Effect of modification of brain serotonin (5-HT), norepinephrine (NE) and dopamine (DA) on ethanol tolerance

Rats were permanently depleted of brain dopamine (DA), serotonin (5-HT), 5-HT + norepinephrine (NE), or NE + DA by intraventricular injection of either 5,7-dihydroxytryptamine (5,7-DHT) or 6-hydroxydopamine (6-OHDA) with or without pretreatment with desmethylimipramine (DMI). Following 1 week of recovery from surgery, daily treatment with ethanol (5 g/kg, PO) or isocaloric sucrose was carried out for a period of 20-25 days. Testing at 5-day intervals showed that chronic ethanol treatment produced tolerance to the hypothermic and motor impairing effects of ethanol. Depletion of 5-HT alone retarded tolerance, while depletion of NE or DA alone produced no effect. Combined depletion of both NE and 5-HT, however, completely inhibited tolerance development. The inhibition of tolerance development by combined depletion of both NE and 5-HT is discussed in terms of a reciprocal relationship between these two systems.