Forskolin delays the ethanol-induced desensitization of hypothalamic beta-endorphin neurons in primary cultures.
Ethanol and its metabolite acetaldehyde have been shown to stimulate immunoreactive beta-endorphin (IR-beta-EP) secretion from hypothalamic neurons in primary cultures. Also, chronic ethanol and acetal-dehyde have been shown to cause the development of tolerance and desensitization of these neurons. In this study, we determined some of the cellular events leading to desensitization of the function of beta-endorphin (beta-EP) secretory neurons. The fetal hypothalamic cells were treated with 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 revealed that ethanol increased IR-beta-EP secretion from these cultures for 12 hr, after this period, the cultured cells did not respond to ethanol. Acetaldehyde stimulated IR-beta-EP secretion from this culture for a period of 48 hr, but the IR-beta-EP secretory response to acetaldehyde reduced gradually with time during the first 48-hr period and reached the basal level at 72 hr. The desensitization of beta-EP neurons 12 hr after treatment with alcohol did not seem to be related to the loss of viable cells, because chronic ethanol exposures did not produce any effect on cell viability. However, reduced IR- beta-EP secretory response to acetaldehyde with time was associated with the time-dependent increase in cell death. Pretreatment of cultures with a cAMP analog, forskolin, increased the activity of functional beta-EP neurons and delayed the ethanol desensitization effects on these neurons. Pretreatment 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 desensitizes beta-EP-secreting neurons due to reduced cellular functions and (ii) chronic acetaldehyde reduces beta-EP neurotransmission due to cell death. Furthermore, data suggest for the first time that cAMP pretreatments delay the ethanol-induced desensitization of opioid neurons and partly protect against the neurotoxic action of acetaldehyde on opioid neurons.
Boyadjieva
N
N
Department of Veterinary and Comparative Anatomy, Pharmacology and Physiology, Washington State University, Pullman 99164-6520, USA.
Reddy
B V
BV
Sarkar
D K
DK
D000818:Animals; D002470:Cell Survival / Q000187:drug effects; D005576:Colforsin / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D000431:Ethanol / Q000037:antagonists & inhibitors* / Q000494:pharmacology; D005260:Female; D005333:Fetus; D007031:Hypothalamus / Q000187:drug effects*; D009474:Neurons / Q000187:drug effects; D011247:Pregnancy; D051381:Rats; D017207:Rats, Sprague-Dawley; D009435:Synaptic Transmission / Q000187:drug effects*; D001615:beta-Endorphin / Q000502:physiology*
D005576:Colforsin; D000431:Ethanol; D001615:beta-Endorphin