Project Title

Hypocretin-Receptor Antagonists for Treatment of Methamphetamine Use Disorder

Authors' Affiliations

Tyler Zarin, Biomedical Sciences Department, Quillen College of Medicine, East Tennessee State University, Johnson City, TN Dr. Brooke Schmeichel, Biomedical Sciences Department, Quillen College of Medicine, East Tennessee State University, Johnson City, TN

Location

Culp Room 304

Start Date

4-6-2022 10:00 AM

End Date

4-6-2022 11:00 AM

Faculty Sponsor’s Department

Biomedical Sciences

Name of Project's Faculty Sponsor

Brooke Schmeichel

Classification of First Author

Graduate Student-Doctoral

Competition Type

Competitive

Type

Oral Presentation

Project's Category

Neuroscience

Abstract or Artist's Statement

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<0.01, p<0.05), 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<0.05). Beam breaks were significantly reduced following RTI-R1 (p<0.05) and SUV-R1/2 (p<0.05) in ShA rats only, although both JNJ-R2 (p<0.05) and SUV-R1/2 (p<0.05) 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.

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Apr 6th, 10:00 AM Apr 6th, 11:00 AM

Hypocretin-Receptor Antagonists for Treatment of Methamphetamine Use Disorder

Culp Room 304

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<0.01, p<0.05), 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<0.05). Beam breaks were significantly reduced following RTI-R1 (p<0.05) and SUV-R1/2 (p<0.05) in ShA rats only, although both JNJ-R2 (p<0.05) and SUV-R1/2 (p<0.05) 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.