The Varodayan Lab

Investigating the synaptic mechanisms and neurocircuitry underlying alcohol use disorder and comorbid neuropsychiatric diseases

Noradrenergic dysfunction in alcohol use disorder

The noradrenergic stress system is a promising therapeutic target for alcohol use disorder. Adrenergic receptor antagonists reduce alcohol cravings and improve drinking outcomes in patients with alcohol use disorder. Furthermore, there are several cases of veterans treated for PTSD with adrenergic receptor antagonists becoming alcohol abstinent. While these clinical findings are promising, their underlying therapeutic mechanisms are unclear and there can be considerable side effects due to norepinephrine's diverse physiological functions. Thus, we aim to elucidate the neurobiological underpinnings of alcohol-induced noradrenergic dysfunction, and how these mechanisms contribute to the pathophysiology of alcohol use disorder. Specifically, we will examine how alcohol induces noradrenergic neuroadaptation within the medial prefrontal cortex to dysregulate its output to the central amygdala, and dissect the role of this circuit in excessive alcohol drinking, stress and anxiety.

Neuroimmune signaling & alcohol-induced cognitive dysfunction

The neuroimmune system regulates normal brain function to influence complex behavior, and its dysfunction is associated with several neuropsychiatric diseases, including alcohol use disorder. While it is well established that chronic alcohol alters neuroimmune expression and signaling, less is known about how specific neuroimmune pathways contribute to the development of alcohol use disorder. In this project we are investigating how interleukin-1β (IL-1β), a potent pro-inflammatory cytokine, influences medial prefrontal cortex activity to regulate normal cognitive function and alcohol-induced cognitive dysfunction.

Synergistic interactions of alcohol & stress in the medial prefrontal cortex

Stress is a major contributor to the pathophysiology of alcohol use disorder. Alcohol is anxiolytic and often used as “self-medication” to cope with stress, while stress can trigger alcohol craving and relapse in abstinent alcoholics. There is also a high rate of comorbidity between alcohol use disorder and stress/anxiety-related psychiatric diseases (e.g. PTSD), which can manifest in significant cognitive deficits including difficulties with emotional processing, riskier decision-making and less impulse control. By developing a combined alcohol/stress exposure model, we aim to identify shared neural substrates in medial prefrontal cortex synapses and circuits that mediate the synergistic effects of alcohol and stress on cognitive function.