Ethanol has been shown to enhance the in vitro release of hypothalamic beta-endorphin (beta-EP). In the present study, the pattern of beta-EP release by the hypothalamus of two strains of mice, bred selectively for their preference (C57BL/6) or aversion (DBA/2) to ethanol, was investigated using a tissue perifusion system. The tissues were perifused with 20 mM ethanol for 30 min and the immunoreactive beta-EP content was estimated in perifusates collected every 2 min. Ethanol induced an enhanced release of hypothalamic beta-EP characterized by an initial spike followed by a gradual decrease toward baseline levels in both strains of mice. The ethanol-induced increase in beta-EP release by the hypothalamus of the C57BL/6 mice was more pronounced and longer lasting than that by the hypothalamus of the DBA/2 mice. Similar to beta-EP, an immediate sharp increase of corticotropin-releasing hormone (CRH) release was induced by ethanol which, however, did not present a spike but was maintained significantly higher than spontaneous release for the duration of ethanol exposure. Both ethanol-induced beta-EP and CRH release returned to basal levels within 10 min following removal of ethanol. That beta-EP levels did not remain elevated for the duration of ethanol exposure was not due to tissue depletion of releasable beta-EP pool, since exposure of the hypothalami to 10(-8) M CRH for 10 min, immediately after the perifusion with 20 mM ethanol, resulted in a large increase of beta-EP release. A second ethanol exposure 30 min after the first one did not induce an increase in beta-EP release. However, when the recovery period from the first ethanol exposure was extended to 60 min, a significant increase in the release of hypothalamic beta-EP was observed from the hypothalamus of the C57BL/6 but not of the DBA/2 mice. It is concluded that hypothalamic endorphinergic neurons present a fast, transient increase of beta-EP release in the presence of 20 mM ethanol, and become insensitive to subsequent ethanol exposures for a period of about 60 min. In addition, genetically determined differences exist with regards to the magnitude and duration of the ethanol-stimulated release of beta-EP, as well as on the length of the ethanol nonresponsive period. These differences may explain in part the differences in the voluntary ethanol consumption exhibited by these strains of mice.