The ability of naltrexone to suppress ethanol drinking has been amply demonstrated in several animal species as well as man. This therapeutic effect of naltrexone has been observed with a number of other opioid antagonist and has led to the development of the """"""""opioid compensation hypothesis"""""""" that postulates an opioidergic mechanism for ethanol's reinforcing effects. Ethanol is not the only substance whose consumption is suppressed by opioid antagonists, however. These drugs also reduce intake of sweet solutions and food, behavior that may also be under the control of opioid mechanisms. However, because there is at least one broad spectrum opioid antagonist quadazocine, that does not reduce intake of sucrose solutions, there is some reason to think that this effect may be due to other behavioral effects of some opioid antagonists. The purpose of this grant is 1) to determine whether naltrexone's suppression of ethanol drinking is through the same mechanism as its suppression of sucrose drinking; 2) to determine whether its therapeutic potential in the treatment of alcohol abuse is because of its opioid antagonist properties, and if so, which opioid receptor is responsible; 3) to determine, if naltrexone is indeed operating through a non-opioid mechanism, whether this is related to a general antiappetitive effect of these drugs to which supersensitivity has been found to develop; 4) to observe the generality of the effect of opioid antagonist on behavior reinforced by intravenously delivered ethanol as well as other drugs; and 5) to determine whether naltrexone's suppressing effects on ethanol drinking is maintained in an experimental situation by chronic administration of naltrexone or by an ultra long-acting insurmountable opioid antagonists. The majority of these experiments will be carried out in rhesus monkeys that drink a range low concentrations of ethanol in preference to water. The effects of a number of opioid antagonist and lithium will be evaluated in these monkeys and in monkeys drinking sucrose or saccharin in preference to water. The effects of several of these drugs in monkeys responding and receiving intravenous ethanol will also be determined. In addition, groups of rats and monkeys that are responding and either receiving food or terminating a stimulus associated with shock will be used to compare the development of supersensitivity to opioid antagonists with this ability of these drugs to suppress ethanol consumption.
