Stress and neurochemical changes associated with chronic alcohol administration
There is considerable recent experimental evidence that suggests that stress plays a major role in the development of dependence on drugs of abuse, but the potential mechanisms involved are not yet fully understood. The aims of this thesis were (I) to examine the effect of stress, and of drugs that act on the hypothalamic-pituitary-adrenal axis, on alcohol consumption in the C57 strain of mice. (II) to investigate whether corticosterone levels or spontaneous locomotor activity could be used to predict subsequent alcohol consumption in mice. (Ill) to investigate long-term neurochemical changes during abstinence following chronic alcohol administration. (IV) to develop a method for measuring brain corticosterone levels. Neither total corticosterone levels nor spontaneous locomotor activity could predict alcohol preference. Saline vehicle injections increased alcohol preference in low alcohol preferring, and raised both circulating corticosterone levels and brain corticosterone. The brain concentrations of corticosterone were measured by a novel procedure developed during the thesis. A CRF antagonist (a-helical CRF) increased alcohol preference in low preferring mice, as did the ACTH fragment 4-10. In high preferring mice, ACTH 4-10 reduced alcohol preference, whereas a-helical CRF did not alter preference in these mice. Inhibition of corticosterone synthesis reduced alcohol preference in high alcohol preferring mice but, blockade of corticosterone receptors with specific antagonists did not alter alcohol preference. Chronic alcohol treatment followed by six days abstinence increased free circulating corticosterone levels and this treatment also increased hippocampal corticosterone levels. Dopamine Dl-like receptor affinity was increased following the same chronic treatment schedule. These results demonstrate an important link between the activation of the hypothalamic-pituitary-adrenal axis and alcohol consumption. The results of the chronic treatment experiments provide useful information that may aid the understanding of the phenomenon of relapse to drinking common in abstaining alcoholics.