Hypocretin-Receptor Antagonists for Treatment of Methamphetamine Use Disorder

The hypocretin/orexin (HCRT) system is associated with compulsive stimulant drug use, involving both HCRT-receptor 1 (-R1) and HCRT-receptor 2 (-R2). Few studies, however, have examined the role of HCRT-R2 or combined HCRT-R1/2 on compulsive methamphetamine (METH) taking behavior. In thus study, we examine the effects of HCRT R1, R2, and R1/2 antagonists on compulsive METH self-administration, as modeled by escalated intake in rats allowed extended access to the drug. Three cohorts of male rats were allowed either short (1h; ShA; n=7-10/cohort) and long (12h; LgA; n=7-9/cohort) access to METH intravenous self-administration for 14 sessions (fixed ratio 1 schedule). Each cohort of rats was systemically administered a single- or dual-HCRT-R antagonist 30 min prior to drug-taking operant testing in a latin-square design: cohort 1, selective HCRT-R1 antagonist (RTIOX-276; RTI-R1; 0, 10, and 20 mg/kg); cohort 2, selective HCRT-R2 antagonist (JNJ-10397049; JNJ-R2; 0, 10, and 20 mg/kg); and cohort 3, dual HCRT-R1/2 antagonist (Suvorexant; SUV-R1/2; 0, 30, and 60 mg/kg). RTI-R1 and SUV-R1/2 dose-dependently reduced METH intake in LgA (p\u3c0.01, p\u3c0.05), but not ShA (p=0.14, p=0.06), rats in the first hour. Administration of JNJ-R2, however, had no effect on METH intake in the first hour in either ShA (p=0.58) or LgA (p=0.58), but had deferred effects in LgA rats reducing overall METH intake over the full 6 h session (p\u3c0.05). Beam breaks were significantly reduced following RTI-R1 (p\u3c0.05) and SUV-R1/2 (p\u3c0.05) in ShA rats only, although both JNJ-R2 (p\u3c0.05) and SUV-R1/2 (p\u3c0.05) reduced beam breaks in METH naïve rats, indicating a possible confound of generalized effects on locomotor. Combined, these results suggest HCRT-R1 neurotransmission, in particular, may contribute to compulsive METH taking associated with stimulant use disorder. Future studies will investigate the contribution of HCRT to pervasive compulsive METH use after a period of drug abstinence