Reduced methamphetamine self-administration following single or dual hypocretin-receptor blockade or viral vector hypocretin-knockdown in adult male rats

Authors' Affiliations

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

Location

Culp Center Ballroom

Start Date

4-25-2023 9:00 AM

End Date

4-25-2023 11:00 AM

Poster Number

17

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

Poster 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 this study, we examined the effects of HCRT-R1, -R2, and -R1/2 antagonists on compulsive METH self-administration, as modeled by escalated intake in adult male Wistar rats allowed extended access to METH. Three cohorts of rats were allowed either short (1h; ShA; n=7-10/cohort) or long (6h; LgA; n=7-9/cohort) access to METH intravenous self-administration for 14 sessions (fixed ratio 1 schedule). Each cohort was then systemically administered a single- or dual-HCRT-R antagonist 30 min prior to METH self-administration testing: 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 elicited a dose-dependent reduction in METH intake in LgA, but not ShA, in the first hour. Administration of JNJ-R2 had no effect on METH intake in the first hour in neither ShA nor LgA rats, but reduced METH intake during the full 6 h session at the lowest dose. SUV-R1/2 administration had no effect on METH intake in ShA rats, but showed significant attenuation of METH-taking at the highest dose in both the first hour and full 6h session for LgA rats. Locomotor activity was significantly reduced following RTI-R1 and SUV-R1/2 in ShA rats only. To further explore the role that HCRT plays in METH dependence after a period of abstinence, we used a shRNA-encoding adeno-associated viral vector (AAV) to silence Hcrt in a separate cohort of previously-escalated METH-dependent rats. Following an initial escalation phase, and prior to a 3-week period of drug abstinence, rats were injected with either a control scramble-RNA AAV (AAV-Scram; n= 4) or a Hcrt-knockdown AAV (AAV-HCRT-KD; n= 5). AAV-Scram rats showed a significant decrease in METH self-administration post-abstinence, and a subsequent increase in METH-taking following a re-escalation period. In contrast, AAV-HCRT-KD rats showed a significant attenuation of METH self-administration following the re-escalation period. Combined, these results suggest HCRT neurotransmission at both HCRT-R1 and -R2 may contribute to compulsive METH-taking behavior.

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Apr 25th, 9:00 AM Apr 25th, 11:00 AM

Reduced methamphetamine self-administration following single or dual hypocretin-receptor blockade or viral vector hypocretin-knockdown in adult male rats

Culp Center Ballroom

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 this study, we examined the effects of HCRT-R1, -R2, and -R1/2 antagonists on compulsive METH self-administration, as modeled by escalated intake in adult male Wistar rats allowed extended access to METH. Three cohorts of rats were allowed either short (1h; ShA; n=7-10/cohort) or long (6h; LgA; n=7-9/cohort) access to METH intravenous self-administration for 14 sessions (fixed ratio 1 schedule). Each cohort was then systemically administered a single- or dual-HCRT-R antagonist 30 min prior to METH self-administration testing: 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 elicited a dose-dependent reduction in METH intake in LgA, but not ShA, in the first hour. Administration of JNJ-R2 had no effect on METH intake in the first hour in neither ShA nor LgA rats, but reduced METH intake during the full 6 h session at the lowest dose. SUV-R1/2 administration had no effect on METH intake in ShA rats, but showed significant attenuation of METH-taking at the highest dose in both the first hour and full 6h session for LgA rats. Locomotor activity was significantly reduced following RTI-R1 and SUV-R1/2 in ShA rats only. To further explore the role that HCRT plays in METH dependence after a period of abstinence, we used a shRNA-encoding adeno-associated viral vector (AAV) to silence Hcrt in a separate cohort of previously-escalated METH-dependent rats. Following an initial escalation phase, and prior to a 3-week period of drug abstinence, rats were injected with either a control scramble-RNA AAV (AAV-Scram; n= 4) or a Hcrt-knockdown AAV (AAV-HCRT-KD; n= 5). AAV-Scram rats showed a significant decrease in METH self-administration post-abstinence, and a subsequent increase in METH-taking following a re-escalation period. In contrast, AAV-HCRT-KD rats showed a significant attenuation of METH self-administration following the re-escalation period. Combined, these results suggest HCRT neurotransmission at both HCRT-R1 and -R2 may contribute to compulsive METH-taking behavior.