Addiction neuroscience最新文献

The non-selective opioid receptor antagonist, naltrexone is one of the most prescribed medications for treating alcohol and opioid addiction. Despite decades of clinical use, the mechanism(s) by which naltrexone reduces addictive behavior remains unclear. Pharmaco-fMRI studies to date have largely focused on naltrexone's impact on brain and behavioral responses to drug or alcohol cues or on decision-making circuitry. We hypothesized that naltrexone's effects on reward-associated brain regions would associate with reduced attentional bias (AB) to non-drug, reward-conditioned cues. Twenty-three adult males, including heavy and light drinkers, completed a two-session, placebo-controlled, double-blind study testing the effects of acute naltrexone (50 mg) on AB to reward-conditioned cues and neural correlates of such bias measured via fMRI during a reward-driven AB task. While we detected significant AB to reward-conditioned cues, naltrexone did not reduce this bias in all participants. A whole-brain analysis found that naltrexone significantly altered activity in regions associated with visuomotor control regardless of whether a reward-conditioned distractor was present. A region-of-interest analysis of reward-associated areas found that acute naltrexone increased BOLD signal in the striatum and pallidum. Moreover, naltrexone effects in the pallidum and putamen predicted individual reduction in AB to reward-conditioned distractors. These findings suggest that naltrexone's effects on AB primarily reflect not reward processing per se, but rather top-down control of attention. Our results suggest that the therapeutic actions of endogenous opioid blockade may reflect changes in basal ganglia function enabling resistance to distraction by attractive environmental cues, which could explain some variance in naltrexone's therapeutic efficacy.

Contextual processing is implicated in the pathophysiology of addictive disorders, but the nature of putative deficiencies remains unclear. We assessed some aspects of contextual processing across multimodal experimental procedures with detoxified subjects who were dependent on opioids (n = 18), alcohol- (n = 20), both opioids and alcohol (n = 22) and healthy controls (n = 24) using a) facial- and b) emotionally laden images; c) gambling task and d) sucrose solutions. Healthy subjects displayed consistent response pattern throughout all categories of the presented stimuli. As a group, dependent subjects rated (i.e., valuated) attractive and average faces respectively more and less attractive in comparison to controls. Dependent subjects' motivational effort, measured in the units of computer keypress to determine the attractive faces' viewing time, accorded the valuational context but was diminished relatively to the average faces’ valuation. Dependent subjects’ motivational effort for pleasant and aversive images respectively mirrored the attractive and average faces; their neutral images’ motivational effort was incongruent with the valuational context framed by the intermixed images. Also, dependent subjects’ emotional responses to counterfactual comparisons of gambling outcomes were unmatched by the riskiness context. Moreover, dependent subjects failed to show greater liking of sweet solutions that normally accompanies low sweetness perceptual context indicative of higher sucrose concentration needed for maximal hedonic experience. Consistent differences among the dependent groups (opioid vs. alcohol vs. comorbid) on the above procedures were not observed. The present findings suggest that opioid and/or alcohol dependence may be associated with amplified hedonic and motivational valuation of pleasant stimuli and with a disrupted link between behavioral/emotional responsivity and contextual variations. Further research is warranted to unravel the distinctive features of contextual processing in opioid- vis-à-vis alcohol addiction and how these features may interrelate in comorbid conditions.

Cue-induced reward-seeking behaviors are regulated by both the affective and cognitive control systems of the brain. This study aimed at investigating how individual differences in affective and cognitive responses to cues predicting food rewards contribute to the regulation of cue-induced eating. We recorded electroencephalogram (EEG) from 59 adults while they viewed emotional and food-related images that preceded the delivery of food rewards (candies) or non-food objects (beads). We measured the amplitude of the late positive potential (LPP) in response to a variety of motivationally relevant images and power in the theta (4-8 Hz) frequency band after candies or beads were dispensed to the participants. We found that individuals with larger LPP responses to food images than to pleasant images (C>P group) ate significantly more during the experiment than those with the opposite response pattern (P>C group, p < 0.001). Furthermore, we found that individuals with higher theta power after dispensation of the candy than of the bead (θCA>θBE) ate significantly more than those with the opposite response pattern (θBE>θCA, p < 0.001). Finally, we found that the crossed P>C and θBE>θCA group ate less (p < 0.001) than did the other three groups formed by crossing the LPP and theta group assignments, who exhibited similar eating behavior on average (p = 0.662). These findings demonstrate that individual differences in both affective and cognitive responses to reward-related cues underlie vulnerability to cue-induced behaviors, underscoring the need for individualized treatments to mitigate maladaptive behaviors.

The hypocretins/orexins (HCRT) have been demonstrated to influence motivation for cocaine through actions on dopamine (DA) transmission. Pharmacological or genetic disruption of the hypocretin receptor 1 (Hcrtr1) reduces cocaine self-administration, blocks reinstatement of cocaine seeking, and decreases conditioned place preference for cocaine. These effects are likely mediated through actions in the ventral tegmental area (VTA) and resulting alterations in DA transmission. For example, HCRT drives VTA DA neuron activity and enhances the effects of cocaine on DA transmission, while disrupting Hcrtr1 attenuates DA responses to cocaine. These findings have led to the perspective that HCRT exerts its effects through Hcrtr1 actions in VTA DA neurons. However, this assumption is complicated by the observation that Hcrtr1 are present on both DA and GABA neurons in the VTA and HCRT drives the activity of both neuronal populations. To address this issue, we selectively knocked down Hcrtr1 on either DA or GABA neurons in the VTA and examined alterations in DA transmission and cocaine self-administration in female and male rats. We found that Hcrtr1 knockdown in DA neurons decreased DA responses to cocaine, increased days to acquire cocaine self-administration, and reduced motivation for cocaine. Although, Hcrtr1 knockdown in GABA neurons enhanced DA responses to cocaine, this manipulation did not affect cocaine self-administration. These observations indicate that while Hcrtr1 on DA versus GABA neurons exert opposing effects on DA transmission, only Hcrtr1 on DA neurons affected acquisition or motivation for cocaine – suggesting a complex interplay between DA transmission and behavior.

Despite impressive results from neuroscience research using rodent models, there is a paucity of successful translation from preclinical findings to effective pharmacological interventions for treatment of substance use disorder (SUD) in humans. One potential reason for lack of translation from animal models is difficulty in accurately replicating the lived experience of people who use drugs. Aspects of substance use in humans that are often not modeled in animal research include but are not limited to 1) voluntary timing and frequency of substance intake, 2) social environment during substance use, and 3) access to multiple substances and multiple concentrations of each substance. Critically, existing commercial equipment that allows for social housing and voluntary polysubstance use (e.g., home cage monitoring system) is prohibitively expensive and no open-source solutions exist. With these goals in mind, here we detail development of the Socially Integrated Polysubstance (SIP) system, an open-source and lower cost solution that allows for group housed rodents to self-administer multiple substances with continuous monitoring and measurement. In our current setup, each SIP cage contains four drinking stations, and each station is equipped with a RFID sensor and sipper tube connected to a unique fluid reservoir. Using this system, we can track which animal (implanted with unique RFID transponder) visits which drinking location and the amount they drink during each visit (in 20 ul increments). Using four flavors of Kool-Aid, here we demonstrate that the SIP system is reliable and accurate with high temporal resolution for long term monitoring of substance intake and behavior tracking in a social environment. The SIP cage system is a first step towards designing an accessible and flexible rodent model of substance use that more closely resembles the experience of people who use drugs.

Craving reflects the subjective urge to use drugs and can be triggered by both positive and negative emotional states. No studies have systematically investigated the relative roles of these mechanisms in the pathophysiology of substance misuse. Here, we performed meta-analyses of drug cue-elicited reactivity and win and loss processing in the monetary incentive delay task to identify distinct neural correlates of appetitive and aversive responses to drug cues. We then characterized the appetitive and aversive cue responses in seventy-six alcohol drinkers performing a cue craving task during fMRI. Imaging data were processed according to published routines. The appetitive circuit involved medial cortical regions and the ventral striatum, and the aversive circuit involved the insula, caudate and mid-cingulate cortex. We observed a significant correlation of cue-elicited activity (β estimates) of the appetitive and aversive circuit. However, individuals varied in appetitive and aversive cue responses. From the regression of appetitive (y) vs. aversive (x) β, we identified participants in the top 1/3 each of those with positive and negative residuals as “approach” (n = 15) and “avoidance” (n = 11) and the others as the “mixed” (n = 50) subtype. In clinical characteristics, the avoidance subtype showed higher sensitivity to punishment and, in contrast, the approach subtype showed higher levels of sensation seeking and alcohol expectancy for social and physical pressure. The findings highlighted distinct neural underpinnings of appetitive and aversive components of cue-elicited reactivity and provided evidence for potential subtypes of alcohol drinkers.

Psychiatric disorders characterized by uncontrolled reward seeking, such as substance use disorders (SUDs), alcohol use disorder (AUD) and some eating disorders, impose a significant burden on individuals and society. Despite their high prevalence and substantial morbidity and mortality rates, treatment options for these disorders remain limited. Over the past two decades, there has been a gradual accumulation of evidence pointing to the sigma-1 receptor (S1R) system as a promising target for therapeutic interventions designed to treat these disorders. S1R is a chaperone protein that resides in the endoplasmic reticulum, but under certain conditions translocates to the plasma membrane. In the brain, S1Rs are expressed in several regions important for reward, and following translocation, they physically associate with several reward-related GPCRs, including dopamine receptors 1 and 2 (D1R and D2R). Psychostimulants, alcohol, as well as palatable foods, all alter expression of S1R in regions important for motivated behavior, and S1R antagonists generally decrease behavioral responses to these rewards. Recent advances in structural modeling have permitted the development of highly-selective S1R antagonists with favorable pharmacokinetic profiles, thus providing a therapeutic avenue for S1R-based medications. Here, we provide an up-to-date overview of work linking S1R with motivated behavior for drugs of abuse and food, as well as evidence supporting the clinical utility of S1R antagonists to reduce their excessive consumption. We also highlight potential challenges associated with targeting the S1R system, including the need for a more comprehensive understanding of the underlying neurobiology and careful consideration of the pharmacological properties of S1R-based drugs.