Differential sex-dependent behavioral effects of methamphetamine in adolescent rats with a history of methamphetamine exposure and kappa opioid receptor manipulation

Abstract ID 93611 Poster Board 502 Methamphetamine abuse amongst adolescents has been on the rise in the United States. Exposure to methamphetamine followed by withdrawal can lead to sensitization of brain circuits, which can promote continued abuse of methamphetamine. However, neural substrates underlying methamphetamine-induced sensitization in adolescents has not been fully explored. In this study, we focused on the behavioral effects of methamphetamine in male and female adolescent rats with a history of methamphetamine exposure and kappa opioid receptors (KOR) manipulation. Adolescent male and female rats (approx. 4 weeks of age) were used in the study, which was conducted over 28 days. All animals were treated with saline on Day 1 to assess baseline locomotor activity and to habituate the animals to the locomotor activity chambers. Methamphetamine (0.5 mg/kg; i.p.) induced locomotor activity (primary dependent measure) was measured on Days 2 and 28 in all animals irrespective of treatment between Days 3-8 (period of intermittent repeated methamphetamine exposure). After assessment of methamphetamine-induced locomotor activity on Day 2, male and female adolescent rats were divided into three groups: Group one animals received an injection saline (1 ml/kg; s.c.; control) 30 minutes prior to treatment with methamphetamine (1 mg/kg; i,p,) daily for 6 days (Days 3-8); Group two animals received an injection of the KOR agonist (U50488; 6 mg/kg; s.c.) 30 minutes prior to treatment with methamphetamine (1 mg/kg; i,p,) daily for 6 days (Days 3-8); Group 3 animals received the KOR antagonist (norBNI; 15 mg/kg; s.c.) on Day 2 approximately four hours after measurement of methamphetamine (0.5 mg/kg; i.p.)-induced locomotor activity. Subsequently, all Group 3 animals were treated with an injection of methamphetamine (1 mg/kg; i,p,) daily for 6 days (Days 3-8). Animals received only one injection of the KOR antagonist (norBNI) because of its long duration of action. Animals received no methamphetamine treatment between Days 9-27 (drug-free/ withdrawal period). This drug-free period has been hypothesized to alter brain circuits resulting in sensitized responses to methamphetamine. Blockade of the KORs prior to methamphetamine (1 mg/kg) exposure (Days 3-8; Group 3) significantly increased methamphetamine-induced locomotor activity measured as percentage of baseline (Day 2) in adolescent male rats, but not female rats, compared to respective saline controls (Group 1). However, there was no significant difference in methamphetamine-induced locomotor activity on Day 28 measured as percentage of baseline (Day 2) in either male or female adolescent rats treated with the KOR agonist during methamphetamine (1 mg/kg) exposure (Days 3-8; Group 2) compared to respective saline controls (Group 1). Based on the data we can suggest an underlying inhibitory role of the KORs on methamphetamine-induced locomotor activity in adolescent male rats, which was unmasked by blocking KORs prior to methamphetamine (1 mg/kg) exposure. Previously, we had reported similar effects of blockade of the KORs on methamphetamine-induced locomotor activity in adult male, but not female, rats. Together, the data suggest a sex-dependent differential role for the KORs on methamphetamine-induced locomotor activity in adolescent male and female rats with a history of methamphetamine exposure and KOR manipulation. Supported by Endowed Pharmacy Centennial Research Award, Raabe College of Pharmacy and Ohio Northern University