A number of neural processing streams converge in the prefrontal cortex (PFC), and balancing the confluence of information processed by this region is critical for regulating behavior. The maintenance and integration of information in this region is primarily achieved through alterations in neuromodulatory drive and is critically altered in individuals with an alcohol use disorder (AUD) or those vulnerable to this condition. Specifically, the modulatory neurotransmitter dopamine (DA) has been strongly implicated in the motivational aspects of reinforcement learning, reward choice behavior, and in processing of reward-related stimuli in both rats and humans. Considering this, identifying how neuromodulators, such as DA, mediate information transfer in the PFC and how they are altered as a consequence of alcohol drinking and in those at risk for excessive drinking represents a currently unmet and critical need. The rationale of this research plan is that imbalanced DA signaling in the PFC leads to alterations in neural processing, which plays a key role in the excessive motivational properties acquired by alcohol in AUD. The uptake and diffusion kinetics of DA in the PFC are unique compared with the rest of the brain, in that they are largely mediated by the enzyme catechol-O-methyl- transferase (COMT). Nine NIH-registered clinical trials are currently assessing if the COMT inhibitor, Tolcapone, is a viable treatment option for a number of neuropsychiatric disorders, including substance use and gambling disorders. However, a clear therapeutic mechanism of this drug has not been identified. Preliminary data from our group strongly indicates that Tolcapone suppresses alcohol-motivated behaviors in a rodent model of excessive drinking. These data inspired a multidisciplinary set of experiments to determine if the effects of Tolcapone are mediated via the PFC DA system and how this drug alters neural processing in this brain region.
Specific Aim 1 will determine if Tolcapone suppresses alcohol-motivated behaviors through PFC DA receptors.
Specific Aim 2 will quantify line and sex differences in COMT and determine if adaptive changes in COMT occur following motivated behavior.
Specific Aim 3 will characterize electrophysiological activity during anticipation and drinking to identify which measures are necessary for alcohol-motivated behaviors. Since Tolcapone administration will suppress alcohol-motivated behaviors it should therefore interfere with the neural processes necessary for them. In this way, these data will move beyond correlations between physiology and behavior and allow causal relationships to be established between changes in neural activity and alcohol-motivated behaviors.
This project will follow up on a series of preliminary studies showing that blocking the activity of the dopamine-metabolizing enzyme, COMT, suppresses excessive alcohol drinking. The proposed experiments employ a multidisciplinary approach with the goal of discovering how inhibiting COMT suppresses ethanol-motivated behaviors. These experiments will trace protein-level changes in COMT to alterations in neural function, and ultimately behavior. These data will potentially lead to the development of novel pharmacotherapies as well as metrics to assess potential treatment strategies.
