Modeling Psychiatric Comorbidity: How Dopaminergic Dysregulation Mediates Nicotine-Induced Escalation of Alcohol Consumption
Abstract
Schizophrenia (SZ) is characterized by a profound comorbidity with substance use disorders (SUDs), with nicotine and alcohol use rates significantly exceeding those of the general population. A leading neurobiological hypothesis for this intersection is the dysregulation of dopamine (DA) signaling, specifically D2-like receptor hypersensitivity. This hypersensitivity, also present in conditions like Tourette’s and bipolar disorder, is thought to hyper-sensitize the brain's reward circuitry, increasing vulnerability to exogenous substances. To investigate the behavioral mechanisms driving this comorbidity, we utilized a quinpirole-primed model of dopamine (DA) dysregulation. This model involved male and female Sprague-Dawley rats, categorized as either the offspring of two neonatally saline-treated rats (SS) or the offspring of two rats treated neonatally with the -like receptor agonist quinpirole (QQ). We modeled alcohol seeking and consumption starting in adolescence (P30) by training rats to self-administer 10% ethanol in an operant setting. To model polydrug co-use, subjects received systemic nicotine (0.6 mg/kg) or saline 30 minutes prior to each 60-minute session. Following stable acquisition on a fixed-ratio 4 (FR4) schedule, rats underwent an extinction protocol in a distinct context, followed by a reinstatement test to assess the return of alcohol-seeking behavior. Behavioral results indicated that QQ rats (a model for DA dysregulation) exposed to nicotine displayed significantly higher rates of alcohol drinking compared to all other experimental groups (p < 0.05). Analysis revealed a significant main effect of founder (F(1,21) = 7.56, p < 0.013) and a significant interaction between founder and drug treatment (F(1,21) = 8.04, p < 0.011). These data suggest that nicotine acts as a potent catalyst for alcohol consumption specifically within the context of D2-like receptor hypersensitivity. These findings underscore the importance of addressing nicotine co-use when treating alcohol use disorders in psychiatric populations characterized by DA signaling dysregulations.
Start Time
15-4-2026 9:00 AM
End Time
15-4-2026 10:00 AM
Room Number
303
Presentation Type
Oral Presentation
Presentation Subtype
Grad/Comp Orals
Presentation Category
Science, Technology, and Engineering
Student Type
Graduate
Faculty Mentor
Justin Gass
Modeling Psychiatric Comorbidity: How Dopaminergic Dysregulation Mediates Nicotine-Induced Escalation of Alcohol Consumption
303
Schizophrenia (SZ) is characterized by a profound comorbidity with substance use disorders (SUDs), with nicotine and alcohol use rates significantly exceeding those of the general population. A leading neurobiological hypothesis for this intersection is the dysregulation of dopamine (DA) signaling, specifically D2-like receptor hypersensitivity. This hypersensitivity, also present in conditions like Tourette’s and bipolar disorder, is thought to hyper-sensitize the brain's reward circuitry, increasing vulnerability to exogenous substances. To investigate the behavioral mechanisms driving this comorbidity, we utilized a quinpirole-primed model of dopamine (DA) dysregulation. This model involved male and female Sprague-Dawley rats, categorized as either the offspring of two neonatally saline-treated rats (SS) or the offspring of two rats treated neonatally with the -like receptor agonist quinpirole (QQ). We modeled alcohol seeking and consumption starting in adolescence (P30) by training rats to self-administer 10% ethanol in an operant setting. To model polydrug co-use, subjects received systemic nicotine (0.6 mg/kg) or saline 30 minutes prior to each 60-minute session. Following stable acquisition on a fixed-ratio 4 (FR4) schedule, rats underwent an extinction protocol in a distinct context, followed by a reinstatement test to assess the return of alcohol-seeking behavior. Behavioral results indicated that QQ rats (a model for DA dysregulation) exposed to nicotine displayed significantly higher rates of alcohol drinking compared to all other experimental groups (p < 0.05). Analysis revealed a significant main effect of founder (F(1,21) = 7.56, p < 0.013) and a significant interaction between founder and drug treatment (F(1,21) = 8.04, p < 0.011). These data suggest that nicotine acts as a potent catalyst for alcohol consumption specifically within the context of D2-like receptor hypersensitivity. These findings underscore the importance of addressing nicotine co-use when treating alcohol use disorders in psychiatric populations characterized by DA signaling dysregulations.
