Mouse model of the OPRM1 (A118G) polymorphism: differential heroin self-administration behavior compared with wild-type mice.

Abstract

Mu-opioid receptors (MOPRs) are the target of heroin and other prescription opioids, which are currently responsible for massive addiction morbidity in the US. The gene coding for the human MOPR (OPRM1) has an important functional single nucleotide polymorphism (SNP), A118G. The OPRM1 A118G genotype results in substantially increased risk of heroin addiction in humans; however, the neurobiological mechanism for this increased risk is not fully understood. This study examined heroin self-administration (SA) behavior in A112G (G/G) mice, harboring a functionally equivalent SNP in Oprm1 with a similar amino acid substitution, in extended (4 h) SA sessions. Adult male and female G/G mice and 'wild-type' litter mates (A/A) were allowed to self-administer heroin (0.25 mg/kg/unit dose, FR1 with a nose poke response) for 4 h/day, for 10 consecutive days. Half of the mice then continued in a heroin dose-response study, while extinction from heroin SA was studied in the other half. In vivo microdialysis was used to measure acute heroin-induced increases of striatal dopamine in the GG vs AA genotypes. Male and female G/G mice responded for heroin significantly more (and thus had greater intake) than A/A mice, in the initial 10 days of heroin SA, and in the subsequent dose-response study. There were no significant differences in extinction of SA between the A/A and G/G mice. Heroin-induced increases in striatal dopamine levels are higher in the GG mice than in the AA mice. Both male and female G/G mice self-administered more heroin than did A/A mice over a 10-day period, possibly because of the greater increases of heroin-induced striatal dopamine in the GG mice. Furthermore, G/G male mice escalated the amount of heroin self-administration across 10 extended-access sessions more than A/A male mice did. These are the first studies to examine the acquisition of heroin SA in this mouse model. These studies may lead to a better understanding of the neurobiological and behavioral mechanisms that underlie greater risk of heroin addiction in carriers of the A118G SNP.