Now or Later? An fMRI study of the effects of endogenous opioid blockade on a decision-making network

Henry J. Wheeler Brain Imaging Center, University of California, Berkeley, United States
Pharmacology Biochemistry and Behavior (Impact Factor: 2.78). 09/2009; 93(3):291-299. DOI: 10.1016/j.pbb.2009.02.008


Previously, we found that distinct brain areas predict individual selection bias in decisions between small immediate (“Now”) and larger delayed rewards (“Later”). Furthermore, such selection bias can be manipulated by endogenous opioid blockade. To test whether blocking endogenous opioids with naltrexone (NTX) alters brain activity during decision-making in areas predicting individual bias, we compared fMRI BOLD signal correlated with Now versus Later decision-making after acute administration of NTX (50 mg) or placebo. We tested abstinent alcoholics and control subjects in a double-blind two-session design. We defined regions of interest (ROIs) centered on activation peaks predicting Now versus Later selection bias. NTX administration significantly increased BOLD signal during decision-making in the right lateral orbital gyrus ROI, an area where enhanced activity during decision-making predicts Later bias. Exploratory analyses identified additional loci where BOLD signal during decision-making was enhanced (left orbitofrontal cortex, left inferior temporal gyrus, and cerebellum) or reduced (right superior temporal pole) by NTX. Additional analyses identified sites, including the right lateral orbital gyrus, in which NTX effects on BOLD signal predicted NTX effects on selection bias. These data agree with opioid receptor expression in human frontal and temporal cortices, and suggest possible mechanisms of NTX's therapeutic effects.

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    • "The present study employed the opioid receptor antagonist naltrexone , which is a competitive antagonist at μ-and κ-opioid receptors, and to a lesser extent at δ-opioid receptors (Kreek, 1996). We used a 50 mg single dose that is widely used in other cognitive studies in healthy volunteers (Katzen-Perez et al., 2001; Mitchell et al., 2007; Boettiger et al., 2009). Dopamine dysregulation has also been indicated in problem gambling, based on genetic data (Lobo and Kennedy, 2009) and studies measuring peripheral markers (Bergh et al., 1997; Meyer et al., 2004), as well as the provocative syndrome in Parkinson's Disease where medications acting at the dopamine D2/D3-receptor are linked to the emergence of disordered gambling as a side-effect (Voon et al., 2009; Djamshidian et al., 2011). "
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    ABSTRACT: Gambling is characterized by cognitive distortions in the processing of chance and skill that are exacerbated in pathological gambling. Opioid and dopamine dysregulation is implicated in pathological gambling, but it is unclear whether these neurotransmitters modulate gambling distortions. The objective of the current study was to assess the effects of the opioid receptor antagonist naltrexone and the dopamine D2 receptor antagonist haloperidol on gambling behavior. Male recreational gamblers (n = 62) were assigned to receive single oral doses of naltrexone 50 mg, haloperidol 2 mg or placebo, in a parallel-groups design. At 2.5 h post-dosing, participants completed a slot machine task to elicit monetary wins, "near-misses," and a manipulation of personal choice, and a roulette game to elicit two biases in sequential processing, the gambler's fallacy and the hot hand belief. Psychophysiological responses (electrodermal activity and heart rate) were taken during the slot machine task, and plasma prolactin increase was assessed. The tasks successfully induced the gambling effects of interest. Some of these effects differed across treatment groups, although the direction of effect was not in line with our predictions. Differences were driven by the naltrexone group, which displayed a greater physiological response to wins, and marginally higher confidence ratings on winning streaks. Prolactin levels increased in the naltrexone group, but did not differ between haloperidol and placebo, implying that naltrexone but not haloperidol may have been functionally active at these doses. Our results support opioid modulation of cognition during gambling-like tasks, but did not support the more specific hypothesis that naltrexone may act to ameliorate cognitive distortions.
    Frontiers in Behavioral Neuroscience 10/2013; 7:138. DOI:10.3389/fnbeh.2013.00138 · 3.27 Impact Factor
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    • "Neuroimaging studies have also examined the effects of NTX and A118G genotype on alcohol-related phenotypes. NTX has been reported to reduce alcohol-cue-elicited activation of reward-related brain areas among nontreatment-seeking alcoholics, including the VS, medial prefrontal cortex (mPFC), and orbitofrontal cortex (OFC; Myrick et al, 2008), and to increase OFC activation during decision-making (Boettiger et al, 2009). A118G genotype has also been reported to affect alcohol cue processing; among heavy drinkers, G-allele carriers have demonstrated greater cue-elicited activation of VS, OFC, mPFC/anterior cingulate, inferior frontal gyrus, and claustrum than A-allele homozygotes (Filbey et al, 2008). "
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    ABSTRACT: Variation at a single nucleotide polymorphism in the μ-opioid receptor gene (OPRM1), A118G (Asn40Asp), may moderate naltrexone (NTX) effects in alcohol dependence. Both NTX and A118G variation have also been reported to affect alcohol cue-elicited brain activation. This study investigated whether sub-acute NTX treatment and A118G genotype interacted in their effects on cue-elicited activation of the ventral striatum (VS), medial prefrontal cortex (mPFC), and orbitofrontal cortex (OFC). Secondarily, variation at a variable number tandem repeat polymorphism in the dopamine transporter gene (DAT1/SLC6A3), which has been associated with increased reward-related activation in VS, was analyzed as a moderator of medication and A118G effects. Seventy-four non-treatment-seeking alcohol-dependent individuals, half preselected to carry at least one copy of the A118G G (Asp) allele, were randomized to NTX (50 mg) or placebo for 7 days, and performed an fMRI alcohol cue reactivity task on day 6. Region-of-interest analyses indicated no main effects of medication or A118G genotype. However, these factors interacted in their effects on OFC activation, such that, among NTX-treated individuals, G-allele carriers had less activation than A-allele homozygotes. DAT1 variation also moderated medication/A118G effects. There was a three-way interaction between medication and A118G and DAT1 genotypes on VS activation, such that, among G-allele carriers who received NTX, DAT1 10-repeat-allele (10R) homozygotes had less activation than 9-repeat-allele (9R) carriers. Further, 10R homozygotes who received NTX had less mPFC activation than 9R carriers. Polymorphic variation in OPRM1 and DAT1 should be considered in future studies of NTX, particularly regarding its effects on reward processing.Neuropsychopharmacology advance online publication, 3 October 2012; doi:10.1038/npp.2012.195.
    Neuropsychopharmacology: official publication of the American College of Neuropsychopharmacology 10/2012; 38(3). DOI:10.1038/npp.2012.195 · 7.05 Impact Factor
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    • "The EOS may also have a role in certain cognitive processes relevant for control of addictive behavior including craving, decision-making and impulsivity (O'Malley et al., 2002; Bencherif et al., 2004; Boettiger et al., 2009; Love et al., 2009). Thus, a dysregulated EOS may contribute to impaired neurocognitive function and reduced regulation of alcohol/drug seeking and consumption . "
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    ABSTRACT: Alcoholism is a chronic relapsing disorder characterized by continued alcohol use despite numerous adverse consequences. Alcohol has been shown to interact with numerous neurotransmitter systems to exert its pharmacological effects. The endogenous opioid system (EOS) has been strongly implicated in the positive and negative reinforcing effects of alcohol. Traditionally recognized as dysphoric/anhedonic in nature, the dynorphin/kappa-opioid receptor (DYN/KOR) system has recently received considerable attention due to evidence suggesting that an upregulated DYN/KOR system may be a critical contributor to the complex factors that result in escalated alcohol consumption once dependent. The present review will discuss alcohol-induced plasticity in the DYN/KOR system and how these neuroadaptations could contribute to excessive alcohol seeking and consumption.
    Frontiers in Molecular Neuroscience 09/2012; 5:95. DOI:10.3389/fnmol.2012.00095 · 4.08 Impact Factor
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