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. Rats (n=8) were given access to a sweetened milk solution for 15min daily 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 (2.0-32mg/kg, i.p.) or heroin (0.4-3.2mg/kg, i.p.) 15min prior to milk access. The dose-response function for cocaine was then determined in combination with either 0.8mg/kg or 1.6mg/kg heroin. Both cocaine and heroin administered alone produced dose-dependent decreases in milk drinking. Combination with 0.8mg/kg and 1.6mg/kg heroin resulted in parallel shifts to the left in the cocaine dose-response function. Isobolographic analysis of these dose-response functions using ED(50) and ED(75) values revealed that the combinations of cocaine and heroin were dose-additive, except at the cocaine plus 1.6mg/kg heroin combination, which was infra-additive. Redetermination of the cocaine-only and heroin-only dose-response functions revealed no significant difference from the first determination. To assess the effects of naltrexone on cocaine- and heroin-induced suppression of milk drinking, rats were first administered four doses of naltrexone (0.1-0.8mg/kg, i.p., 15min pretreatment). Then, naltrexone doses were combined with a dose of heroin or cocaine that suppressed milk drinking (3.2 and 16mg/kg, respectively). Naltrexone alone produced modest, but not dose-related, suppression of milk drinking, and had no reliable effect on suppression of milk drinking produced by 16mg/kg cocaine. In contrast, naltrexone dose-dependently blocked heroin-induced suppression of milk drinking and, at naltrexone doses that had no effect on milk drinking when administered alone, produced a parallel shift to the right in the heroin dose-response function. In vivo apparent pK(B) analyses revealed that naltrexone antagonism of heroin-induced suppression of milk drinking involved µ-opioid receptors. Taken together, these results suggest that the effects of cocaine and heroin on milk drinking are either dose-additive or infra-additive and that cocaine-induced suppression of milk drinking does not directly involve the µ-opioid receptor system.