COMT Inhibition Alters Cue-Evoked Oscillatory Dynamics during Alcohol Drinking in the Rat

Alterations in the corticostriatal system have been implicated in numerous substance use disorders, including alcohol use disorder (AUD). Adaptations in this neural system are associated with enhanced drug-seeking behaviors following exposure to cues predicting drug availability. Therefore, understanding how potential treatments alter neural activity in this system could lead to more refined and effective approaches for AUD. Local field potentials (LFPs) were acquired simultaneously in the prefrontal cortex (PFC) and nucleus accumbens (NA) of both alcohol preferring (P) and Wistar rats engaged in a Pavlovian conditioning paradigm wherein a light cue signaled the availability of ethanol (EtOH). On test days, the catechol-o-methyl-transferase (COMT) inhibitor tolcapone was administered prior to conditioning. Stimulus-evoked voltage changes were observed following the presentation of the EtOH cue in both strains and were most pronounced in the PFC of P rats. Phase analyses of LFPs in the θ band (5-11 Hz) revealed that PFC-NA synchrony was reduced in P rats relative to Wistars but was robustly increased during drinking. Presentation of the cue resulted in a larger phase reset in the PFC of P rats but not Wistars, an effect that was attenuated by tolcapone. Additionally, tolcapone reduced cued EtOH intake in P rat but not Wistars. These results suggest a link between corticostriatal synchrony and genetic risk for excessive drinking. Moreover, inhibition of COMT within these systems may result in reduced attribution of salience to reward paired stimuli via modulation of stimulus-evoked changes to cortical oscillations in genetically susceptible populations.