Endogenous Opioid Blockade and Impulsive Responding in Alcoholics and Healthy Controls

University of California, Berkeley, Berkeley, California, United States
Neuropsychopharmacology (Impact Factor: 7.05). 03/2007; 32(2):439-49. DOI: 10.1038/sj.npp.1301226
Source: PubMed


The opioid receptor antagonist naltrexone (NTX) is one of few approved treatments for alcoholism, yet the mechanism by which it reduces drinking remains unclear. In rats, NTX reduces morphine-induced impulsive choice bias; however, nothing is known about the drug's effect on discrete aspects of impulsive behavior in humans, such as decision-making and inhibitory control. Here, we used a modified delay discounting procedure to investigate whether NTX improves decision-making or inhibitory control in humans. We measured the effect of acute NTX (50 mg) on choice between smaller sooner (SS) and larger later monetary rewards and on response errors (motor mismatch) in a high conflict condition in a group of abstinent alcoholics (AA) and healthy control subjects (CS). We previously reported that AA selected the SS option significantly more often than did CS in this paradigm. If the choice bias of AA is due to enhanced endogenous opioid signaling in response to potential reward, NTX should reduce such bias in the AA group. We found that NTX did not reliably reduce impulsive choice in the AA group; however, NTX's effect on choice bias across individuals was robustly predictable. NTX's effect on choice bias was significantly correlated with scores on Rotter's Locus of Control (LOC) scale; increasingly internal LOC scores predicted increasing likelihood of impulsive choices on NTX. In addition, we found that NTX significantly enhanced control of motor responses, particularly within the CS group. These results suggest that endogenous opioids may impair response selection during decision-making under conflict, and that NTX's effects on explicit decision-making are personality-dependent. Determining the biological basis of this dependence could have important implications for effective alcoholism treatment.

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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.
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    • "In each trial of the task, subjects were instructed to choose between two amounts of money, a smaller amount available " Now " (e.g., " $80 TODAY " ) or a larger amount available " Later " (e.g., " $100 in 1 month " ) (see Fig. 1). Results from a previous study, in which we manipulated endogenous opioid levels of subjects engaged in this task, suggested that basal frontal dopamine (DA) levels are inversely related to the frequency of impulsive choices (Mitchell et al., 2007). Moreover , acute elevation of DA reduces immediate reward bias in humans (de Wit et al., 2002). "
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    ABSTRACT: Impulsivity, a risk factor for substance abuse disorders, is modulated by the Val158 variant of the catechol-O-methyltransferase (COMT) gene. Rodent studies have shown that opioids enhance impulsivity. Furthermore, alcohol consumption leads to endogenous opioid release in the cortex and nucleus accumbens (NAc), and this opioid release is correlated with greater positive hedonic effect. Using the selective mu opioid receptor radioligand [(11) C] carfentanil, we find that, following alcohol consumption, individuals with the COMT Val158 allele have greater opioid release in the right NAc but less release in medial orbital frontal cortex (OFC). These data suggest that genetic regulation of dopamine levels can affect alcohol consumption in part by modulating endogenous opioid release in specific brain regions implicated in reward, which in turn promotes impulsive choice.
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    • "Participants are faced with the choice of a small immediate reward, or a larger delayed reward; choosing the smaller immediate reward indicates a higher degree of impulsivity. Increased discounting of larger delayed rewards has been found in heroin-(Madden et al., 1997; Kirby et al., 1999; Kirby and Petry, 2004), cocaine-(Coffey et al., 2003; Kirby and Petry, 2004), and alcohol (Petry, 2001; Bjork et al., 2004a; Mitchell et al., 2007) -dependent individuals. Drug rewards are discounted at an even higher rate than monetary rewards (Madden et al., 1997, 1999; Kirby et al., 1999). "
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