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

Abstract

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.

Sex differences in the ability of corticostriatal oscillations to predict rodent alcohol consumption

“…This change in NAcSh β power coincides with an increase in NAcSh dopamine content, suggesting that changes in NAcSh β oscillations are influenced by dopamine signaling in the striatum (or vice-versa). Additionally, alcohol-preferring P rats (sex unspecified) show reduced PFC-NAc θ coherence, which is enhanced during alcohol drinking, compared to Wistar rats, suggesting that reduced connectivity in corticostriatal circuits may be related to the increased alcohol consumption in P rats [26]. A significant amount of future work is required to understand the neural circuit dynamics of reward behavior across rat strains and across spatial resolutions (e.g., from single-cell to multi-cell to LFP recordings), but the current data supports the notion that electrical signals recorded in the NAcSh can serve as a valuable readout of substance use behaviors in male rodents.…”

“…For instance, in male rats, low-frequency oscillations decrease while high-frequency oscillations increase following an injection of alcohol [25]. Furthermore, low-frequency oscillations in the cortex and NAc appear to be hypoconnected in alcohol-preferring rats (sex not reported) compared to outbred rats, which was reversed by alcohol exposure [26]. LFP oscillations can therefore be a valuable readout of circuit dynamics related to alcohol-drinking behaviors (i.e., amount of alcohol consumed) in rodents.…”

Accumbens coordinated reset stimulation in mice exhibits ameliorating aftereffects on binge alcohol drinking

“…Coordinated reset stimulation (CRS) is designed to desynchronize hypersynchrony [10]. CRS has been reported to reshape connectivity patterns by inducing long-lasting desynchronization [11,16].…”

Sex differences in the ability of corticostriatal oscillations to predict rodent alcohol consumption

“…This change in NAcSh β power coincides with an increase in NAcSh dopamine content, suggesting that changes in NAcSh β oscillations are influenced by dopamine signaling in the striatum (or vice-versa). Additionally, alcohol-preferring P rats (sex unspecified) show reduced PFC-NAc θ coherence, which is enhanced during alcohol drinking, compared to Wistar rats, suggesting that reduced connectivity in corticostriatal circuits may be related to the increased alcohol consumption in P rats (26). A significant amount of future work is required to understand the neural circuit dynamics of reward behavior across spatial resolutions (e.g., from single-cell to multi-cell to LFP recordings), but the current data supports the notion that electrical signals recorded in the NAcSh can serve as a valuable readout of substance use behaviors in male rodents.…”