Effects of kappa opioid receptor manipulation on methamphetamine-induced behavioral sensitization in adolescent male and female rats

Methamphetamine abuse amongst adolescents has been on the rise in the United States. In this study, we assessed the effects of manipulation of KORs on methamphetamine-induced behavioral sensitization in adolescent male and female rats. Methamphetamine-induced behavioral sensitization is an animal model to study methamphetamine addiction. Behavioral sensitization usually occurs in animals who have been treated with methamphetamine followed by a period of withdrawal. It is hypothesized that brain circuits are altered during the period of withdrawal after methamphetamine exposure resulting in sensitized (increased) responses to methamphetamine at the end of the withdrawal period. The experiment was conducted over 28 days. Animals were exposed to methamphetamine (1 mg/kg) for 6 days (Days 3-8) followed by withdrawal of methamphetamine from Days 9-27. KORs were manipulated during methamphetamine exposure using the KOR agonist (U50488; 1.5 & 6 mg/kg) and antagonist (NorBNI; 15 mg/kg). Blockade of the KORs during methamphetamine exposure resulted in significantly increased methamphetamine-induced locomotor sensitization in adolescent male rats, but not female rats, compared to respective saline controls. However, activation of KORs during methamphetamine exposure did not influence methamphetamine-induced locomotor sensitization compared to saline controls irrespective of sex. Based on the data, we hypothesize a sex-dependent underlying inhibitory role of the KORs in methamphetamine-induced locomotor sensitization in adolescent animals, which was unmasked by blockade of KORs in male, but not female rats. Although more work is required, the present data suggests that KORs can serve as potential target for the treatment of methamphetamine addiction.Key words: sensitization, methamphetamine, opioid receptors, agonist, antagonist, sex, adolescent, stereotypy, abuse, addiction