Acute naltrexone does not remediate fronto‐striatal disturbances in alcoholic and alcoholic polysubstance‐dependent populations during a monetary incentive delay task

Abstract

There is a concerted research effort to investigate brain mechanisms underlying addiction processes that may predicate the development of new compounds for treating addiction. One target is the brain's opioid system, due to its role in the reinforcing effects of substances of abuse. Substance-dependent populations have increased numbers of the mu opioid receptor (MOR) in fronto-striatal regions that predict drug relapse, and demonstrate disturbances in these regions during the processing of non-drug rewards. Naltrexone is currently licensed for alcohol and opiate dependence, and may remediate such disturbances through the blockade of MORs in fronto-striatal reward circuitry. Therefore, we examined the potential acute modulating effects of naltrexone on the anticipation of, and instrumental responding for, non-drug rewards in long-term abstinent alcoholics, alcoholic poly substance-dependent individuals and controls using a monetary incentive delay (MID) task during a randomized double blind placebo controlled fMRI study. We report that the alcoholic poly substance-dependent group exhibited slower and less accurate instrumental responding compared to alcoholics and controls that was less evident after acute naltrexone treatment. However, naltrexone treatment was unable to remediate disturbances within fronto-striatal regions during reward anticipation and "missed" rewards in either substance-dependent group. While we have not been able to identify the underlying neural mechanisms for improvement observed with naltrexone in the alcoholic poly-substance dependent group, we can confirm that both substance-dependent groups exhibit substantial neural deficits during an MID task, despite being in long-term abstinence.

Neuroimaging findings from an experimental pharmacology trial of naltrexone in heavy drinkers of East Asian descent

“…Notably, nonsignificant naltrexone effects were found both at the whole-brain voxel-wise level and in ROI analyses of reward processing regions (namely, VS, ACC, and OFC) that have previously been shown to be attenuate with naltrexone during alcohol consumption and cue paradigms (Mann et al, 2014;Myrick et al, 2008;Schacht et al, 2013b;,. These null findings do, however, corroborate and extend previous studies that have failed to observe significant naltrexone-induced changes in VS and in response to alcohol cues (Lukas et al, 2013) or during a monetary incentive delay task (Nestor et al, 2017).…”

The role of the opioid system in decision making and cognitive control: A review

“…Results from a study of opioid effects on financial decisions (trading game) suggest decreased reinforcement learning after naltrexone (50 mg, n = 62) compared to placebo (n = 116) in healthy participants (Efremidze, Sarraf, Miotto, & Zak, 2017). In contrast to these findings, one study reported no effects of opioid blockade (50 mg naltrexone) on BOLD responses to monetary wins and losses (Monetary Incentive Delay task) in 35 healthy participants (Nestor et al, 2017).…”

Naltrexone differentially modulates the neural correlates of motor impulse control in abstinent alcohol‐dependent and polysubstance‐dependent individuals

“…The insula cortex contains a high number of MORs (Zubieta et al ., ), also making it a target for the modulating effects of naltrexone. We previously reported that the same poly substance group showed a diminished response in the left AIC during acute naltrexone in response to missed rewards on a monetary incentive delay task (Nestor et al ., ), suggesting a blunting of error‐related signalling by naltrexone. The current study, however, suggests an opposing effect of naltrexone in the AIC, possibly by amplifying the detection of no‐go events under the demands of heightened performance monitoring.…”

“…For a full description of the cohort used in the current study, please see Nestor et al . (), which examined the same participant groups using a monetary incentive delay task (Nestor et al ., ). In the current study, the AUD group was made up of 21 abstinent alcoholics, with the poly‐SUD group comprised of 25 abstinent alcoholic polysubstance‐dependent individuals (having met criteria for dependence to alcohol plus one or more other substances of dependence).…”