EFFECTS OF CHRONIC ALCOHOL ON IMMUNOREACTIVE BETA-ENDORPHIN SECRETIONFROM HYPOTHALAMIC NEURONS IN PRIMARY CULTURES - EVIDENCE FOR ALCOHOL TOLERANCE, WITHDRAWAL, AND SENSITIZATION RESPONSES

Endogenous opioid peptides are known to be involved in the alcohol tol erance and dependence following alcohol abuse. However, the cellular m echanisms involved in the ethanol tolerance and dependence are not wel l established. We have previously shown that low concentrations of eth anol stimulate immunoreactive beta-endorphin (IR-beta-EP) release from the cultured hypothalamic neurons and that chronic ethanol exposure d esensitizes these neurons to ethanol challenges. In this study, we det ermined the IR-beta-EP response to increasing doses of ethanol during the desensitizing phase of moderate ethanol doses to test whether the cultured IR-beta-EP-secreting neurons develop tolerance to ethanol fol lowing constant exposure. We also determined IR-beta-EP responses foll owing withdrawal from chronic ethanol challenge and compared the IR-be ta-EP secretory response to various doses of ethanol in ethanol-naive and ethanol-preexposed cultures. The IR-beta-EP responses to increasin g doses of ethanol (50-150 mM) were markedly reduced in the cultures p reexposed to a 50 mM dose of ethanol when compared with those that wer e naive to ethanol. The ethanol-exposed cultures showed hypersecretion of IR-beta-EP after removal from 48 hr of constant ethanol, as compar ed with ethanol-naive cultures. When ethanol-preexposed cultures were challenged with various doses of ethanol 4 days after ethanol withdraw al, the cultures showed higher IR-beta-EP secretory responses than did the ethanol-naive cultures. These data suggest that IR-beta-EP secret ory neurons in primary cultures develop tolerance to chronic ethanol, show withdrawal response after removal of chronic ethanol exposure, an d develop sensitization following repeated ethanol challenges.