Effects of kappa opioid receptor manipulation on the development of methamphetamine-induced locomotor sensitization in adult male and female rats.

Abstract

Neural substrates playing a role in the development of sensitized behavioral responses after repeated methamphetamine exposure are not fully understood. In this study, we investigated the role of kappa opioid receptors (KORs) in the development of methamphetamine-induced locomotor sensitization, which is used as a rodent model for methamphetamine-induced sensitized behavioral responses. The study was conducted over 28 days using adult male and female rats. Methamphetamine (0.5mg/kg; i.p.)-induced increase in locomotor activity was measured on Days 2 and 28. On Days 3-8, animals were treated with methamphetamine (1mg/kg) injections followed by a period of no drug administration (Days 9-27). Manipulation of KORs was done using the KOR agonist (±U50488; 1.5 & 6mg/kg; s.c.; Days 3-8) or the KOR antagonist (norBNI; 5 & 15mg/kg; s.c.; Day 2) prior to methamphetamine (1mg/kg) treatment on Days 3-8. Difference in total distance travelled on Day 28 from Day 2 after methamphetamine administration was used as measure of methamphetamine-induced locomotor sensitization. Pretreatment with norBNI (15mg/kg but not 5mg/kg) prior to repeated methamphetamine (1mg/kg) treatment (Days 3-8) facilitated development of methamphetamine-induced locomotor sensitization in adult male, but not female rats. In contrast, pretreatment with ±U50488 (6mg/kg or 1.5mg/kg) prior to repeated methamphetamine (1mg/kg) treatment (Days 3-8) did not influence development of methamphetamine-induced locomotor sensitization in either adult male or female rats. Together, the data suggests differential sex-dependent effects of KOR blockade on the development of methamphetamine-induced locomotor sensitization.