Activation of lateral hypothalamic melanin-concentrating hormone neurons mediates sex-specific patterns of methamphetamine self-administration in rats.

Methamphetamine use disorder remains an ongoing public health concern. The neural systems underlying differences in methamphetamine reinforcement, especially between sexes, remain poorly understood. Here, we investigated the role of lateral hypothalamic melanin-concentrating hormone (MCH) neurons in methamphetamine self-administration. A combinatorial viral approach was used to deliver activating DREADDs (Designer Receptors Exclusively Activated by Designer Drugs, hM3D) to these MCH neurons in female and male rats. Rats were trained with daily 2-hour sessions of intravenous methamphetamine self-administration (0.05 mg/kg/inf). Then, MCH neurons were activated during test sessions across 5 different methamphetamine doses. LH MCH activation produced bidirectional, sex-specific effects: enhanced methamphetamine intake in female and reduced intake in male rats, particularly at lower methamphetamine doses. Despite equivalent acquisition rates between sexes during training, divergent behavioral outcomes emerged specifically after targeted MCH activation. These findings demonstrate that MCH signaling exerts unique effects on reinforcement behavior and suggest that it regulates methamphetamine's reinforcing properties in both a sex- and methamphetamine dose-dependent manner. Other measures such as latency to first infusion and inter-infusion intervals remained unchanged across groups, supporting the specificity of MCH's impact on methamphetamine reinforcement rather than general arousal, locomotor output, or a specific effect of CNO pretreatment. These findings underscore the critical role of hypothalamic MCH neurons in modulating drug reward and highlight sex as a necessary biological factor for developing pharmacotherapeutic interventions that target this area for the treatment of psychostimulant use disorders.