Effects of Single and Dual Hypocretin-receptor Blockade or Knockdown of Hypocretin Amygdalar Projections on Alcohol Drinking in Dependent Male Rats
Location
Culp Ballroom
Start Date
4-7-2022 9:00 AM
End Date
4-7-2022 12:00 PM
Poster Number
88
Faculty Sponsor’s Department
Biomedical Sciences
Name of Project's Faculty Sponsor
Brooke Schmeichel
Additional Sponsors
Cerrone Foster, Patrick Bradshaw
Competition Type
Competitive
Type
Poster Presentation
Project's Category
Neuroscience
Abstract or Artist's Statement
Hypocretin/Orexin (HCRT) is a neuropeptide that is associated with both stress and reward systems in humans and rodents. The different contributions of signaling at hypocretin-receptor 1 (HCRT-R1) and hypocretin-receptor 2 (HCRT-R2) to compulsive alcohol drinking are not yet fully understood. Thus, the current studies used pharmacological and viral-mediated targeting of HCRT to determine participation in compulsive alcohol drinking and measured HCRT-receptor mRNA expression in the extended amygdala of both alcohol-dependent and non-dependent male rats. Rats were made dependent through chronic intermittent exposure to alcohol vapor and were tested for the acute effect of HCRT-R1-selective (SB-408124; SB-R1), HCRT-R2-selective (NBI-80713; NB-R2), or dual HCRT-R1/2 (NBI-87571; NB-R1/2) antagonism on alcohol intake. NB-R2 and NB-R1/2 antagonists each dose-dependently decreased overall alcohol drinking in alcohol-dependent rats, whereas, SB-R1 decreased alcohol drinking in both alcohol-dependent and non-dependent rats at the highest dose (30 mg/kg). SB-R1, NB-R2, and NB-R1/2 treatment did not significantly affect water drinking in either alcohol-dependent or non-dependent rats. Additional PCR analyses revealed a significant decrease in Hcrtr1 mRNA expression within the central amygdala (CeA) of dependent rats under acute withdrawal conditions compared to nondependent rats. Lastly, a shRNA-encoding adeno-associated viral vector with retrograde function was used to knockdown HCRT in CeA-projecting neurons from the lateral hypothalamus (LH). LH-CeA HCRT knockdown significantly attenuated alcohol self-administration in alcohol-dependent rats. These observations suggest that HCRT signaling in the CeA is necessary for alcohol-seeking behavior during dependence. Together, these data highlight a role for both HCRT-R1 and -R2 in dependent alcohol-seeking behavior.
Effects of Single and Dual Hypocretin-receptor Blockade or Knockdown of Hypocretin Amygdalar Projections on Alcohol Drinking in Dependent Male Rats
Culp Ballroom
Hypocretin/Orexin (HCRT) is a neuropeptide that is associated with both stress and reward systems in humans and rodents. The different contributions of signaling at hypocretin-receptor 1 (HCRT-R1) and hypocretin-receptor 2 (HCRT-R2) to compulsive alcohol drinking are not yet fully understood. Thus, the current studies used pharmacological and viral-mediated targeting of HCRT to determine participation in compulsive alcohol drinking and measured HCRT-receptor mRNA expression in the extended amygdala of both alcohol-dependent and non-dependent male rats. Rats were made dependent through chronic intermittent exposure to alcohol vapor and were tested for the acute effect of HCRT-R1-selective (SB-408124; SB-R1), HCRT-R2-selective (NBI-80713; NB-R2), or dual HCRT-R1/2 (NBI-87571; NB-R1/2) antagonism on alcohol intake. NB-R2 and NB-R1/2 antagonists each dose-dependently decreased overall alcohol drinking in alcohol-dependent rats, whereas, SB-R1 decreased alcohol drinking in both alcohol-dependent and non-dependent rats at the highest dose (30 mg/kg). SB-R1, NB-R2, and NB-R1/2 treatment did not significantly affect water drinking in either alcohol-dependent or non-dependent rats. Additional PCR analyses revealed a significant decrease in Hcrtr1 mRNA expression within the central amygdala (CeA) of dependent rats under acute withdrawal conditions compared to nondependent rats. Lastly, a shRNA-encoding adeno-associated viral vector with retrograde function was used to knockdown HCRT in CeA-projecting neurons from the lateral hypothalamus (LH). LH-CeA HCRT knockdown significantly attenuated alcohol self-administration in alcohol-dependent rats. These observations suggest that HCRT signaling in the CeA is necessary for alcohol-seeking behavior during dependence. Together, these data highlight a role for both HCRT-R1 and -R2 in dependent alcohol-seeking behavior.