Our research
A fundamental characteristic of chronic alcohol use is the comorbidity of alcohol dependence and disorders of affect, such as depression or anxiety disorders that are hypothesized to promote maladaptive behavioral regulation in the form of escalated alcohol self-administration and deficits in executive function.
Thus our research interests comprise:
- Neurobiology of Motivational Systems
- Excessive Self-Administration resulting from Alcohol and Drug Dependence
- Chronic Alcohol and Drug-Induced Depression and Anxiety
- Alcohol and Drug-Induced Alterations in Impulsivity
- Plasticity Associated with Negative Reinforcement Mechanisms
- Molecular and Genetic Determinants of Chronic Alcohol and Drug-related Altered Behavioral Regulation
- Trauma / Alcohol Use Disorder Co-morbidity
Alcohol Self-Administration
We use operant conditioning chambers to study motivated alcohol drinking in rodents. In our rat model, animals learn to press a lever to receive a small dose of 10% alcohol as a reinforcer. For mice, we use a similar setup where nose pokes trigger access to a sipper tube containing a solution of 15% alcohol.
These procedures allow us to precisely measure voluntary alcohol intake, motivation to drink, and the impact of experimental manipulations on reinforcement-related behavior.
Modeling Alcohol Use Disorder in rats
To model components of alcohol use disorder (AUD) such as alcohol dependence in rodents, one method we use is chronic intermittent ethanol exposure. This approach mimics cycles of intoxication and withdrawal seen in humans with AUD. This procedure produces stable blood alcohol levels and leads to behavioral and physiological signs of dependence similar to those observed in humans who are alcohol dependent and in withdrawal. Following vapor exposure, animals show hallmark phenotypes of AUD including increased alcohol consumption (see figure on the left), negative-affective like behaviors, and compromised executive function that provide a reliable platform to study the neurobiological mechanisms driving AUD.
Dynorphin and Kappa-Opioid Receptors
Dynorphin is an endogenous opioid peptide that activates kappa-opioid receptors (KORs), which are G protein-coupled receptors signaling primarily through inhibitory Gi/o pathways. KORs also engage a β-arrestin pathway, which mediates stress-like and aversive effects. Together, these pathways allow KORs to regulate multiple neurotransmitters, including dopamine, GABA, glutamate, norepinephrine, and serotonin, positioning them as key modulators of mood, motivation, and stress.
KORs are widely expressed in circuits controlling reward and addiction. In the mesolimbic dopamine pathway, which, in part, projects from the ventral tegmental area (VTA) to nucleus accumbens, KOR activation suppresses dopamine release, opposing the rewarding effects of endogenous opioids like β-endorphin. In the extended amygdala, including the bed nucleus of the stria terminalis, central amygdala and shell of the nucleus accumbens, KORs contribute to stress, anxiety, and negative emotional states that can drive maladaptive behaviors when dysregulated.
This duality makes KORs both protective and potentially harmful. While they can blunt addictive behaviors or reduce pain, they can also trigger dysphoria and anxiety, which may drive maladaptive decision-making and relapse.
By modulating dopamine in both the mesolimbic and mesocortical projections from the VTA, KORs provide a biological mechanism for stress-, trauma- and withdrawal-induced dysphoria that can drive maladaptive behavioral regulation in multiple domains, highlighting their central role in addictive, affective and executive function disorders.
The Opponent Role of μ- and κ-Opioid Receptors in Alcohol Use Disorder
When we drink alcohol, in the brain, natural opioid systems are activated in a carefully timed sequence. Initially, μ-opioid receptors (MORs) are triggered, promoting dopamine release in key reward regions like the ventral tegmental area (VTA) and nucleus accumbens, creating pleasurable, euphoric, reinforcing effects. Shortly after, κ-opioid receptors (KORs) are activated, inhibiting dopamine and producing a mild aversive or stress-like state.
In healthy, non-dependent individuals, this balance between MOR-mediated reward and KOR-mediated negative feedback keeps alcohol use in check. But with chronic alcohol exposure, the system shifts: MOR signaling becomes weaker, reducing the pleasurable effects, while KOR signaling becomes stronger, amplifying dysphoria and negative emotional states.
This shift underlies the opponent process in addiction from drinking to feel good, to drinking just to avoid feeling bad, driving the cycle of dependence.
Understanding how the dynorphin / kappa-opioid receptor system influences important emotional, motivational and executive function circuitry is a central focus of our lab, as it provides insights into the neurobiology of alcohol use disorder comorbid with certain psychiatric disorders to identify potential therapeutic targets.
From The Lab
Research fellows presenting at USF Research Days
