NEUROHYPOPHYSEAL PEPTIDES AND ETHANOL TOLERANCE

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Arginine vasopressin (AVP) and related peptides, when administered exogenously, prolong the duration of tolerance to ethanol. Using peptide agonists and antagonists that interact selectively with vasopressin V1 and V2 receptors. we characterized as V1 the receptors in brain that mediate the ability of vasopressin to maintain ethanol tolerance. We have also characterized vasopressin binding sites in brain by quantitative autoradiography. The highest concentration of binding sites was in the lateral septum, with lower densities in dorsal hippocampus, hypothalamus and thalamic areas. Displacement studies with V1- and V2-selective agonists and antagonists indicated that binding sites in the lateral septum have characteristics of V1 receptors. 6-0HDA treatment significantly reduced the number of AVP binding sites in lateral septum, while 5,7-DHT treatment did not. Previous work showed that intact brain noradrenergic systems are necessary for AVP to maintain ethanol tolerance: thus, AVP may act at V1 receptors on terminals of noradrenergic neurons to alter neurotransmitter release and thus influence tolerance. Another possible (postsynaptic) mechanism of action involves stimulation of expression of the proto-oncogene c-fos, which has previously been postulated to be involved in learning or memory. AVP increases c-fos expression in lateral septum after icv injection. This may represent a direct or indirect action of AVP. Our work also showed that endogenous AVP plays a role in maintenance of ethanol tolerance, leading us to investigate AVP synthesis during chronic ethanol treatment. In mice and rats exposed to ethanol by different methods, hypothalamic AVP mRNA was decreased. However. AVP levels in plasma varied, depending on the method of ethanol treatment, suggesting that other factors such as dehydration or stress may influence these levels. Understanding the role and mechanism of action of AVP in development, expression and dissipation of tolerance to ethanol may lead to benign means for the manipulation of tolerance and, possibly, of ethanol intake.