Hypocretin signaling in the central amygdala drives methamphetamine self-administration in male rats

Methamphetamine use is growing in the United States and around the world. Hypocretin/orexin (HCRT) is a neuropeptide closely associated with drug-taking behaviors and stress response systems in humans and rodents. HCRT signaling occurs at HCRT-receptor 1 (HCRT-R1) and -receptor 2 (HCRT-R2); the contribution of signaling at each of these receptors to methamphetamine self-administration in rodents is largely unknown. These studies investigate the extent to which pharmacological HCRT-R1 and -R2 antagonists (RTIOX-276 [RTI] and JNJ-10397049 [JNJ], respectively) attenuate methamphetamine intake in adult male Wistar rats allowed either short or long access to intravenous methamphetamine self-administration under fixed and progressive ratio schedules of reinforcement. RTI and JNJ each elicited a dose-dependent attenuation of methamphetamine intake in rats allowed long, but not short, access to methamphetamine. Each antagonist also produced mild sedative-like effects on locomotor activity in drug naïve and short, but not long, access self-administration in rats. To further examine the role of HCRT in methamphetamine long access conditions, we measured HCRT-1 and HCRT-receptor densities in the amygdala, finding increased HCRT-1 and HCRT-R1 in the central amygdala (CeA), suggesting CeA as a target for HCRT activity in methamphetamine addiction-like behavior. Subsequent chemogenetic silencing of HCRT-neuronal projections from the dorsal hypothalamus to the CeA, a stress sensitive brain region implicated in addiction-like behaviors, significantly attenuated methamphetamine self-administration in rats allowed long access. Combined, these results suggest that HCRT signaling in the CeA is necessary for escalated methamphetamine-taking behavior characteristic of methamphetamine addiction.