Reduced Polysubstance Self-Administration and Stress-Induced Reinstatement Following Systemic or Central Amygdala Hypocretin-Receptor Blockade in Rats
Location
D.P. Culp Center Ballroom
Start Date
4-5-2024 9:00 AM
End Date
4-5-2024 11:30 AM
Poster Number
129
Name of Project's Faculty Sponsor
Brooke Schmeichel
Faculty Sponsor's Department
Biomedical Sciences
Competition Type
Competitive
Type
Poster Presentation
Presentation Category
Health
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 combined HCRT-R1/2 on compulsive drug taking behavior, and fewer have examined the role of HCRT in drug-taking behavior involving a combined methamphetamine and fentanyl polysubstance. In this study, we examined the effects of systemic and intracranial site specific HCRT-R1/2 antagonism on compulsive polysubstance self-administration and stress-induced reinstatement, as modeled by escalated intake in rats allowed extended access to polysubstance. Male and female adult Wistar rats (N=40) were allowed either short (1h; ShA; n=8 male) or long (6h; LgA; n=16 male, n=15 female) access to polysubstance intravenous self-administration for 12 sessions (fixed ratio 1 reinforcement schedule). Those in the LgA group significantly increased their drug-taking over the 12 sessions (p<.01) and were taking significantly higher amounts of polysubstance during the first hour compared to the ShA group (p<.01). After escalation, a subset of LgA males and females were systemically administered a dual-HCRT-R antagonist (suvorexant; SUV-R1/2, 0 and 30mg/kg) 30 min prior to polysubstance self-administration testing. Systemic SUV-R1/2 administration showed significant attenuation of polysubstance-taking in both the first hour (p<.01) and full 6h (p<.05) session for male and female LgA rats. Another subset of brains from ShA and LgA male rats (n=8 each) were collected 1 day after the last self-administration session and assessed for HCRT-1, HCRT-R1 and -R2 optical density using immunohistochemical assays. LgA rats had a significantly higher density of HCRT-1 peptide in the central amygdala (CeA) when compared to naïve rats (p<.05), and higher HCRT-R1 compared to both ShA and naïve rats (p<.01). There was no change in HCRT-R2 density across groups. A final subset rats extinguished their drug-seeking behavior via substitution of saline for polysubstance during self-administration. Once lever pressing was extinguished, the rats were then tested for yohimbine-induced (2mg/kg) reinstatement of drug-seeking behavior. Stress-induced reinstatement was significantly attenuated in both males and females with systemic SUV administration (p<.01), and in females following intracerebral injections of SUV into the CeA (p<.01). Combined, these results suggest HCRT neurotransmission at both HCRT-R1 and -R2, particularly in the CeA, may contribute to polysubstance-taking and stress-induced polysubstance-seeking behavior.
Reduced Polysubstance Self-Administration and Stress-Induced Reinstatement Following Systemic or Central Amygdala Hypocretin-Receptor Blockade in Rats
D.P. 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 combined HCRT-R1/2 on compulsive drug taking behavior, and fewer have examined the role of HCRT in drug-taking behavior involving a combined methamphetamine and fentanyl polysubstance. In this study, we examined the effects of systemic and intracranial site specific HCRT-R1/2 antagonism on compulsive polysubstance self-administration and stress-induced reinstatement, as modeled by escalated intake in rats allowed extended access to polysubstance. Male and female adult Wistar rats (N=40) were allowed either short (1h; ShA; n=8 male) or long (6h; LgA; n=16 male, n=15 female) access to polysubstance intravenous self-administration for 12 sessions (fixed ratio 1 reinforcement schedule). Those in the LgA group significantly increased their drug-taking over the 12 sessions (p<.01) and were taking significantly higher amounts of polysubstance during the first hour compared to the ShA group (p<.01). After escalation, a subset of LgA males and females were systemically administered a dual-HCRT-R antagonist (suvorexant; SUV-R1/2, 0 and 30mg/kg) 30 min prior to polysubstance self-administration testing. Systemic SUV-R1/2 administration showed significant attenuation of polysubstance-taking in both the first hour (p<.01) and full 6h (p<.05) session for male and female LgA rats. Another subset of brains from ShA and LgA male rats (n=8 each) were collected 1 day after the last self-administration session and assessed for HCRT-1, HCRT-R1 and -R2 optical density using immunohistochemical assays. LgA rats had a significantly higher density of HCRT-1 peptide in the central amygdala (CeA) when compared to naïve rats (p<.05), and higher HCRT-R1 compared to both ShA and naïve rats (p<.01). There was no change in HCRT-R2 density across groups. A final subset rats extinguished their drug-seeking behavior via substitution of saline for polysubstance during self-administration. Once lever pressing was extinguished, the rats were then tested for yohimbine-induced (2mg/kg) reinstatement of drug-seeking behavior. Stress-induced reinstatement was significantly attenuated in both males and females with systemic SUV administration (p<.01), and in females following intracerebral injections of SUV into the CeA (p<.01). Combined, these results suggest HCRT neurotransmission at both HCRT-R1 and -R2, particularly in the CeA, may contribute to polysubstance-taking and stress-induced polysubstance-seeking behavior.