Qualitative differences between C57BL/6J and DBA/2J mice in morphine potentiation of brain stimulation reward and intravenous self-administration

The C57BL/6J (C57) and DBA/2J (DBA) mice are the most common genotypes used to identify chromosomal regions and neurochemical mechanisms of interest in opioid addiction. Unfortunately, outside of the oral two-bottle choice procedure, limited and sometimes controversial evidence is available for determining their relative sensitivity to the rewarding effects of morphine. The purpose of this study was to utilize classically accepted models of drug abuse liability to determine relative susceptibility to the rewarding effects of morphine. The ability of morphine or amphetamine to potentiate lateral hypothalamic brain stimulation and intravenous morphine self-administration (across three doses in a fixed ratio schedule and at the highest dose in progressive ratio schedules) was investigated in both genotypes. In both measures, C57 and DBA mice differed dramatically in their response to morphine. Morphine potentiated rewarding stimulation in the C57 mice but antagonized it in the DBA mice. Consistent with these findings, intravenous morphine did not serve as a positive reinforcer in DBA mice under conditions that were effective in the C57 mice using a fixed ratio schedule and failed to sustain levels of responding sufficient to maintain a constant rate of drug intake under a progressive ratio schedule. In contrast, amphetamine potentiated the rewarding effects of brain stimulation similarly in the two genotypes. These findings provide strong evidence that morphine is rewarding in the C57 genotype and not in the DBA genotype. Understanding their relative susceptibility is important given the prominence of these genotypes in candidate gene identification and gene mapping.