Tolcapone Suppresses Ethanol Intake in Alcohol‐Preferring Rats Performing a Novel Cued Access Protocol

Abstract

Background Dopamine (DA) has been shown to play a central role in regulating motivated behavior and encoding reward. Chronic drug abuse elicits a state of hypodopaminergia in the mesocorticolimbic (MCL) system in both humans and preclinical rodent models of addiction, including those modeling alcohol use disorders (AUD). Methods Working under the hypothesis that reductions in the bioavailability of DA play an integral role in the expression of the excessive drinking phenotype, the COMT inhibitor Tolcapone was used as a means to amplify cortical DA efflux and drinking behaviors were then assessed. Sucrose and ethanol consumption were measured in P and Wistar rats in both a free choice drinking protocol and a novel cued access protocol. Results Tolcapone attenuated the consumption of ethanol, and to a lesser extent sucrose, in P rats in the cued access protocol, while no effect was observed in the free choice drinking protocol. Tolcapone also decreased ethanol consumption in high drinking Wistar rats. A follow-up experiment using the DA agonist D-amphetamine (AMPH) showed no change in ethanol consumption. Conclusions Collectively, these data suggest that COMT inhibitors may be capable of alleviating the extremely motivating or salient nature of stimuli associated with alcohol. The hypothesis is put forth that the relative specificity of Tolcapone for cortical DA systems may mediate the suppression of the high seeking/drinking phenotype.

Encoding of the Intent to Drink Alcohol by the Prefrontal Cortex Is Blunted in Rats with a Family History of Excessive Drinking

“…A summary of statistics for each figure is provided in table format (Table 1). To assess the neural dynamics of alcohol-associated cues within mPFC, extracellular electrophysiological activity was obtained from ensembles of neurons during performance of an alcohol-drinking task in Wistar and P rats matched for alcohol history (McCane et al, 2014; Linsenbardt and Lapish, 2015). Neural recordings were performed in well-trained animals that had more than seven weeks of prior alcohol experience.…”

Methamphetamine self‐administration reduces alcohol consumption and preference in alcohol‐preferring P rats

“…Acute treatments of non‐selective dopamine receptor agonists, as well as selective D 1 and D 2 receptor agonists, decrease alcohol consumption in alcohol‐preferring rats (Weiss et al ; Dyr et al ; McMillen et al ). Further support comes from a recent study where the catechol‐o‐methyltransferase inhibitor, talcapone, reduced alcohol consumption in a cued‐access paradigm (McCane et al ). Together, these studies suggest that increasing dopamine neurotransmission by inhibiting dopamine breakdown or enhancing dopamine receptor signaling may decrease alcohol intake.…”

Inhibition of Catechol-O-methyltransferase Does Not Alter Effort-Related Choice Behavior in a Fixed Ratio/Concurrent Chow Task in Male Mice

“…COMT inhibition has been proposed as a therapeutic strategy for combating cognitive impairment, particularly disorders of cognitive control (Apud and Weinberger, 2007). There is evidence in humans and rodents that COMT inhibition may be beneficial for specific populations (Gasparini et al, 1997;Kayser et al, 2012;McCane et al, 2014) or on specific cognitive tasks (Tunbridge et al, 2004;Byers et al, 2019). Determining the utility of COMT inhibitors will require data showing the effects of these compounds across multiple cognitive domains so that clinical populations that would benefit from this class of compounds can be identified.…”