BETAINE MITIGATES REINSTATEMENT OF METHAMPHETAMINE- INDUCED CONDITIONED PLACE PREFERENCE IN RATS: INVOLVEMENT OF CAMKK2/AMPK SIGNALING

Abstract Background Methamphetamine (MA) use represents a significant worldwide public health concern. Currently, no pharmacological therapy has established efficacy for treating MA use disorder. Betaine has been found to reduce MA-induced behavioral sensitization. In addition, betaine activates adenosine monophosphate (AMP)-activated protein kinase (AMPK) which has been associated with reinstatement of cocaine seeking. Aims & Objectives This study aimed to examine the effects of betaine on conditioning and reinstatement of MA-conditioned place preference (CPP). Additionally, it sought to explore the involvement of AMPK and its upstream activator, calcium/calmodulin-dependent protein kinase (CAMKK2), in the reducing effect of betaine on the reinstatement of MA CPP. Method Male Sprague-Dawley rats underwent a three-compartment CPP paradigm. Betaine or saline was administered 30 minutes prior to each MA (2 mg/kg) conditioning session or 30 minutes before MA (1 mg/kg) priming-induced reinstatement. To determine the roles of AMPK and CAMKK2 in betaine's reducing effect on the reinstatement of MA CPP, rats received bilateral intra-NAc core infusions of the AMPK inhibitor dorsomorphin or STO-609, a selective inhibitor of CAMKK2, followed by betaine (100 μ g/μ l) before MA priming-induced reinstatement. Results Betaine did not affect conditioning, but significantly reduced reinstatement of MA CPP at 100 mg/kg. Furthermore, acute intra-NAc core infusions of betaine effectively ameliorated the reinstatement of MA CPP, and this effect was abolished by co-treatment with dorsomorphin or STO- 609. Discussion & Conclusions These findings suggest that betaine may be a novel therapeutic agent for the treatment of MA use disorder, and activation of the CAMKK2-AMPK pathway might be one of the mechanisms underlying the MA relapse-preventing effect of betaine.