EVALUATION OF THE EFFECTS OF COCAINE, HEROIN AND NALTREXONE, ALONE AND IN COMBINATION, ON MILK DRINKING IN RATS

The effects of cocaine, alone and in combination with either heroin or naltrexone, were examined using a milk drinking procedure in rats. Ra ts (n = 8) were given access to a sweetened milk solution for 15 min d aily until intake had stabilized (3 days with less than 10% variation across days). Rats were first administered saline or one of five doses of either cocaine (2.0-32 mg/kg, i.p.) or heroin (0.4-3.2 mg/kg, i.p. ) 15 min prior to milk access. The dose-response function for cocaine was then determined in combination with either 0.8 mg/kg or 1.6 mg/kg heroin. Both cocaine and heroin administered alone produced dose-depen dent decreases in milk drinking. Combination with 0.8 mg/kg and 1.6 mg /kg heroin resulted in parallel shifts to the left in the cocaine dose -response function. Isobolographic analysis of these dose-response fun ctions using ED(50) and ED(75) values revealed that the combinations o f cocaine and heroin were dose-additive, except at the cocaine plus 1. 6 mg/kg heroin combination, which was infra-additive. Redetermination of the cocaine-only and heroin-only dose-response functions revealed n o significant difference from the first determination. To assess the e ffects of naltrexone on cocaine- and heroin-induced suppression of mil k drinking, rats were first administered four doses of naltrexone (0.1 -0.8 mg/kg, i.p., 15 min pretreatment). Then, naltrexone doses were co mbined with a dose of heroin or cocaine that suppressed milk drinking (3.2 and 16 mg/kg, respectively), Naltrexone alone produced modest, bu t not dose-related, suppression of milk drinking, and had no reliable effect on suppression of milk drinking produced by 16 mg/kg cocaine. I n contrast, naltrexone dose-dependently blocked heroin-induced suppres sion of milk drinking and, at naltrexone doses that had no effect on m ilk drinking when administered alone, produced a parallel shift to the right in the heroin dose-response function. In vivo apparent pK(B) an alyses revealed that naltrexone antagonism of heroin-induced suppressi on of milk drinking involved mu-opioid receptors. Taken together, thes e results suggest that the effects of cocaine and heroin on milk drink ing are either dose-additive or infra-additive and that cocaine-induce d suppression of milk drinking does not directly involve the mu-opioid receptor system.