. Accumulating evidence suggests that treatment of alcoholism, including withdrawal, should be tailored to the patient's gender and hormonal status.