Potency of naltrexone to reduce ethanol self-administration in rats is greater for subcutaneous versus intraperitoneal injection.

The opioid antagonist naltrexone (NTX) is used to treat alcohol dependence and may reduce alcohol consumption by selectively blocking opioid receptors. In rat experiments, discrepancy exists across studies regarding the potency of NTX to reduce ethanol consumption. One cause of this discrepancy may be the use of different routes of NTX administration (e.g., intraperitoneal vs. subcutaneous). The purpose of this study was to directly compare the effects of intraperitoneal and subcutaneous injections of NTX on ethanol self-administration. Rats pressed a lever for a sweetened ethanol solution (10% wt/vol in 0.1% saccharin) during 20 min daily sessions. One group received intraperitoneal injections of 1, 3, 10, and 30 mg/kg NTX before the sessions. Another group received subcutaneous injections of 0.03, 0.1, 0.3, and 1 mg/kg NTX before the sessions. The group that received subcutaneous NTX was also tested with a single intraperitoneal injection of 0.3 mg/kg NTX. Naltrexone significantly reduced ethanol self-administration, and NTX was more potent when administered via subcutaneous injection versus intraperitoneal injection. Ethanol intake (g/kg) was significantly reduced after subcutaneous injection of NTX 0.1 mg/kg and higher. In contrast, ethanol intake was significantly reduced after intraperitoneal injection of NTX 3 mg/kg and higher. A comparison of the NTX ED(50) values showed that subcutaneous NTX was approximately 30-fold more potent than intraperitoneal NTX. For the subcutaneous 0.3 mg/kg NTX dose, a detailed bin analysis showed that responding during the first 2 min after injection was similar to that during the first 2 min after a saline injection while responding after NTX decreased in subsequent bins. These findings suggest that researchers should carefully consider the route of NTX administration when discussing potency and selectivity of NTX's effects on ethanol-related behaviors in rats. These findings further support the notion that NTX acts by terminating responding early rather than reducing the initial responding.