The role of reward pathways in the development of drug dependence

The mesolimbic dopamine pathway plays a major role in drug reinforcement and is likely involved also in the development of drug addiction. Ethanol, like most addictive drugs, acutely activates the mesolimbic dopamine system and releases dopamine, and ethanol-associated stimuli also appear to trigger dopamine release. In addition, chronic exposure to ethanol reduces the baseline function of the mesolimbic dopamine system. The molecular mechanisms underlying ethanol´s interaction with this system remain, however, to be unveiled. Here research on the actions of ethanol in the mesolimbic dopamine system, focusing on the involvement of cystein-loop ligand-gated ion channels, opiate receptors, gastric peptides and acetaldehyde is briefly reviewed. In summary, a great complexity as regards ethanol´s mechanism(s) of action along the mesolimbic dopamine system has been revealed. Consequently, several new targets and possibilities for pharmacotherapies for alcohol use disorder have emerged.

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.

Drug abuse is a major public health concern throughout the United States and the rest of the world, both due to the adverse effects of addiction in drug-taking adults and because of neurodevelopmental toxicity in children exposed in utero. Model systems derived from either human embryonic stem cells or induced pluripotent stem cells (hiPSC) can be used to examine the mechanisms underlying both addiction in adults and drug-induced neurodevelopmental deficits. Here we discuss the use of hiPSC to examine genetic factors that influence the susceptibility of an individual to addiction. In the past several years, the approach of comparing induced pluripotent stem cells (iPSC) derived from individual drug-addicted patients to those of nonaddicted individuals after in vitro differentiation to specific neuronal subtypes, such as dopaminergic neurons, has been developed. This approach can be used to examine the effects of specific suspected allelic variations of genes involved in neurotransmitter systems common to the mesolimbic reward pathway. Initial studies of this type have been used to verify the correlation of specific genetic polymorphisms with addiction to a drug of abuse. Additionally, iPSC-derived neurons have been used to test drugs for potential efficacy in treatment of addiction. In terms of studying the neurodevelopmental effects of drugs of abuse, the use of stem cell technology is especially promising. For example, we have generated three-dimensional (3D) neocortical organoids from human pluripotent stem cells to examine the effects of cocaine on neocortical development, demonstrating an important and selective role of the cytochrome P450 enzyme CYP3A5 in adverse neurodevelopmental effects of cocaine. The use of in vitro neuronal differentiation models and 3D brain organoids generated from hiPSC allows for a direct study of genetic risk factors and cellular mechanisms that underlie substance-induced developmental abnormalities of the brain.

Reinforcement, reward, and aversion are fundamental processes for guiding appropriate behaviors. Longstanding theories have pointed to dopaminergic neurons of the ventral tegmental area (VTA) and the limbic systems’ descending pathways as crucial systems for modulating these behaviors. The application of optogenetic techniques in neurotransmitter- and projection-specific circuits has supported and enhanced many preexisting theories but has also revealed many unexpected results. Here, we review the past decade of optogenetic experiments to study the neural circuitry of reinforcement and reward/aversion with a focus on the mesolimbic dopamine system and brain areas along the medial forebrain bundle (MFB). The cumulation of these studies to date has revealed generalizable findings across molecularly defined cell types in areas of the basal forebrain and anterior hypothalamus. Optogenetic stimulation of GABAergic neurons in these brain regions drives reward and can support positive reinforcement and optogenetic stimulation of glutamatergic neurons in these regions drives aversion. We also review studies of the activity dynamics of neurotransmitter defined populations in these areas which have revealed varied response patterns associated with motivated behaviors.

This article is part of the special Issue on ‘Neurocircuitry Modulating Drug and Alcohol Abuse'.

Exercise is a reinforcer for both animals and humans, as they will work progressively harder to gain access for the opportunity to exercise. Exercise activates brain reward pathways similar to drugs of abuse, and the magnitude of the reinforcing value of exercise is a predictor of exercise behavior. The majority of research on exercise reinforcement has studied moderate intensity aerobic exercise (MIAE) or resistance training. There is limited research on the relative reinforcing value (RRV) of high intensity interval training (HIIT), which is often reported to be a preferred form of exercise in comparison to MIAE. Experiment 1 was a pilot study of 20 sedentary females designed to compare the reliability of differences in RRV_HIIT vs RRV_MIAE over two sessions, assess protocols comparing different volumes of HIIT in comparison to MIAE, and estimate sample sizes needed for a fully powered study to assess which type of exercise protocol was a better substitute for a highly liked sedentary activity. Experiment 2 studied 44 participants to assess whether HIIT or MIAE would be better substitutes for highly liked sedentary activities. Experiment 1 showed that measures of RRV_HIIT or RRV_MIAE were reliable, and that volume of HIIT did not influence RRV_HIIT, even if it was of equal amount or duration to MIAE. Experiment 2 showed that HIIT was a more preferred substitute for sedentary behaviors than MIAE. Predictors of RRV_MIAE were liking of MIAE and pleasantness of affect post MIAE. These results suggest inactive people may find interval training to be more reinforcing than MIAE, and may be more likely to adopt and maintain an exercise program involving HIIT rather than MIAE. The next stage of research should be to understand how to sensitize the RRV of exercise to motivate sedentary people to be more active.

The orexigenic peptide ghrelin increases the release of dopamine in the nucleus accumbens (NAc) shell via central ghrelin receptors, especially those located in the ventral tegmental area (VTA). The activity of the VTA dopamine neurons projecting to NAc shell, involves somatodendritic dopamine release within the VTA. However, the effects of ghrelin on the concomitant dopamine release in the VTA and NAc shell is unknown. It is further unknown whether addictive drugs, such as alcohol and amphetamine, enhance the dopamine levels in both these areas via ghrelin receptor dependent mechanisms. Thus, the effects of a ghrelin receptor antagonist, JMV2959, on the ability of i) central ghrelin ii) systemic alcohol or iii) systemic amphetamine to increase the dopamine release in the VTA and in the NAc shell in rats by using in vivo microdialysis was explored. We showed that systemic administration of JMV2959 blocks the ability of central ghrelin to increases dopamine release in the VTA and the NAc shell, and reduces the alcohol- and amphetamine-induced dopamine release in both these areas. Locomotor activity studies was then conducted in an attempt to correlate the ghrelin-induced dopamine release in the VTA to a behavioural outcome. These revealed that local infusion of a dopamine D₁ receptor antagonist into the VTA blocks the ability of central ghrelin to cause a locomotor stimulation in mice. Collectively, this study adds to the growing body of evidence indicating that ghrelin signalling modulates the ability of ghrelin, and addictive drugs, to activate the mesoaccumbal dopamine pathway.