FORSKOLIN DELAYS THE ETHANOL-INDUCED DESENSITIZATION OF HYPOTHALAMIC BETA-ENDORPHIN NEURONS IN PRIMARY CULTURES

Ethanol and its metabolite acetaldehyde have been shown to stimulate i mmunoreactive beta-endorphin (IR-beta-EP) secretion from hypothalamic neurons in primary cultures, Also, chronic ethanol and acetaldehyde ha ve been shown to cause the development of tolerance and desensitizatio n of these neurons, In this study, we determined some of the cellular events leading to desensitization of the function of beta-endorphin (b eta-EP) secretory neurons. The fetal hypothalamic cells were treated w ith various doses of ethanol (25 and 50 mM) or acetaldehyde (6.25, 12. 5, and 25 mM) for 6 hr or treated with these drugs at 12 hr intervals for 72 hr, Determination of IR-beta-EP concentrations in the media rev ealed that ethanol increased IR-beta-EP secretion from these cultures for 12 hr; after this period, the cultured cells did not respond to et hanol, Acetaldehyde stimulated IR-beta-EP secretion from this culture for a period of 48 hr, but the IR-beta-EP secretory response to acetal dehyde reduced gradually with time during the first 48-hr period and r eached the basal level at 72 hr, The desensitization of beta-EP neuron s 12 hr after treatment with alcohol did not seem to be related to the loss of viable cells, because chronic ethanol exposures did not produ ce any effect on cell viability, However, reduced IR-beta-EP secretory response to acetaldehyde with time was associated with the time-depen dent increase in cell death, Pretreatment of cultures with a cAMP anal og, forskolin, increased the activity of functional beta-EP neurons an d delayed the ethanol desensitization effects on these neurons. Pretre atment of forskolin did not delay the acetaldehyde desensitization of beta-EP neurons, but protected these cells from acetaldehyde toxicity. These results suggest that (i) chronic treatment with ethanol desensi tizes beta-EP-secreting neurons due to reduced cellular functions and (ii) chronic acetaldehyde reduces beta-EP neurotransmission due to cel l death, Furthermore, data suggest for the first time that cAMP pretre atments delay the ethanol-induced desensitization of opioid neurons an d partly protect against the neurotoxic action of acetaldehyde on opio id neurons.