Dopamine controls the neural dynamics of memory signals and retrieval accuracy.

PubMed

Apitz, Thore; Bunzeck, Nico

2013-11-01

The human brain is capable of differentiating between new and already stored information rapidly to allow optimal behavior and decision-making. Although the neural mechanisms of novelty discrimination were often described as temporally constant (ie, with specific latencies), recent electrophysiological studies have demonstrated that the onset of neural novelty signals (ie, differences in event-related responses to new and old items) can be accelerated by reward motivation. While the precise physiological mechanisms underlying this acceleration remain unclear, the involvement of the neurotransmitter dopamine in both novelty and reward processing suggests that enhanced dopamine levels in the context of reward prospect may have a role. To investigate this hypothesis, we used magnetoencephalography (MEG) in combination with an old/new recognition memory task in which correct discrimination between old and new items was rewarded. Importantly, before the task, human subjects received either 150 mg of the dopamine precursor levodopa or placebo. For the placebo group, old/new signals peaked at ∼100 ms after stimulus onset over left temporal/occipital sensors. In contrast, after levodopa administration earliest old/new effects only emerged after ∼400 ms and retrieval accuracy was reduced as expressed in lower d' values. As such, our results point towards a previously unreported role of dopamine in controlling the chronometry of neural processes underlying the distinction between old and new information. They also suggest that this relationship follows a nonlinear function whereby slightly enhanced dopamine levels accelerate neural/cognitive processes and excessive dopamine levels impair them.

Dopamine and extinction: a convergence of theory with fear and reward circuitry.

PubMed

Abraham, Antony D; Neve, Kim A; Lattal, K Matthew

2014-02-01

Research on dopamine lies at the intersection of sophisticated theoretical and neurobiological approaches to learning and memory. Dopamine has been shown to be critical for many processes that drive learning and memory, including motivation, prediction error, incentive salience, memory consolidation, and response output. Theories of dopamine's function in these processes have, for the most part, been developed from behavioral approaches that examine learning mechanisms in reward-related tasks. A parallel and growing literature indicates that dopamine is involved in fear conditioning and extinction. These studies are consistent with long-standing ideas about appetitive-aversive interactions in learning theory and they speak to the general nature of cellular and molecular processes that underlie behavior. We review the behavioral and neurobiological literature showing a role for dopamine in fear conditioning and extinction. At a cellular level, we review dopamine signaling and receptor pharmacology, cellular and molecular events that follow dopamine receptor activation, and brain systems in which dopamine functions. At a behavioral level, we describe theories of learning and dopamine function that could describe the fundamental rules underlying how dopamine modulates different aspects of learning and memory processes. Copyright © 2013 Elsevier Inc. All rights reserved.

Dopamine and extinction: A convergence of theory with fear and reward circuitry

PubMed Central

Abraham, Antony D.; Neve, Kim A.; Lattal, K. Matthew

2014-01-01

Research on dopamine lies at the intersection of sophisticated theoretical and neurobiological approaches to learning and memory. Dopamine has been shown to be critical for many processes that drive learning and memory, including motivation, prediction error, incentive salience, memory consolidation, and response output. Theories of dopamine’s function in these processes have, for the most part, been developed from behavioral approaches that examine learning mechanisms in reward-related tasks. A parallel and growing literature indicates that dopamine is involved in fear conditioning and extinction. These studies are consistent with long-standing ideas about appetitive-aversive interactions in learning theory and they speak to the general nature of cellular and molecular processes that underlie behavior. We review the behavioral and neurobiological literature showing a role for dopamine in fear conditioning and extinction. At a cellular level, we review dopamine signaling and receptor pharmacology, cellular and molecular events that follow dopamine receptor activation, and brain systems in which dopamine functions. At a behavioral level, we describe theories of learning and dopamine function that could describe the fundamental rules underlying how dopamine modulates different aspects of learning and memory processes. PMID:24269353

The motivational drive to natural rewards is modulated by prenatal glucocorticoid exposure

PubMed Central

Soares-Cunha, C; Coimbra, B; Borges, S; Carvalho, M M; Rodrigues, A J; Sousa, N

2014-01-01

Exposure to elevated levels of glucocorticoids (GCs) during neurodevelopment has been identified as a triggering factor for the development of reward-associated disorders in adulthood. Disturbances in the neural networks responsible for the complex processes that assign value to rewards and associated stimuli are critical for disorders such as depression, obsessive–compulsive disorders, obesity and addiction. Essential in the understanding on how cues influence behavior is the Pavlovian–instrumental transfer (PIT), a phenomenon that refers to the capacity of a Pavlovian stimulus that predicts a reward to elicit instrumental responses for that same reward. Here, we demonstrate that in utero exposure to GCs (iuGC) impairs both general and selective versions of the PIT paradigm, suggestive of deficits in motivational drive. The iuGC animals presented impaired neuronal activation pattern upon PIT performance in cortical and limbic regions, as well as morphometric changes and reduced levels of dopamine in prefrontal and orbitofrontal cortices, key regions involved in the integration of Pavlovian and instrumental stimuli. Normalization of dopamine levels rescued this behavior, a process that relied on D2/D3, but not D1, dopamine receptor activation. In summary, iuGC exposure programs the mesocorticolimbic dopaminergic circuitry, leading to a reduction in the attribution of the incentive salience to cues, in a dopamine-D2/D3-dependent manner. Ultimately, these results are important to understand how GCs bias incentive processes, a fact that is particularly relevant for disorders where differential attribution of incentive salience is critical. PMID:25928947

Midbrain dopamine neurons signal aversion in a reward-context-dependent manner

PubMed Central

Matsumoto, Hideyuki; Tian, Ju; Uchida, Naoshige; Watabe-Uchida, Mitsuko

2016-01-01

Dopamine is thought to regulate learning from appetitive and aversive events. Here we examined how optogenetically-identified dopamine neurons in the lateral ventral tegmental area of mice respond to aversive events in different conditions. In low reward contexts, most dopamine neurons were exclusively inhibited by aversive events, and expectation reduced dopamine neurons’ responses to reward and punishment. When a single odor predicted both reward and punishment, dopamine neurons’ responses to that odor reflected the integrated value of both outcomes. Thus, in low reward contexts, dopamine neurons signal value prediction errors (VPEs) integrating information about both reward and aversion in a common currency. In contrast, in high reward contexts, dopamine neurons acquired a short-latency excitation to aversive events that masked their VPE signaling. Our results demonstrate the importance of considering the contexts to examine the representation in dopamine neurons and uncover different modes of dopamine signaling, each of which may be adaptive for different environments. DOI: http://dx.doi.org/10.7554/eLife.17328.001 PMID:27760002

Levodopa administration modulates striatal processing of punishment-associated items in healthy participants.

PubMed

Wittmann, Bianca C; D'Esposito, Mark

2015-01-01

Appetitive and aversive processes share a number of features such as their relevance for action and learning. On a neural level, reward and its predictors are associated with increased firing of dopaminergic neurons, whereas punishment processing has been linked to the serotonergic system and to decreases in dopamine transmission. Recent data indicate, however, that the dopaminergic system also responds to aversive stimuli and associated actions. In this pharmacological functional magnetic resonance imaging study, we investigated the contribution of the dopaminergic system to reward and punishment processing in humans. Two groups of participants received either placebo or the dopamine precursor levodopa and were scanned during alternating reward and punishment anticipation blocks. Levodopa administration increased striatal activations for cues presented in punishment blocks. In an interaction with individual personality scores, levodopa also enhanced striatal activation for punishment-predictive compared with neutral cues in participants scoring higher on the novelty-seeking dimension. These data support recent indications that dopamine contributes to punishment processing and suggest that the novelty-seeking trait is a measure of susceptibility to drug effects on motivation. These findings are also consistent with the possibility of an inverted U-shaped response function of dopamine in the striatum, suggesting an optimal level of dopamine release for motivational processing.

Levodopa administration modulates striatal processing of punishment-associated items in healthy participants

PubMed Central

Wittmann, Bianca C.; D’Esposito, Mark

2014-01-01

Rationale Appetitive and aversive processes share a number of features such as their relevance for action and learning. On a neural level, reward and its predictors are associated with increased firing of dopaminergic neurons, whereas punishment processing has been linked to the serotonergic system and to decreases in dopamine transmission. Recent data indicate, however, that the dopaminergic system also responds to aversive stimuli and associated actions. Objectives In this pharmacological functional magnetic resonance imaging (fMRI) study, we investigated the contribution of the dopaminergic system to reward and punishment processing in humans. Methods Two groups of participants received either placebo or the dopamine precursor levodopa and were scanned during alternating reward and punishment anticipation blocks. Results Levodopa administration increased striatal activations for cues presented in punishment blocks. In an interaction with individual personality scores, levodopa also enhanced striatal activation for punishment-predictive compared to neutral cues in participants scoring higher on the novelty-seeking dimension. Conclusions These data support recent indications that dopamine contributes to punishment processing and suggest that the novelty-seeking trait is a measure of susceptibility to drug effects on motivation. These findings are also consistent with the possibility of an inverted U-shaped response function of dopamine in the striatum, suggesting an optimal level of dopamine release for motivational processing. PMID:24923987

Dopamine reward prediction error coding.

PubMed

Schultz, Wolfram

2016-03-01

Reward prediction errors consist of the differences between received and predicted rewards. They are crucial for basic forms of learning about rewards and make us strive for more rewards-an evolutionary beneficial trait. Most dopamine neurons in the midbrain of humans, monkeys, and rodents signal a reward prediction error; they are activated by more reward than predicted (positive prediction error), remain at baseline activity for fully predicted rewards, and show depressed activity with less reward than predicted (negative prediction error). The dopamine signal increases nonlinearly with reward value and codes formal economic utility. Drugs of addiction generate, hijack, and amplify the dopamine reward signal and induce exaggerated, uncontrolled dopamine effects on neuronal plasticity. The striatum, amygdala, and frontal cortex also show reward prediction error coding, but only in subpopulations of neurons. Thus, the important concept of reward prediction errors is implemented in neuronal hardware.

Opposite initialization to novel cues in dopamine signaling in ventral and posterior striatum in mice

PubMed Central

Menegas, William; Babayan, Benedicte M; Uchida, Naoshige; Watabe-Uchida, Mitsuko

2017-01-01

Dopamine neurons are thought to encode novelty in addition to reward prediction error (the discrepancy between actual and predicted values). In this study, we compared dopamine activity across the striatum using fiber fluorometry in mice. During classical conditioning, we observed opposite dynamics in dopamine axon signals in the ventral striatum (‘VS dopamine’) and the posterior tail of the striatum (‘TS dopamine’). TS dopamine showed strong excitation to novel cues, whereas VS dopamine showed no responses to novel cues until they had been paired with a reward. TS dopamine cue responses decreased over time, depending on what the cue predicted. Additionally, TS dopamine showed excitation to several types of stimuli including rewarding, aversive, and neutral stimuli whereas VS dopamine showed excitation only to reward or reward-predicting cues. Together, these results demonstrate that dopamine novelty signals are localized in TS along with general salience signals, while VS dopamine reliably encodes reward prediction error. DOI: http://dx.doi.org/10.7554/eLife.21886.001 PMID:28054919

Dopamine reward prediction error coding

PubMed Central

Schultz, Wolfram

2016-01-01

Reward prediction errors consist of the differences between received and predicted rewards. They are crucial for basic forms of learning about rewards and make us strive for more rewards—an evolutionary beneficial trait. Most dopamine neurons in the midbrain of humans, monkeys, and rodents signal a reward prediction error; they are activated by more reward than predicted (positive prediction error), remain at baseline activity for fully predicted rewards, and show depressed activity with less reward than predicted (negative prediction error). The dopamine signal increases nonlinearly with reward value and codes formal economic utility. Drugs of addiction generate, hijack, and amplify the dopamine reward signal and induce exaggerated, uncontrolled dopamine effects on neuronal plasticity. The striatum, amygdala, and frontal cortex also show reward prediction error coding, but only in subpopulations of neurons. Thus, the important concept of reward prediction errors is implemented in neuronal hardware. PMID:27069377

Subsecond dopamine fluctuations in human striatum encode superposed error signals about actual and counterfactual reward

PubMed Central

Kishida, Kenneth T.; Saez, Ignacio; Lohrenz, Terry; Witcher, Mark R.; Laxton, Adrian W.; Tatter, Stephen B.; White, Jason P.; Ellis, Thomas L.; Phillips, Paul E. M.; Montague, P. Read

2016-01-01

In the mammalian brain, dopamine is a critical neuromodulator whose actions underlie learning, decision-making, and behavioral control. Degeneration of dopamine neurons causes Parkinson’s disease, whereas dysregulation of dopamine signaling is believed to contribute to psychiatric conditions such as schizophrenia, addiction, and depression. Experiments in animal models suggest the hypothesis that dopamine release in human striatum encodes reward prediction errors (RPEs) (the difference between actual and expected outcomes) during ongoing decision-making. Blood oxygen level-dependent (BOLD) imaging experiments in humans support the idea that RPEs are tracked in the striatum; however, BOLD measurements cannot be used to infer the action of any one specific neurotransmitter. We monitored dopamine levels with subsecond temporal resolution in humans (n = 17) with Parkinson’s disease while they executed a sequential decision-making task. Participants placed bets and experienced monetary gains or losses. Dopamine fluctuations in the striatum fail to encode RPEs, as anticipated by a large body of work in model organisms. Instead, subsecond dopamine fluctuations encode an integration of RPEs with counterfactual prediction errors, the latter defined by how much better or worse the experienced outcome could have been. How dopamine fluctuations combine the actual and counterfactual is unknown. One possibility is that this process is the normal behavior of reward processing dopamine neurons, which previously had not been tested by experiments in animal models. Alternatively, this superposition of error terms may result from an additional yet-to-be-identified subclass of dopamine neurons. PMID:26598677

Subsecond dopamine fluctuations in human striatum encode superposed error signals about actual and counterfactual reward.

PubMed

Kishida, Kenneth T; Saez, Ignacio; Lohrenz, Terry; Witcher, Mark R; Laxton, Adrian W; Tatter, Stephen B; White, Jason P; Ellis, Thomas L; Phillips, Paul E M; Montague, P Read

2016-01-05

In the mammalian brain, dopamine is a critical neuromodulator whose actions underlie learning, decision-making, and behavioral control. Degeneration of dopamine neurons causes Parkinson's disease, whereas dysregulation of dopamine signaling is believed to contribute to psychiatric conditions such as schizophrenia, addiction, and depression. Experiments in animal models suggest the hypothesis that dopamine release in human striatum encodes reward prediction errors (RPEs) (the difference between actual and expected outcomes) during ongoing decision-making. Blood oxygen level-dependent (BOLD) imaging experiments in humans support the idea that RPEs are tracked in the striatum; however, BOLD measurements cannot be used to infer the action of any one specific neurotransmitter. We monitored dopamine levels with subsecond temporal resolution in humans (n = 17) with Parkinson's disease while they executed a sequential decision-making task. Participants placed bets and experienced monetary gains or losses. Dopamine fluctuations in the striatum fail to encode RPEs, as anticipated by a large body of work in model organisms. Instead, subsecond dopamine fluctuations encode an integration of RPEs with counterfactual prediction errors, the latter defined by how much better or worse the experienced outcome could have been. How dopamine fluctuations combine the actual and counterfactual is unknown. One possibility is that this process is the normal behavior of reward processing dopamine neurons, which previously had not been tested by experiments in animal models. Alternatively, this superposition of error terms may result from an additional yet-to-be-identified subclass of dopamine neurons.

Dynamic shaping of dopamine signals during probabilistic Pavlovian conditioning.

PubMed

Hart, Andrew S; Clark, Jeremy J; Phillips, Paul E M

2015-01-01

Cue- and reward-evoked phasic dopamine activity during Pavlovian and operant conditioning paradigms is well correlated with reward-prediction errors from formal reinforcement learning models, which feature teaching signals in the form of discrepancies between actual and expected reward outcomes. Additionally, in learning tasks where conditioned cues probabilistically predict rewards, dopamine neurons show sustained cue-evoked responses that are correlated with the variance of reward and are maximal to cues predicting rewards with a probability of 0.5. Therefore, it has been suggested that sustained dopamine activity after cue presentation encodes the uncertainty of impending reward delivery. In the current study we examined the acquisition and maintenance of these neural correlates using fast-scan cyclic voltammetry in rats implanted with carbon fiber electrodes in the nucleus accumbens core during probabilistic Pavlovian conditioning. The advantage of this technique is that we can sample from the same animal and recording location throughout learning with single trial resolution. We report that dopamine release in the nucleus accumbens core contains correlates of both expected value and variance. A quantitative analysis of these signals throughout learning, and during the ongoing updating process after learning in probabilistic conditions, demonstrates that these correlates are dynamically encoded during these phases. Peak CS-evoked responses are correlated with expected value and predominate during early learning while a variance-correlated sustained CS signal develops during the post-asymptotic updating phase. Copyright © 2014 Elsevier Inc. All rights reserved.

A review of reward processing and motivational impairment in schizophrenia.

PubMed

Strauss, Gregory P; Waltz, James A; Gold, James M

2014-03-01

This article reviews and synthesizes research on reward processing in schizophrenia, which has begun to provide important insights into the cognitive and neural mechanisms associated with motivational impairments. Aberrant cortical-striatal interactions may be involved with multiple reward processing abnormalities, including: (1) dopamine-mediated basal ganglia systems that support reinforcement learning and the ability to predict cues that lead to rewarding outcomes; (2) orbitofrontal cortex-driven deficits in generating, updating, and maintaining value representations; (3) aberrant effort-value computations, which may be mediated by disrupted anterior cingulate cortex and midbrain dopamine functioning; and (4) altered activation of the prefrontal cortex, which is important for generating exploratory behaviors in environments where reward outcomes are uncertain. It will be important for psychosocial interventions targeting negative symptoms to account for abnormalities in each of these reward processes, which may also have important interactions; suggestions for novel behavioral intervention strategies that make use of external cues, reinforcers, and mobile technology are discussed.

Dopamine neurons learn relative chosen value from probabilistic rewards

PubMed Central

Lak, Armin; Stauffer, William R; Schultz, Wolfram

2016-01-01

Economic theories posit reward probability as one of the factors defining reward value. Individuals learn the value of cues that predict probabilistic rewards from experienced reward frequencies. Building on the notion that responses of dopamine neurons increase with reward probability and expected value, we asked how dopamine neurons in monkeys acquire this value signal that may represent an economic decision variable. We found in a Pavlovian learning task that reward probability-dependent value signals arose from experienced reward frequencies. We then assessed neuronal response acquisition during choices among probabilistic rewards. Here, dopamine responses became sensitive to the value of both chosen and unchosen options. Both experiments showed also the novelty responses of dopamine neurones that decreased as learning advanced. These results show that dopamine neurons acquire predictive value signals from the frequency of experienced rewards. This flexible and fast signal reflects a specific decision variable and could update neuronal decision mechanisms. DOI: http://dx.doi.org/10.7554/eLife.18044.001 PMID:27787196

When performance and risk taking are related: Working for rewards is related to risk taking when the value of rewards is presented briefly.

PubMed

Veling, Harm; Bijleveld, Erik

2015-12-01

Valuable monetary rewards can boost human performance on various effortful tasks even when the value of the rewards is presented too briefly to allow for strategic decision making. However, the mechanism by which briefly-presented reward information influences performance has remained unclear. One possibility is that performance after briefly-presented reward information is primarily boosted via activation of the dopamine reward system, whereas performance after very visible reward information is driven more by strategic processes. To examine this hypothesis, we first presented participants with a task in which they could earn rewards of relatively low (1 cent) or high (10 cents) value, and the value information was presented either briefly (17 ms) or for an extended duration (300 ms). Furthermore, responsiveness of the dopamine system was indirectly estimated with a measure of risk taking, the Balloon Analogue Risk Task (BART). Results showed that performance after high- compared to low-value rewards was indeed related to the BART scores only when reward information was presented briefly. These results are suggestive of the possibility that brief presentation of reward information boosts performance directly via activating the dopamine system, whereas extended presentation of reward information leads to more strategic reward-driven behavior. Copyright © 2015 Elsevier Inc. All rights reserved.

Cerebral interactions of pain and reward and their relevance for chronic pain.

PubMed

Becker, Susanne; Gandhi, Wiebke; Schweinhardt, Petra

2012-06-29

Pain and reward are opponent, interacting processes. Such interactions are enabled by neuroanatomical and neurochemical overlaps of brain systems that process pain and reward. Cerebral processing of hedonic ('liking') and motivational ('wanting') aspects of reward can be separated: the orbitofrontal cortex and opioids play an important role for the hedonic experience, and the ventral striatum and dopamine predominantly process motivation for reward. Supported by neuroimaging studies, we present here the hypothesis that the orbitofrontal cortex and opioids are responsible for pain modulation by hedonic experience, while the ventral striatum and dopamine mediate motivational effects on pain. A rewarding stimulus that appears to be particularly important in the context of pain is pain relief. Further, reward, including pain relief, leads to operant learning, which can affect pain sensitivity. Indirect evidence points at brain mechanisms that might underlie pain relief as a reward and related operant learning but studies are scarce. Investigating the cerebral systems underlying pain-reward interactions as well as related operant learning holds the potential of better understanding mechanisms that contribute to the development and maintenance of chronic pain, as detailed in the last section of this review. Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.

Activation of D1/5 Dopamine Receptors: A Common Mechanism for Enhancing Extinction of Fear and Reward-Seeking Behaviors.

PubMed

Abraham, Antony D; Neve, Kim A; Lattal, K Matthew

2016-07-01

Dopamine is critical for many processes that drive learning and memory, including motivation, prediction error, incentive salience, memory consolidation, and response output. Theories of dopamine's function in these processes have, for the most part, been developed from behavioral approaches that examine learning mechanisms in appetitive tasks. A parallel and growing literature indicates that dopamine signaling is involved in consolidation of memories into stable representations in aversive tasks such as fear conditioning. Relatively little is known about how dopamine may modulate memories that form during extinction, when organisms learn that the relation between previously associated events is severed. We investigated whether fear and reward extinction share common mechanisms that could be enhanced with dopamine D1/5 receptor activation. Pharmacological activation of dopamine D1/5 receptors (with SKF 81297) enhanced extinction of both cued and contextual fear. These effects also occurred in the extinction of cocaine-induced conditioned place preference, suggesting that the observed effects on extinction were not specific to a particular type of procedure (aversive or appetitive). A cAMP/PKA biased D1 agonist (SKF 83959) did not affect fear extinction, whereas a broadly efficacious D1 agonist (SKF 83822) promoted fear extinction. Together, these findings show that dopamine D1/5 receptor activation is a target for the enhancement of fear or reward extinction.

Compromised NMDA/Glutamate Receptor Expression in Dopaminergic Neurons Impairs Instrumental Learning, But Not Pavlovian Goal Tracking or Sign Tracking

PubMed

James, Alex S; Pennington, Zachary T; Tran, Phu; Jentsch, James David

2015-01-01

Two theories regarding the role for dopamine neurons in learning include the concepts that their activity serves as a (1) mechanism that confers incentive salience onto rewards and associated cues and/or (2) contingency teaching signal reflecting reward prediction error. While both theories are provocative, the causal role for dopamine cell activity in either mechanism remains controversial. In this study mice that either fully or partially lacked NMDARs in dopamine neurons exclusively, as well as appropriate controls, were evaluated for reward-related learning; this experimental design allowed for a test of the premise that NMDA/glutamate receptor (NMDAR)-mediated mechanisms in dopamine neurons, including NMDA-dependent regulation of phasic discharge activity of these cells, modulate either the instrumental learning processes or the likelihood of pavlovian cues to become highly motivating incentive stimuli that directly attract behavior. Loss of NMDARs in dopamine neurons did not significantly affect baseline dopamine utilization in the striatum, novelty evoked locomotor behavior, or consumption of a freely available, palatable food solution. On the other hand, animals lacking NMDARs in dopamine cells exhibited a selective reduction in reinforced lever responses that emerged over the course of instrumental learning. Loss of receptor expression did not, however, influence the likelihood of an animal acquiring a pavlovian conditional response associated with attribution of incentive salience to reward-paired cues (sign tracking). These data support the view that reductions in NMDAR signaling in dopamine neurons affect instrumental reward-related learning but do not lend support to hypotheses that suggest that the behavioral significance of this signaling includes incentive salience attribution.

Effects of pramipexole on the processing of rewarding and aversive taste stimuli.

PubMed

McCabe, Ciara; Harwood, James; Brouwer, Sietske; Harmer, Catherine J; Cowen, Philip J

2013-07-01

Pramipexole, a D2/D3 dopamine receptor agonist, has been implicated in the development of impulse control disorders in patients with Parkinson's disease. Investigation of single doses of pramipexole in healthy participants in reward-based learning tasks has shown inhibition of the neural processing of reward, presumptively through stimulation of dopamine autoreceptors. This study aims to examine the effects of pramipexole on the neural response to the passive receipt of rewarding and aversive sight and taste stimuli. We used functional magnetic resonance imaging to examine the neural responses to the sight and taste of pleasant (chocolate) and aversive (mouldy strawberry) stimuli in 16 healthy volunteers who received a single dose of pramipexole (0.25 mg) and placebo in a double-blind, within-subject, design. Relative to placebo, pramipexole treatment reduced blood oxygen level-dependent activation to the chocolate stimuli in the areas known to play a key role in reward, including the ventromedial prefrontal cortex, the orbitofrontal cortex, striatum, thalamus and dorsal anterior cingulate cortex. Pramipexole also reduced activation to the aversive condition in the dorsal anterior cingulate cortex. There were no effects of pramipexole on the subjective ratings of the stimuli. Our results are consistent with an ability of acute, low-dose pramipexole to diminish dopamine-mediated responses to both rewarding and aversive taste stimuli, perhaps through an inhibitory action of D2/3 autoreceptors on phasic burst activity of midbrain dopamine neurones. The ability of pramipexole to inhibit aversive processing might potentiate its adverse behavioural effects and could also play a role in its proposed efficacy in treatment-resistant depression.

Dopaminergic circuitry and risk/reward decision making: implications for schizophrenia.

PubMed

Stopper, Colin M; Floresco, Stan B

2015-01-01

Abnormal reinforcement learning and representations of reward value are present in schizophrenia, and these impairments can manifest as deficits in risk/reward decision making. These abnormalities may be due in part to dopaminergic dysfunction within cortico-limbic-striatal circuitry. Evidence from studies with laboratory animal have revealed that normal DA activity within different nodes of these circuits is critical for mediating dissociable processes that can refine decision biases. Moreover, both phasic and tonic dopamine transmission appear to play separate yet complementary roles in these processes. Tonic dopamine release within the prefrontal cortex and nucleus accumbens, serves as a "running rate-meter" of reward and reflects contextual information such as reward uncertainty and overt choice behavior. On the other hand, manipulations of outcome-related phasic dopamine bursts and dips suggest these signals provide rapid feedback to allow for quick adjustments in choice as reward contingencies change. The lateral habenula is a key input to the DA system that phasic signals is necessary for expressing subjective decision biases; as suppression of activity within this nucleus leads to catastrophic impairments in decision making and random patterns of choice behavior. As schizophrenia is characterized by impairments in using positive and negative feedback to appropriately guide decision making, these findings suggest that these deficits in these processes may be mediated, at least in part, by abnormalities in both tonic and phasic dopamine transmission. © The Author 2014. Published by Oxford University Press on behalf of the Maryland Psychiatric Research Center. All rights reserved. For permissions, please email: journals.permissions@oup.com.

Striatal Sensitivity during Reward Processing in Attention-Deficit/Hyperactivity Disorder

ERIC Educational Resources Information Center

Paloyelis, Yannis; Mehta, Mitul A.; Faraone, Stephen V.; Asherson, Philip; Kuntsi, Jonna

2012-01-01

Objective: Attention-deficit/hyperactivity disorder (ADHD) has been linked to deficits in the dopaminergic reward-processing circuitry; yet, existing evidence is limited, and the influence of genetic variation affecting dopamine signaling remains unknown. We investigated striatal responsivity to rewards in ADHD combined type (ADHD-CT) using…

The role of dopamine in human addiction: from reward to motivated attention.

PubMed

Franken, Ingmar H A; Booij, Jan; van den Brink, Wim

2005-12-05

There is general consensus among preclinical researchers that dopamine plays an important role in the development and persistence of addiction. However, the precise role of dopamine in addictive behaviors is far from clear and only a few clinical studies on the role of dopamine in human addiction have been conducted so far. The present paper reviews studies addressing the role of dopamine in humans. There is substantial and consistent evidence that dopamine is involved in the experience of drug reward in humans. Dopamine may also be involved in motivational processes such as drug craving. However, given the inconsistent findings of studies using dopamine receptor (ant)agonists, the role of dopamine in the experience of craving is far from resolved. Recent theories claiming that dopamine signals salience and makes the brain paying attention to biological relevant stimuli may provide an interesting framework for explaining addictive behaviors. There is accumulating evidence that patients with drug and alcohol addiction have an aberrant focus on drug-related stimuli. Although there is some preliminary support for the role of dopamine in these attention processes, more studies have to be carried out in order to test the validity of these theories in human subjects.

Motivational salience and genetic variability of dopamine D2 receptor expression interact in the modulation of interference processing

PubMed Central

Richter, Anni; Richter, Sylvia; Barman, Adriana; Soch, Joram; Klein, Marieke; Assmann, Anne; Libeau, Catherine; Behnisch, Gusalija; Wüstenberg, Torsten; Seidenbecher, Constanze I.; Schott, Björn H.

2013-01-01

Dopamine has been implicated in the fine-tuning of complex cognitive and motor function and also in the anticipation of future rewards. This dual function of dopamine suggests that dopamine might be involved in the generation of active motivated behavior. The DRD2 TaqIA polymorphism of the dopamine D2 receptor gene (rs1800497) has previously been suggested to affect striatal function with carriers of the less common A1 allele exhibiting reduced striatal D2 receptor density and increased risk for addiction. Here we aimed to investigate the influences of DRD2 TaqIA genotype on the modulation of interference processing by reward and punishment. Forty-six young, healthy volunteers participated in a behavioral experiment, and 32 underwent functional magnetic resonance imaging (fMRI). Participants performed a flanker task with a motivation manipulation (monetary reward, monetary loss, neither, or both). Reaction times (RTs) were shorter in motivated flanker trials, irrespective of congruency. In the fMRI experiment motivation was associated with reduced prefrontal activation during incongruent vs. congruent flanker trials, possibly reflecting increased processing efficiency. DRD2 TaqIA genotype did not affect overall RTs, but interacted with motivation on the congruency-related RT differences, with A1 carriers showing smaller interference effects to reward alone and A2 homozygotes exhibiting a specific interference reduction during combined reward (REW) and punishment trials (PUN). In fMRI, anterior cingulate activity showed a similar pattern of genotype-related modulation. Additionally, A1 carriers showed increased anterior insula activation relative to A2 homozygotes. Our results point to a role for genetic variations of the dopaminergic system in individual differences of cognition-motivation interaction. PMID:23760450

Mesolimbic Dopamine Signals the Value of Work

PubMed Central

Hamid, Arif A.; Pettibone, Jeffrey R.; Mabrouk, Omar S.; Hetrick, Vaughn L.; Schmidt, Robert; Vander Weele, Caitlin M.; Kennedy, Robert T.; Aragona, Brandon J.; Berke, Joshua D.

2015-01-01

Dopamine cell firing can encode errors in reward prediction, providing a learning signal to guide future behavior. Yet dopamine is also a key modulator of motivation, invigorating current behavior. Existing theories propose that fast (“phasic”) dopamine fluctuations support learning, while much slower (“tonic”) dopamine changes are involved in motivation. We examined dopamine release in the nucleus accumbens across multiple time scales, using complementary microdialysis and voltammetric methods during adaptive decision-making. We first show that minute-by-minute dopamine levels covary with reward rate and motivational vigor. We then show that second-by-second dopamine release encodes an estimate of temporally-discounted future reward (a value function). We demonstrate that changing dopamine immediately alters willingness to work, and reinforces preceding action choices by encoding temporal-difference reward prediction errors. Our results indicate that dopamine conveys a single, rapidly-evolving decision variable, the available reward for investment of effort, that is employed for both learning and motivational functions. PMID:26595651

Optogenetically-induced tonic dopamine release from VTA-nucleus accumbens projections inhibits reward consummatory behaviors

PubMed Central

Mikhailova, Maria A.; Bass, Caroline E.; Grinevich, Valentina P.; Chappell, Ann M.; Deal, Alex L.; Bonin, Keith D.; Weiner, Jeff L.; Gainetdinov, Raul R.; Budygin, Evgeny A.

2016-01-01

Recent optogenetic studies demonstrated that phasic dopamine release in the nucleus accumbens may play a causal role in multiple aspects of natural and drug reward-related behaviors. The role of tonic dopamine release in reward consummatory behavior remains unclear. The current study used a combinatorial viral-mediated gene delivery approach to express ChR2 on mesolimbic dopamine neurons in rats. We used optical activation of this dopamine circuit to mimic tonic dopamine release in the nucleus accumbens and to explore the causal relationship between this form of dopamine signaling within the ventral tegmental area (VTA)-nucleus accumbens projection and consumption of a natural reward. Using a two bottle choice paradigm (sucrose vs. water), the experiments revealed that tonic optogenetic stimulation of mesolimbic dopamine transmission significantly decreased reward consummatory behaviors. Specifically, there was a significant decrease in the number of bouts, licks and amount of sucrose obtained during the drinking session. Notably, activation of VTA dopamine cell bodies or dopamine terminals in the nucleus accumbens resulted in identical behavioral consequences. No changes in the water intake were evident under the same experimental conditions. Collectively, these data demonstrate that tonic optogenetic stimulation of VTA-nucleus accumbens dopamine release is sufficient to inhibit reward consummatory behavior, possibly by preventing this circuit from engaging in phasic activity that is thought to be essential for reward-based behaviors. PMID:27421228

Compromised NMDA/Glutamate Receptor Expression in Dopaminergic Neurons Impairs Instrumental Learning, But Not Pavlovian Goal Tracking or Sign Tracking1,2,3

PubMed Central

James, Alex S.; Pennington, Zachary T.; Tran, Phu

2015-01-01

Abstract Two theories regarding the role for dopamine neurons in learning include the concepts that their activity serves as a (1) mechanism that confers incentive salience onto rewards and associated cues and/or (2) contingency teaching signal reflecting reward prediction error. While both theories are provocative, the causal role for dopamine cell activity in either mechanism remains controversial. In this study mice that either fully or partially lacked NMDARs in dopamine neurons exclusively, as well as appropriate controls, were evaluated for reward-related learning; this experimental design allowed for a test of the premise that NMDA/glutamate receptor (NMDAR)-mediated mechanisms in dopamine neurons, including NMDA-dependent regulation of phasic discharge activity of these cells, modulate either the instrumental learning processes or the likelihood of pavlovian cues to become highly motivating incentive stimuli that directly attract behavior. Loss of NMDARs in dopamine neurons did not significantly affect baseline dopamine utilization in the striatum, novelty evoked locomotor behavior, or consumption of a freely available, palatable food solution. On the other hand, animals lacking NMDARs in dopamine cells exhibited a selective reduction in reinforced lever responses that emerged over the course of instrumental learning. Loss of receptor expression did not, however, influence the likelihood of an animal acquiring a pavlovian conditional response associated with attribution of incentive salience to reward-paired cues (sign tracking). These data support the view that reductions in NMDAR signaling in dopamine neurons affect instrumental reward-related learning but do not lend support to hypotheses that suggest that the behavioral significance of this signaling includes incentive salience attribution. PMID:26464985

Dopaminergic control of motivation and reinforcement learning: a closed-circuit account for reward-oriented behavior.

PubMed

Morita, Kenji; Morishima, Mieko; Sakai, Katsuyuki; Kawaguchi, Yasuo

2013-05-15

Humans and animals take actions quickly when they expect that the actions lead to reward, reflecting their motivation. Injection of dopamine receptor antagonists into the striatum has been shown to slow such reward-seeking behavior, suggesting that dopamine is involved in the control of motivational processes. Meanwhile, neurophysiological studies have revealed that phasic response of dopamine neurons appears to represent reward prediction error, indicating that dopamine plays central roles in reinforcement learning. However, previous attempts to elucidate the mechanisms of these dopaminergic controls have not fully explained how the motivational and learning aspects are related and whether they can be understood by the way the activity of dopamine neurons itself is controlled by their upstream circuitries. To address this issue, we constructed a closed-circuit model of the corticobasal ganglia system based on recent findings regarding intracortical and corticostriatal circuit architectures. Simulations show that the model could reproduce the observed distinct motivational effects of D1- and D2-type dopamine receptor antagonists. Simultaneously, our model successfully explains the dopaminergic representation of reward prediction error as observed in behaving animals during learning tasks and could also explain distinct choice biases induced by optogenetic stimulation of the D1 and D2 receptor-expressing striatal neurons. These results indicate that the suggested roles of dopamine in motivational control and reinforcement learning can be understood in a unified manner through a notion that the indirect pathway of the basal ganglia represents the value of states/actions at a previous time point, an empirically driven key assumption of our model.

Amphetamine Paradoxically Augments Exocytotic Dopamine Release and Phasic Dopamine Signals

PubMed Central

Daberkow, DP; Brown, HD; Bunner, KD; Kraniotis, SA; Doellman, MA; Ragozzino, ME; Garris, PA; Roitman, MF

2013-01-01

Drugs of abuse hijack brain reward circuitry during the addiction process by augmenting action potential-dependent phasic dopamine release events associated with learning and goal-directed behavior. One prominent exception to this notion would appear to be amphetamine (AMPH) and related analogs, which are proposed instead to disrupt normal patterns of dopamine neurotransmission by depleting vesicular stores and promoting non-exocytotic dopamine efflux via reverse transport. This mechanism of AMPH action, though, is inconsistent with its therapeutic effects and addictive properties - which are thought to be reliant on phasic dopamine signaling. Here we used fast-scan cyclic voltammetry in freely moving rats to interrogate principal neurochemical responses to AMPH in the striatum and relate these changes to behavior. First, we showed that AMPH dose-dependently enhanced evoked dopamine responses to phasic-like current pulse trains for up to two hours. Modeling the data revealed that AMPH inhibited dopamine uptake but also unexpectedly potentiated vesicular dopamine release. Second, we found that AMPH increased the amplitude, duration and frequency of spontaneous dopamine transients, the naturally occurring, non-electrically evoked, phasic increases in extracellular dopamine. Finally, using an operant sucrose reward paradigm, we showed that low-dose AMPH augmented dopamine transients elicited by sucrose-predictive cues. However, operant behavior failed at high-dose AMPH, which was due to phasic dopamine hyperactivity and the decoupling of dopamine transients from the reward predictive cue. These findings identify up-regulation of exocytotic dopamine release as a key AMPH action in behaving animals and support a unified mechanism of abused drugs to activate phasic dopamine signaling. PMID:23303926

Dopamine D2/3- and μ-opioid receptor antagonists reduce cue-induced responding and reward impulsivity in humans.

PubMed

Weber, S C; Beck-Schimmer, B; Kajdi, M-E; Müller, D; Tobler, P N; Quednow, B B

2016-07-05

Increased responding to drug-associated stimuli (cue reactivity) and an inability to tolerate delayed gratification (reward impulsivity) have been implicated in the development and maintenance of drug addiction. Whereas data from animal studies suggest that both the dopamine and opioid system are involved in these two reward-related processes, their role in humans is less clear. Moreover, dopaminergic and opioidergic drugs have not been directly compared with regard to these functions, even though a deeper understanding of the underlying mechanisms might inform the development of specific treatments for elevated cue reactivity and reward impulsivity. In a randomized, double-blind, between-subject design we administered the selective dopamine D2/D3 receptor antagonist amisulpride (400 mg, n=41), the unspecific opioid receptor antagonist naltrexone (50 mg, n=40) or placebo (n=40) to healthy humans and measured cue-induced responding with a Pavlovian-instrumental transfer task and reward impulsivity with a delay discounting task. Mood was assessed using a visual analogue scale. Compared with placebo, amisulpride significantly suppressed cue-induced responding and reward impulsivity. The effects of naltrexone were similar, although less pronounced. Both amisulpride and naltrexone decreased average mood ratings compared with placebo. Our results demonstrate that a selective blockade of dopamine D2/D3 receptors reduces cue-induced responding and reward impulsivity in healthy humans. Antagonizing μ-opioid receptors has similar effects for cue-induced responding and to a lesser extent for reward impulsivity.

Dopamine in motivational control: rewarding, aversive, and alerting

PubMed Central

Bromberg-Martin, Ethan S.; Matsumoto, Masayuki; Hikosaka, Okihide

2010-01-01

SUMMARY Midbrain dopamine neurons are well known for their strong responses to rewards and their critical role in positive motivation. It has become increasingly clear, however, that dopamine neurons also transmit signals related to salient but non-rewarding experiences such as aversive and alerting events. Here we review recent advances in understanding the reward and non-reward functions of dopamine. Based on this data, we propose that dopamine neurons come in multiple types that are connected with distinct brain networks and have distinct roles in motivational control. Some dopamine neurons encode motivational value, supporting brain networks for seeking, evaluation, and value learning. Others encode motivational salience, supporting brain networks for orienting, cognition, and general motivation. Both types of dopamine neurons are augmented by an alerting signal involved in rapid detection of potentially important sensory cues. We hypothesize that these dopaminergic pathways for value, salience, and alerting cooperate to support adaptive behavior. PMID:21144997

Reward modulation of cognitive function in adult attention-deficit/hyperactivity disorder: a pilot study on the role of striatal dopamine.

PubMed

Aarts, Esther; van Holstein, Mieke; Hoogman, Martine; Onnink, Marten; Kan, Cornelis; Franke, Barbara; Buitelaar, Jan; Cools, Roshan

2015-02-01

Attention-deficit/hyperactivity disorder (ADHD) is accompanied by impairments in cognitive control, such as task-switching deficits. We investigated whether such problems, and their remediation by medication, reflect abnormal reward motivation and associated striatal dopamine transmission in ADHD. We used functional genetic neuroimaging to assess the effects of dopaminergic medication and reward motivation on task-switching and striatal BOLD signal in 23 adults with ADHD, ON and OFF methylphenidate, and 26 healthy controls. Critically, we took into account interindividual variability in striatal dopamine by exploiting a common genetic polymorphism (3'-UTR VNTR) in the DAT1 gene coding for the dopamine transporter. The results showed a highly significant group by genotype interaction in the striatum. This was because a subgroup of patients with ADHD showed markedly exaggerated effects of reward on the striatal BOLD signal during task-switching when they were OFF their dopaminergic medication. Specifically, patients carrying the 9R allele showed a greater striatal signal than healthy controls carrying this allele, whereas no effect of diagnosis was observed in 10R homozygotes. Aberrant striatal responses were normalized when 9R-carrying patients with ADHD were ON medication. These pilot data indicate an important role for aberrant reward motivation, striatal dopamine and interindividual genetic differences in cognitive processes in adult ADHD.

Reward modulation of cognitive function in adult attention-deficit/hyperactivity disorder: a pilot study on the role of striatal dopamine

PubMed Central

Aarts, Esther; Hoogman, Martine; Onnink, Marten; Kan, Cornelis; Franke, Barbara; Buitelaar, Jan; Cools, Roshan

2015-01-01

Attention-deficit/hyperactivity disorder (ADHD) is accompanied by impairments in cognitive control, such as task-switching deficits. We investigated whether such problems, and their remediation by medication, reflect abnormal reward motivation and associated striatal dopamine transmission in ADHD. We used functional genetic neuroimaging to assess the effects of dopaminergic medication and reward motivation on task-switching and striatal BOLD signal in 23 adults with ADHD, ON and OFF methylphenidate, and 26 healthy controls. Critically, we took into account interindividual variability in striatal dopamine by exploiting a common genetic polymorphism (3′-UTR VNTR) in the DAT1 gene coding for the dopamine transporter. The results showed a highly significant group by genotype interaction in the striatum. This was because a subgroup of patients with ADHD showed markedly exaggerated effects of reward on the striatal BOLD signal during task-switching when they were OFF their dopaminergic medication. Specifically, patients carrying the 9R allele showed a greater striatal signal than healthy controls carrying this allele, whereas no effect of diagnosis was observed in 10R homozygotes. Aberrant striatal responses were normalized when 9R-carrying patients with ADHD were ON medication. These pilot data indicate an important role for aberrant reward motivation, striatal dopamine and interindividual genetic differences in cognitive processes in adult ADHD. PMID:25485641

Dissociated roles of the anterior cingulate cortex in reward and conflict processing as revealed by the feedback error-related negativity and N200.

PubMed

Baker, Travis E; Holroyd, Clay B

2011-04-01

The reinforcement learning theory of the error-related negativity (ERN) holds that the impact of reward signals carried by the midbrain dopamine system modulates activity of the anterior cingulate cortex (ACC), alternatively disinhibiting and inhibiting the ACC following unpredicted error and reward events, respectively. According to a recent formulation of the theory, activity that is intrinsic to the ACC produces a component of the event-related brain potential (ERP) called the N200, and following unpredicted rewards, the N200 is suppressed by extrinsically applied positive dopamine reward signals, resulting in an ERP component called the feedback-ERN (fERN). Here we demonstrate that, despite extensive spatial and temporal overlap between the two ERP components, the functional processes indexed by the N200 (conflict) and the fERN (reward) are dissociable. These results point toward avenues for future investigation. Copyright © 2011 Elsevier B.V. All rights reserved.

A Selective Role for Dopamine in Learning to Maximize Reward But Not to Minimize Effort: Evidence from Patients with Parkinson's Disease.

PubMed

Skvortsova, Vasilisa; Degos, Bertrand; Welter, Marie-Laure; Vidailhet, Marie; Pessiglione, Mathias

2017-06-21

Instrumental learning is a fundamental process through which agents optimize their choices, taking into account various dimensions of available options such as the possible reward or punishment outcomes and the costs associated with potential actions. Although the implication of dopamine in learning from choice outcomes is well established, less is known about its role in learning the action costs such as effort. Here, we tested the ability of patients with Parkinson's disease (PD) to maximize monetary rewards and minimize physical efforts in a probabilistic instrumental learning task. The implication of dopamine was assessed by comparing performance ON and OFF prodopaminergic medication. In a first sample of PD patients ( n = 15), we observed that reward learning, but not effort learning, was selectively impaired in the absence of treatment, with a significant interaction between learning condition (reward vs effort) and medication status (OFF vs ON). These results were replicated in a second, independent sample of PD patients ( n = 20) using a simplified version of the task. According to Bayesian model selection, the best account for medication effects in both studies was a specific amplification of reward magnitude in a Q-learning algorithm. These results suggest that learning to avoid physical effort is independent from dopaminergic circuits and strengthen the general idea that dopaminergic signaling amplifies the effects of reward expectation or obtainment on instrumental behavior. SIGNIFICANCE STATEMENT Theoretically, maximizing reward and minimizing effort could involve the same computations and therefore rely on the same brain circuits. Here, we tested whether dopamine, a key component of reward-related circuitry, is also implicated in effort learning. We found that patients suffering from dopamine depletion due to Parkinson's disease were selectively impaired in reward learning, but not effort learning. Moreover, anti-parkinsonian medication restored the ability to maximize reward, but had no effect on effort minimization. This dissociation suggests that the brain has evolved separate, domain-specific systems for instrumental learning. These results help to disambiguate the motivational role of prodopaminergic medications: they amplify the impact of reward without affecting the integration of effort cost. Copyright © 2017 the authors 0270-6474/17/376087-11$15.00/0.

Advances in studying phasic dopamine signaling in brain reward mechanisms

PubMed Central

Wickham, Robert J.; Solecki, Wojciech; Rathbun, Liza R.; Neugebauer, Nichole M.; Wightman, R. Mark; Addy, Nii A.

2013-01-01

The last sixty years of research have provided extraordinary advances of our knowledge of the reward system. Since its initial discovery as a neurotransmitter by Carlsson and colleagues (Carlsson et al., 1957), dopamine (DA) has emerged as an important mediator of reward processing. As a result, a number of electrochemical techniques have been developed to directly measure DA levels in the brain using various preparations. Many of these techniques and preparations differ in the types of questions that they can address. Together, these techniques have begun to elucidate the complex roles of tonic and phasic DA signaling in reward processing and in addiction. In this review, we will first provide a guide for the most commonly used electrochemical methods for DA detection and describe their utility in furthering our knowledge about DA's role in reward and addiction. Second, we will review the value of common in vitro and in vivo preparations and describe their ability to address different types of questions. Last, we will review recent data that has provided new insight of the mechanisms of in vivo phasic DA signaling and its role in reward processing and reward-mediated behavior. PMID:23747914

Ventral Tegmental Area Dopamine Cell Activation during Male Rat Sexual Behavior Regulates Neuroplasticity and d-Amphetamine Cross-Sensitization following Sex Abstinence.

PubMed

Beloate, Lauren N; Omrani, Azar; Adan, Roger A; Webb, Ian C; Coolen, Lique M

2016-09-21

Experience with sexual behavior causes cross-sensitization of amphetamine reward, an effect dependent on a period of sexual reward abstinence. We previously showed that ΔFosB in the nucleus accumbens (NAc) is a key mediator of this cross-sensitization, potentially via dopamine receptor activation. However, the role of mesolimbic dopamine for sexual behavior or cross-sensitization between natural and drug reward is unknown. This was tested using inhibitory designer receptors exclusively activated by designer drugs in ventral tegmental area (VTA) dopamine cells. rAAV5/hSvn-DIO-hm4D-mCherry was injected into the VTA of TH::Cre adult male rats. Males received clozapine N-oxide (CNO) or vehicle injections before each of 5 consecutive days of mating or handling. Following an abstinence period of 7 d, males were tested for amphetamine conditioned place preference (CPP). Next, males were injected with CNO or vehicle before mating or handling for analysis of mating-induced cFos, sex experience-induced ΔFosB, and reduction of VTA dopamine soma size. Results showed that CNO did not affect mating behavior. Instead, CNO prevented sexual experience-induced cross-sensitization of amphetamine CPP, ΔFosB in the NAc and medial prefrontal cortex, and decreases in VTA dopamine soma size. Expression of hm4D-mCherry was specific to VTA dopamine cells and CNO blocked excitation and mating-induced cFos expression in VTA dopamine cells. These findings provide direct evidence that VTA dopamine activation is not required for initiation or performance of sexual behavior. Instead, VTA dopamine directly contributes to increased vulnerability for drug use following loss of natural reward by causing neuroplasticity in the mesolimbic pathway during the natural reward experience. Drugs of abuse act on the neural pathways that mediate natural reward learning and memory. Exposure to natural reward behaviors can alter subsequent drug-related reward. Specifically, experience with sexual behavior, followed by a period of abstinence from sexual behavior, causes increased reward for amphetamine in male rats. This study demonstrates that activation of ventral tegmental area dopamine neurons during sexual experience regulates cross-sensitization of amphetamine reward. Finally, ventral tegmental area dopamine cell activation is essential for experience-induced neural adaptations in the nucleus accumbens, prefrontal cortex, and ventral tegmental area. These findings demonstrate a role of mesolimbic dopamine in the interaction between natural and drug rewards, and identify mesolimbic dopamine as a key mediator of changes in vulnerability for drug use after loss of natural reward. Copyright © 2016 the authors 0270-6474/16/369949-13$15.00/0.

The genetic basis of individual differences in reward processing and the link to addictive behavior and social cognition.

PubMed

Yacubian, J; Büchel, C

2009-11-24

Dopaminergic neurotransmission is widely recognized to be critical to the neurobiology of reward, motivation and addiction. Interestingly, social interactions and related behavior also activate the same neuronal system. Consequently, genetic variations of dopamine neurotransmission are thought influence reward processing that in turn may affect distinctive social behavior and susceptibility to addiction. This review focuses on advances made to date in an effort to link genetic individual variations and reward processing as a possible basis for addictive behaviors.

Ethanol Exposure History and Alcoholic Reward Differentially Alter Dopamine Release in the Nucleus Accumbens to a Reward-Predictive Cue.

PubMed

Fiorenza, Amanda M; Shnitko, Tatiana A; Sullivan, Kaitlin M; Vemuru, Sudheer R; Gomez-A, Alexander; Esaki, Julie Y; Boettiger, Charlotte A; Da Cunha, Claudio; Robinson, Donita L

2018-06-01

Conditioned stimuli (CS) that predict reward delivery acquire the ability to induce phasic dopamine release in the nucleus accumbens (NAc). This dopamine release may facilitate conditioned approach behavior, which often manifests as approach to the site of reward delivery (called "goal-tracking") or to the CS itself (called "sign-tracking"). Previous research has linked sign-tracking in particular to impulsivity and drug self-administration, and addictive drugs may promote the expression of sign-tracking. Ethanol (EtOH) acutely promotes phasic release of dopamine in the accumbens, but it is unknown whether an alcoholic reward alters dopamine release to a CS. We hypothesized that Pavlovian conditioning with an alcoholic reward would increase dopamine release triggered by the CS and subsequent sign-tracking behavior. Moreover, we predicted that chronic intermittent EtOH (CIE) exposure would promote sign-tracking while acute administration of naltrexone (NTX) would reduce it. Rats received 14 doses of EtOH (3 to 5 g/kg, intragastric) or water followed by 6 days of Pavlovian conditioning training. Rewards were a chocolate solution with or without 10% (w/v) alcohol. We used fast-scan cyclic voltammetry to measure phasic dopamine release in the NAc core in response to the CS and the rewards. We also determined the effect of NTX (1 mg/kg, subcutaneous) on conditioned approach. Both CIE and alcoholic reward, individually but not together, associated with greater dopamine to the CS than control conditions. However, this increase in dopamine release was not linked to greater sign-tracking, as both CIE and alcoholic reward shifted conditioned approach from sign-tracking behavior to goal-tracking behavior. However, they both also increased sensitivity to NTX, which reduced goal-tracking behavior. While a history of EtOH exposure or alcoholic reward enhanced dopamine release to a CS, they did not promote sign-tracking under the current conditions. These findings are consistent with the interpretation that EtOH can stimulate conditioned approach, but indicate that the conditioned response may manifest as goal-tracking. Copyright © 2018 by the Research Society on Alcoholism.

Phasic dopamine signals: from subjective reward value to formal economic utility

PubMed Central

Schultz, Wolfram; Carelli, Regina M; Wightman, R Mark

2015-01-01

Although rewards are physical stimuli and objects, their value for survival and reproduction is subjective. The phasic, neurophysiological and voltammetric dopamine reward prediction error response signals subjective reward value. The signal incorporates crucial reward aspects such as amount, probability, type, risk, delay and effort. Differences of dopamine release dynamics with temporal delay and effort in rodents may derive from methodological issues and require further study. Recent designs using concepts and behavioral tools from experimental economics allow to formally characterize the subjective value signal as economic utility and thus to establish a neuronal value function. With these properties, the dopamine response constitutes a utility prediction error signal. PMID:26719853

Examination of Rapid Dopamine Dynamics with Fast Scan Cyclic Voltammetry During Intra-oral Tastant Administration in Awake Rats.

PubMed

Wickham, Robert J; Park, Jinwoo; Nunes, Eric J; Addy, Nii A

2015-08-12

Rapid, phasic dopamine (DA) release in the mammalian brain plays a critical role in reward processing, reinforcement learning, and motivational control. Fast scan cyclic voltammetry (FSCV) is an electrochemical technique with high spatial and temporal (sub-second) resolution that has been utilized to examine phasic DA release in several types of preparations. In vitro experiments in single-cells and brain slices and in vivo experiments in anesthetized rodents have been used to identify mechanisms that mediate dopamine release and uptake under normal conditions and in disease models. Over the last 20 years, in vivo FSCV experiments in awake, freely moving rodents have also provided insight of dopaminergic mechanisms in reward processing and reward learning. One major advantage of the awake, freely moving preparation is the ability to examine rapid DA fluctuations that are time-locked to specific behavioral events or to reward or cue presentation. However, one limitation of combined behavior and voltammetry experiments is the difficulty of dissociating DA effects that are specific to primary rewarding or aversive stimuli from co-occurring DA fluctuations that mediate reward-directed or other motor behaviors. Here, we describe a combined method using in vivo FSCV and intra-oral infusion in an awake rat to directly investigate DA responses to oral tastants. In these experiments, oral tastants are infused directly to the palate of the rat--bypassing reward-directed behavior and voluntary drinking behavior--allowing for direct examination of DA responses to tastant stimuli.

Putting desire on a budget: dopamine and energy expenditure, reconciling reward and resources

PubMed Central

Beeler, Jeff A.; Frazier, Cristianne R. M.; Zhuang, Xiaoxi

2012-01-01

Accumulating evidence indicates integration of dopamine function with metabolic signals, highlighting a potential role for dopamine in energy balance, frequently construed as modulating reward in response to homeostatic state. Though its precise role remains controversial, the reward perspective of dopamine has dominated investigation of motivational disorders, including obesity. In the hypothesis outlined here, we suggest instead that the primary role of dopamine in behavior is to modulate activity to adapt behavioral energy expenditure to the prevailing environmental energy conditions, with the role of dopamine in reward and motivated behaviors derived from its primary role in energy balance. Dopamine has long been known to modulate activity, exemplified by psychostimulants that act via dopamine. More recently, there has been nascent investigation into the role of dopamine in modulating voluntary activity, with some investigators suggesting that dopamine may serve as a final common pathway that couples energy sensing to regulated voluntary energy expenditure. We suggest that interposed between input from both the internal and external world, dopamine modulates behavioral energy expenditure along two axes: a conserve-expend axis that regulates generalized activity and an explore-exploit axes that regulates the degree to which reward value biases the distribution of activity. In this view, increased dopamine does not promote consumption of tasty food. Instead increased dopamine promotes energy expenditure and exploration while decreased dopamine favors energy conservation and exploitation. This hypothesis provides a mechanistic interpretation to an apparent paradox: the well-established role of dopamine in food seeking and the findings that low dopaminergic functions are associated with obesity. Our hypothesis provides an alternative perspective on the role of dopamine in obesity and reinterprets the “reward deficiency hypothesis” as a perceived energy deficit. We propose that dopamine, by facilitating energy expenditure, should be protective against obesity. We suggest the apparent failure of this protective mechanism in Western societies with high prevalence of obesity arises as a consequence of sedentary lifestyles that thwart energy expenditure. PMID:22833718

Abnormal Reward System Activation in Mania

PubMed Central

Abler, Birgit; Greenhouse, Ian; Ongur, Dost; Walter, Henrik; Heckers, Stephan

2008-01-01

Transmission of reward signals is a function of dopamine, a neurotransmitter known to be involved in the mechanism of psychosis. Using functional magnetic resonance imaging (fMRI), we investigated how expectation and receipt of monetary rewards modulate brain activation in patients with bipolar mania and schizophrenia. We studied 12 acutely manic patients with a history of bipolar disorder, 12 patients with a current episode of schizoaffective disorder or schizophrenia and 12 healthy subjects. All patients were treated with dopamine antagonists at the time of the study. Subjects performed a delayed incentive paradigm with monetary reward in the scanner that allowed for investigating effects of expectation, receipt, and omission of rewards. Patients with schizophrenia and healthy control subjects showed the expected activation of dopaminergic brain areas, that is, ventral tegmentum activation upon expectation of monetary rewards and nucleus accumbens activation during receipt vs omission of rewards. In manic patients, however, we did not find a similar pattern of brain activation and the differential signal in the nucleus accumbens upon receipt vs omission of rewards was significantly lower compared to the healthy control subjects. Our findings provide evidence for abnormal function of the dopamine system during receipt or omission of expected rewards in bipolar disorder. These deficits in prediction error processing in acute mania may help to explain symptoms of disinhibition and abnormal goal pursuit regulation. PMID:17987058

Ventral tegmental area dopamine revisited: effects of acute and repeated stress

PubMed Central

Holly, Elizabeth N.; Miczek, Klaus A.

2015-01-01

Aversive events rapidly and potently excite certain dopamine neurons in the ventral tegmental area (VTA), promoting phasic increases in the medial prefrontal cortex and nucleus accumbens. This is in apparent contradiction to a wealth of literature demonstrating that most VTA dopamine neurons are strongly activated by reward and reward-predictive cues while inhibited by aversive stimuli. How can these divergent processes both be mediated by VTA dopamine neurons? The answer may lie within the functional and anatomical heterogeneity of the VTA. We focus on VTA heterogeneity in anatomy, neurochemistry, electrophysiology, and afferent/efferent connectivity. Second, recent evidence for a critical role of VTA dopamine neurons in response to both acute and repeated stress will be discussed. Understanding which dopamine neurons are activated by stress, the neural mechanisms driving the activation, and where these neurons project will provide valuable insight into how stress can promote psychiatric disorders associated with the dopamine system, such as addiction and depression. PMID:26676983

Compromised Dopaminergic Encoding of Reward Accompanying Suppressed Willingness to Overcome High Effort Costs Is a Prominent Prodromal Characteristic of the Q175 Mouse Model of Huntington's Disease.

PubMed

Covey, Dan P; Dantrassy, Hannah M; Zlebnik, Natalie E; Gildish, Iness; Cheer, Joseph F

2016-05-04

Huntington's disease (HD) is a heritable neurodegenerative disorder caused by expansion of CAG (glutamine) repeats in the HTT gene. A prodromal stage characterized by psychiatric disturbances normally precedes primary motor symptoms and suppressed motivation represents one of the earliest and most common psychiatric symptoms. Although dopamine in the nucleus accumbens (NAc) critically regulates motivation and altered dopamine signaling is implicated in HD, the nature of dopaminergic deficits and contribution to symptoms in HD is poorly understood. We therefore tested whether altered NAc dopamine release accompanies motivational deficits in the Q175 knock-in HD mouse model. Q175 mice express a CAG expansion of the human mutant huntingtin allele in the native mouse genome and gradually manifest symptoms late in life, closely mimicking the genotypic context and disease progression in human HD. Sub-second extracellular dopamine release dynamics were monitored using fast-scan cyclic voltammetry, whereas motivation was assessed using a progressive ratio reinforcement schedule. As the response ratio (lever presses per reward) escalated, Q175 mice exerted less effort to earn fewer rewards versus wild-type (WT). Moreover, dopamine released at reward delivery dynamically encoded increasing reward cost in WT but not Q175 mice. Deficits were specific to situations of high effortful demand as no difference was observed in locomotion, free feeding, hedonic processing, or reward seeking when the response requirement was low. This compromised dopaminergic encoding of reward delivery coincident with suppressed motivation to work for reward in Q175 mice provides novel, neurobiological insight into an established and clinically relevant endophenotype of prodromal HD. Psychiatric impairments in Huntington's disease (HD) typically manifest early in disease progression, before motor deficits. However, the neurobiological factors contributing to psychiatric symptoms are poorly understood. We used a mouse HD model and assessed whether impaired dopamine release in the nucleus accumbens (NAc), a brain region critical to goal-directed behaviors, accompanies motivational deficits, one of the most common early HD symptoms. HD mice exhibited blunted motivation to work for food reward coincident with diminished dopamine release to reward receipt. Motivational and NAc dopaminergic deficits were not associated with gross motor deficits or impaired food seeking when effortful demands were low. This work identifies a specific prodromal HD phenotype associated with a prominent and previously unidentified neurobiological impairment. Copyright © 2016 the authors 0270-6474/16/364993-10$15.00/0.

Reward and aversion in a heterogeneous midbrain dopamine system.

PubMed

Lammel, Stephan; Lim, Byung Kook; Malenka, Robert C

2014-01-01

The ventral tegmental area (VTA) is a heterogeneous brain structure that serves a central role in motivation and reward processing. Abnormalities in the function of VTA dopamine (DA) neurons and the targets they influence are implicated in several prominent neuropsychiatric disorders including addiction and depression. Recent studies suggest that the midbrain DA system is composed of anatomically and functionally heterogeneous DA subpopulations with different axonal projections. These findings may explain a number of previously confusing observations that suggested a role for DA in processing both rewarding as well as aversive events. Here we will focus on recent advances in understanding the neural circuits mediating reward and aversion in the VTA and how stress as well as drugs of abuse, in particular cocaine, alter circuit function within a heterogeneous midbrain DA system. This article is part of a Special Issue entitled 'NIDA 40th Anniversary Issue'. Copyright © 2013 Elsevier Ltd. All rights reserved.

The rostromedial tegmental nucleus (RMTg), a major GABAergic afferent to midbrain dopamine neurons, selectively encodes aversive stimuli and promotes behavioral inhibition

PubMed Central

Jhou, Thomas C.; Fields, Howard L.; Baxter, Mark G.; Saper, Clifford B.; Holland, Peter C.

2009-01-01

Summary Separate studies have implicated the lateral habenula (LHb) or amygdala-related regions in processing aversive stimuli, but their relationships to each other and to appetitive motivational systems are poorly understood. We show that neurons in the recently identified GABAergic rostromedial tegmental nucleus (RMTg), which receive a major LHb input, project heavily to midbrain dopamine neurons, and show phasic activations and/or Fos induction after aversive stimuli (footshocks, shock-predictive cues, food deprivation, or reward omission) and inhibitions after rewards or reward-predictive stimuli. RMTg lesions markedly reduce passive fear behaviors (freezing, open-arm avoidance) dependent on the extended amygdala, periaqueductal gray, or septum, all regions that project directly to the RMTg. In contrast, RMTg lesions spare or enhance active fear responses (treading, escape) in these same paradigms. These findings suggest that aversive inputs from widespread brain regions and stimulus modalities converge onto the RMTg, which opposes reward and motor-activating functions of midbrain dopamine neurons PMID:19285474

Dynamics of rapid dopamine release in the nucleus accumbens during goal-directed behaviors for cocaine versus natural rewards

PubMed Central

Cameron, Courtney M.; Wightman, R. Mark; Carelli, Regina M.

2014-01-01

Electrophysiological studies show that distinct subsets of nucleus accumbens (NAc) neurons differentially encode information about goal-directed behaviors for intravenous cocaine versus natural (food/water) rewards. Further, NAc rapid dopamine signaling occurs on a timescale similar to phasic cell firing during cocaine and natural reward-seeking behaviors. However, it is not known whether dopamine signaling is reinforcer specific (i.e., is released during responding for only one type of reinforcer) within discrete NAc locations, similar to neural firing dynamics. Here, fast-scan cyclic voltammetry (FSCV) was used to measure rapid dopamine release during multiple schedules involving sucrose reward and cocaine self-administration (n=8 rats) and, in a separate group of rats (n = 6), during a sucrose/food multiple schedule. During the sucrose/cocaine multiple schedule, dopamine increased within seconds of operant responding for both reinforcers. Although dopamine release was not reinforcer specific, more subtle differences were observed in peak dopamine concentration [DA] across reinforcer conditions. Specifically, peak [DA] was higher during the first phase of the multiple schedule, regardless of reinforcer type. Further, the time to reach peak [DA] was delayed during cocaine-responding compared to sucrose. During the sucrose/food multiple schedule, increases in dopamine release were also observed relative to operant responding for both natural rewards. However, peak [DA] was higher relative to responding for sucrose than food, regardless of reinforcer order. Overall, the results reveal the dynamics of rapid dopamine signaling in discrete locations in the NAc across reward conditions, and provide novel insight into the functional role of this system in reward-seeking behaviors. PMID:25174553

Dopamine neurons share common response function for reward prediction error

PubMed Central

Eshel, Neir; Tian, Ju; Bukwich, Michael; Uchida, Naoshige

2016-01-01

Dopamine neurons are thought to signal reward prediction error, or the difference between actual and predicted reward. How dopamine neurons jointly encode this information, however, remains unclear. One possibility is that different neurons specialize in different aspects of prediction error; another is that each neuron calculates prediction error in the same way. We recorded from optogenetically-identified dopamine neurons in the lateral ventral tegmental area (VTA) while mice performed classical conditioning tasks. Our tasks allowed us to determine the full prediction error functions of dopamine neurons and compare them to each other. We found striking homogeneity among individual dopamine neurons: their responses to both unexpected and expected rewards followed the same function, just scaled up or down. As a result, we could describe both individual and population responses using just two parameters. Such uniformity ensures robust information coding, allowing each dopamine neuron to contribute fully to the prediction error signal. PMID:26854803

Dopamine prediction error responses integrate subjective value from different reward dimensions

PubMed Central

Lak, Armin; Stauffer, William R.; Schultz, Wolfram

2014-01-01

Prediction error signals enable us to learn through experience. These experiences include economic choices between different rewards that vary along multiple dimensions. Therefore, an ideal way to reinforce economic choice is to encode a prediction error that reflects the subjective value integrated across these reward dimensions. Previous studies demonstrated that dopamine prediction error responses reflect the value of singular reward attributes that include magnitude, probability, and delay. Obviously, preferences between rewards that vary along one dimension are completely determined by the manipulated variable. However, it is unknown whether dopamine prediction error responses reflect the subjective value integrated from different reward dimensions. Here, we measured the preferences between rewards that varied along multiple dimensions, and as such could not be ranked according to objective metrics. Monkeys chose between rewards that differed in amount, risk, and type. Because their choices were complete and transitive, the monkeys chose “as if” they integrated different rewards and attributes into a common scale of value. The prediction error responses of single dopamine neurons reflected the integrated subjective value inferred from the choices, rather than the singular reward attributes. Specifically, amount, risk, and reward type modulated dopamine responses exactly to the extent that they influenced economic choices, even when rewards were vastly different, such as liquid and food. This prediction error response could provide a direct updating signal for economic values. PMID:24453218

Midbrain dopamine neurons associated with reward processing innervate the neurogenic subventricular zone.

PubMed

Lennington, Jessica B; Pope, Sara; Goodheart, Anna E; Drozdowicz, Linda; Daniels, Stephen B; Salamone, John D; Conover, Joanne C

2011-09-14

Coordinated regulation of the adult neurogenic subventricular zone (SVZ) is accomplished by a myriad of intrinsic and extrinsic factors. The neurotransmitter dopamine is one regulatory molecule implicated in SVZ function. Nigrostriatal and ventral tegmental area (VTA) midbrain dopamine neurons innervate regions adjacent to the SVZ, and dopamine synapses are found on SVZ cells. Cell division within the SVZ is decreased in humans with Parkinson's disease and in animal models of Parkinson's disease following exposure to toxins that selectively remove nigrostriatal neurons, suggesting that dopamine is critical for SVZ function and nigrostriatal neurons are the main suppliers of SVZ dopamine. However, when we examined the aphakia mouse, which is deficient in nigrostriatal neurons, we found no detrimental effect to SVZ proliferation or organization. Instead, dopamine innervation of the SVZ tracked to neurons at the ventrolateral boundary of the VTA. This same dopaminergic neuron population also innervated the SVZ of control mice. Characterization of these neurons revealed expression of proteins indicative of VTA neurons. Furthermore, exposure to the neurotoxin MPTP depleted neurons in the ventrolateral VTA and resulted in decreased SVZ proliferation. Together, these results reveal that dopamine signaling in the SVZ originates from a population of midbrain neurons more typically associated with motivational and reward processing.

Mechanisms of Nicotine Addiction

DOE Office of Scientific and Technical Information (OSTI.GOV)

McGehee, Daniel

Nicotine reinforces the use of tobacco products primarily through its interaction with specific receptor proteins within the brain’s reward centers. A critical step in the process of addiction for many drugs, including nicotine, is the release of the neurotransmitter dopamine. A single nicotine exposure will enhance dopamine levels for hours, however, nicotinic receptors undergo both activation and then desensitization in minutes, which presents an important problem. How does the time course of receptor activity lead to the prolonged release of dopamine? We have found that persistent modulation of both inhibitory and excitatory synaptic connections by nicotine underlies the sustained increasemore » in dopamine release. Because these inputs express different types of nicotinic receptors there is a coordinated shift in the balance of synaptic inputs toward excitation of the dopamine neurons. Excitatory inputs are turned on while inhibitory inputs are depressed, thereby boosting the brain’s reward system.« less

Disruptions in effort-based decision-making and consummatory behavior following antagonism of the dopamine D2 receptor.

PubMed

Robles, Cindee F; Johnson, Alexander W

2017-03-01

Dopamine is known to influence motivational processes, however the precise role of this neurotransmitter remains a contentious issue. In the current study we sought to further characterize dopamine signaling in reward-based decision-making and consummatory behavior in mice, via lateral ventricle infusion of the dopamine D2 receptor antagonist eticlopride. In Experiment 1, we examined effort-based decision-making, in which mice had a choice between one lever, where a single response led to the delivery of a low value reward (2% sucrose); and a second lever, which led to a higher value reward (20% sucrose) that gradually required more effort to obtain. As the response schedule for the high value reward became more strict, low dose (4μg in 0.5μl) central infusions of eticlopride biased preference away from the high value reward, and toward the lever that led to the low value reward. Similarly, a higher dose of eticlopride (8μg in 0.5μl) also disrupted choice responding for the high value reward, however it did so by increasing omissions. In Experiment 2, we assessed the effects of eticlopride on consumption of 20% sucrose. The antagonist led to a dose-dependent reduction in intake, and through an analysis of licking microstructure, it was revealed that this in part reflected a reduction in the motivation to engage in consummatory behavior, rather than alterations in the evaluation of the reward. These results suggest that disruptions in D2 receptor signaling reduce the willingness to engage in effortful operant responding and consumption of a desirable outcome. Copyright © 2016 Elsevier B.V. All rights reserved.

Striatal dopamine release codes uncertainty in pathological gambling.

PubMed

Linnet, Jakob; Mouridsen, Kim; Peterson, Ericka; Møller, Arne; Doudet, Doris Jeanne; Gjedde, Albert

2012-10-30

Two mechanisms of midbrain and striatal dopaminergic projections may be involved in pathological gambling: hypersensitivity to reward and sustained activation toward uncertainty. The midbrain-striatal dopamine system distinctly codes reward and uncertainty, where dopaminergic activation is a linear function of expected reward and an inverse U-shaped function of uncertainty. In this study, we investigated the dopaminergic coding of reward and uncertainty in 18 pathological gambling sufferers and 16 healthy controls. We used positron emission tomography (PET) with the tracer [(11)C]raclopride to measure dopamine release, and we used performance on the Iowa Gambling Task (IGT) to determine overall reward and uncertainty. We hypothesized that we would find a linear function between dopamine release and IGT performance, if dopamine release coded reward in pathological gambling. If, on the other hand, dopamine release coded uncertainty, we would find an inversely U-shaped function. The data supported an inverse U-shaped relation between striatal dopamine release and IGT performance if the pathological gambling group, but not in the healthy control group. These results are consistent with the hypothesis of dopaminergic sensitivity toward uncertainty, and suggest that dopaminergic sensitivity to uncertainty is pronounced in pathological gambling, but not among non-gambling healthy controls. The findings have implications for understanding dopamine dysfunctions in pathological gambling and addictive behaviors. Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.

Distinct effects of apathy and dopamine on effort-based decision-making in Parkinson's disease.

PubMed

Le Heron, Campbell; Plant, Olivia; Manohar, Sanjay; Ang, Yuen-Siang; Jackson, Matthew; Lennox, Graham; Hu, Michele T; Husain, Masud

2018-05-01

Effort-based decision-making is a cognitive process crucial to normal motivated behaviour. Apathy is a common and disabling complication of Parkinson's disease, but its aetiology remains unclear. Intriguingly, the neural substrates associated with apathy also subserve effort-based decision-making in animal models and humans. Furthermore, the dopaminergic system plays a core role in motivating effortful behaviour for reward, and its dysfunction has been proposed to play a crucial role in the aetiology of apathy in Parkinson's disease. We hypothesized that disrupted effort-based decision-making underlies the syndrome of apathy in Parkinson's disease, and that this disruption may be modulated by the dopaminergic system. An effort-based decision-making task was administered to 39 patients with Parkinson's disease, with and without clinical apathy, ON and OFF their normal dopaminergic medications across two separate sessions, as well as 32 healthy age- and gender-matched controls. On a trial-by-trial basis, participants decided whether to accept or reject offers of monetary reward in return for exerting different levels of physical effort via handheld, individually calibrated dynamometers. Effort and reward were manipulated independently, such that offers spanned the full range of effort/reward combinations. Apathy was assessed using the Lille apathy rating scale. Motor effects of the dopamine manipulation were assessed using the Unified Parkinson's Disease Rating Scale part three motor score. The primary outcome variable was choice (accept/decline offer) analysed using a hierarchical generalized linear mixed effects model, and the vigour of squeeze (Newtons exerted above required force). Both apathy and dopamine depletion were associated with reduced acceptance of offers. However, these effects were driven by dissociable patterns of responding. While apathy was characterized by increased rejection of predominantly low reward offers, dopamine increased responding to high effort, high reward offers, irrespective of underlying motivational state. Dopamine also exerted a main effect on motor vigour, increasing force production independently of reward offered, while apathy did not affect this measure. The findings demonstrate that disrupted effort-based decision-making underlies Parkinson's disease apathy, but in a manner distinct to that caused by dopamine depletion. Apathy is associated with reduced incentivization by the rewarding outcomes of actions. In contrast, dopamine has a general effect in motivating behaviour for high effort, high reward options without altering the response pattern that characterizes the apathetic state. Thus, the motivational deficit observed in Parkinson's disease appears not to be simply secondary to dopaminergic depletion of mesocorticolimbic pathways, suggesting non-dopaminergic therapeutic strategies for apathy may be important future targets.

The Iowa Gambling Task and the three fallacies of dopamine in gambling disorder

PubMed Central

Linnet, Jakob

2013-01-01

Gambling disorder sufferers prefer immediately larger rewards despite long term losses on the Iowa Gambling Task (IGT), and these impairments are associated with dopamine dysfunctions. Dopamine is a neurotransmitter linked with temporal and structural dysfunctions in substance use disorder, which has supported the idea of impaired decision-making and dopamine dysfunctions in gambling disorder. However, evidence from substance use disorders cannot be directly transferred to gambling disorder. This article focuses on three hypotheses of dopamine dysfunctions in gambling disorder, which appear to be “fallacies,” i.e., have not been supported in a series of positron emission tomography (PET) studies. The first “fallacy” suggests that gambling disorder sufferers have lower dopamine receptor availability, as seen in substance use disorders. However, no evidence supported this hypothesis. The second “fallacy” suggests that maladaptive decision-making in gambling disorder is associated with higher dopamine release during gambling. No evidence supported the hypothesis, and the literature on substance use disorders offers limited support for this hypothesis. The third “fallacy” suggests that maladaptive decision-making in gambling disorder is associated with higher dopamine release during winning. The evidence did not support this hypothesis either. Instead, dopaminergic coding of reward prediction and uncertainty might better account for dopamine dysfunctions in gambling disorder. Studies of reward prediction and reward uncertainty show a sustained dopamine response toward stimuli with maximum uncertainty, which may explain the continued dopamine release and gambling despite losses in gambling disorder. The findings from the studies presented here are consistent with the notion of dopaminergic dysfunctions of reward prediction and reward uncertainty signals in gambling disorder. PMID:24115941

Distinct Roles of Opioid and Dopamine Systems in Lateral Hypothalamic Intracranial Self-Stimulation.

PubMed

Ide, Soichiro; Takahashi, Takehiro; Takamatsu, Yukio; Uhl, George R; Niki, Hiroaki; Sora, Ichiro; Ikeda, Kazutaka

2017-05-01

Opioid and dopamine systems play crucial roles in reward. Similarities and differences in the neural mechanisms of reward that are mediated by these 2 systems have remained largely unknown. Thus, in the present study, we investigated the differences in reward function in both µ-opioid receptor knockout mice and dopamine transporter knockout mice, important molecules in the opioid and dopamine systems. Mice were implanted with electrodes into the right lateral hypothalamus (l hour). Mice were then trained to put their muzzle into the hole in the head-dipping chamber for intracranial electrical stimulation, and the influences of gene knockout were assessed. Significant differences are observed between opioid and dopamine systems in reward function. µ-Opioid receptor knockout mice exhibited enhanced intracranial electrical stimulation, which induced dopamine release. They also exhibited greater motility under conditions of "despair" in both the tail suspension test and water wheel test. In contrast, dopamine transporter knockout mice maintained intracranial electrical stimulation responding even when more active efforts were required to obtain the reward. The absence of µ-opioid receptor or dopamine transporter did not lead to the absence of intracranial electrical stimulation responsiveness but rather differentially altered it. The present results in µ-opioid receptor knockout mice are consistent with the suppressive involvement of µ-opioid receptors in both positive incentive motivation associated with intracranial electrical stimulation and negative incentive motivation associated with depressive states. In contrast, the results in dopamine transporter knockout mice are consistent with the involvement of dopamine transporters in positive incentive motivation, especially its persistence. Differences in intracranial electrical stimulation in µ-opioid receptor and dopamine transporter knockout mice underscore the multidimensional nature of reward. © The Author 2016. Published by Oxford University Press on behalf of CINP.

Belief state representation in the dopamine system.

PubMed

Babayan, Benedicte M; Uchida, Naoshige; Gershman, Samuel J

2018-05-14

Learning to predict future outcomes is critical for driving appropriate behaviors. Reinforcement learning (RL) models have successfully accounted for such learning, relying on reward prediction errors (RPEs) signaled by midbrain dopamine neurons. It has been proposed that when sensory data provide only ambiguous information about which state an animal is in, it can predict reward based on a set of probabilities assigned to hypothetical states (called the belief state). Here we examine how dopamine RPEs and subsequent learning are regulated under state uncertainty. Mice are first trained in a task with two potential states defined by different reward amounts. During testing, intermediate-sized rewards are given in rare trials. Dopamine activity is a non-monotonic function of reward size, consistent with RL models operating on belief states. Furthermore, the magnitude of dopamine responses quantitatively predicts changes in behavior. These results establish the critical role of state inference in RL.

Dynamics of rapid dopamine release in the nucleus accumbens during goal-directed behaviors for cocaine versus natural rewards.

PubMed

Cameron, Courtney M; Wightman, R Mark; Carelli, Regina M

2014-11-01

Electrophysiological studies show that distinct subsets of nucleus accumbens (NAc) neurons differentially encode information about goal-directed behaviors for intravenous cocaine versus natural (food/water) rewards. Further, NAc rapid dopamine signaling occurs on a timescale similar to phasic cell firing during cocaine and natural reward-seeking behaviors. However, it is not known whether dopamine signaling is reinforcer specific (i.e., is released during responding for only one type of reinforcer) within discrete NAc locations, similar to neural firing dynamics. Here, fast-scan cyclic voltammetry (FSCV) was used to measure rapid dopamine release during multiple schedules involving sucrose reward and cocaine self-administration (n = 8 rats) and, in a separate group of rats (n = 6), during a sucrose/food multiple schedule. During the sucrose/cocaine multiple schedule, dopamine increased within seconds of operant responding for both reinforcers. Although dopamine release was not reinforcer specific, more subtle differences were observed in peak dopamine concentration [DA] across reinforcer conditions. Specifically, peak [DA] was higher during the first phase of the multiple schedule, regardless of reinforcer type. Further, the time to reach peak [DA] was delayed during cocaine-responding compared to sucrose. During the sucrose/food multiple schedule, increases in dopamine release were also observed relative to operant responding for both natural rewards. However, peak [DA] was higher relative to responding for sucrose than food, regardless of reinforcer order. Overall, the results reveal the dynamics of rapid dopamine signaling in discrete locations in the NAc across reward conditions, and provide novel insight into the functional role of this system in reward-seeking behaviors. Copyright © 2014 Elsevier Ltd. All rights reserved.

Dopamine selectively remediates ‘model-based’ reward learning: a computational approach

PubMed Central

Sharp, Madeleine E.; Foerde, Karin; Daw, Nathaniel D.

2016-01-01

Patients with loss of dopamine due to Parkinson’s disease are impaired at learning from reward. However, it remains unknown precisely which aspect of learning is impaired. In particular, learning from reward, or reinforcement learning, can be driven by two distinct computational processes. One involves habitual stamping-in of stimulus-response associations, hypothesized to arise computationally from ‘model-free’ learning. The other, ‘model-based’ learning, involves learning a model of the world that is believed to support goal-directed behaviour. Much work has pointed to a role for dopamine in model-free learning. But recent work suggests model-based learning may also involve dopamine modulation, raising the possibility that model-based learning may contribute to the learning impairment in Parkinson’s disease. To directly test this, we used a two-step reward-learning task which dissociates model-free versus model-based learning. We evaluated learning in patients with Parkinson’s disease tested ON versus OFF their dopamine replacement medication and in healthy controls. Surprisingly, we found no effect of disease or medication on model-free learning. Instead, we found that patients tested OFF medication showed a marked impairment in model-based learning, and that this impairment was remediated by dopaminergic medication. Moreover, model-based learning was positively correlated with a separate measure of working memory performance, raising the possibility of common neural substrates. Our results suggest that some learning deficits in Parkinson’s disease may be related to an inability to pursue reward based on complete representations of the environment. PMID:26685155

Investigating expectation and reward in human opioid addiction with [(11) C]raclopride PET.

PubMed

Watson, Ben J; Taylor, Lindsay G; Reid, Alastair G; Wilson, Sue J; Stokes, Paul R; Brooks, David J; Myers, James F; Turkheimer, Federico E; Nutt, David J; Lingford-Hughes, Anne R

2014-11-01

The rewarding properties of some abused drugs are thought to reside in their ability to increase striatal dopamine levels. Similar increases have been shown in response to expectation of a positive drug effect. The actions of opioid drugs on striatal dopamine release are less well characterized. We examined whether heroin and the expectation of heroin reward increases striatal dopamine levels in human opioid addiction. Ten opioid-dependent participants maintained on either methadone or buprenorphine underwent [(11) C]raclopride positron emission tomography imaging. Opioid-dependent participants were scanned three times, receiving reward from 50-mg intravenous heroin (diamorphine; pharmaceutical heroin) during the first scan to generate expectation of the same reward at the second scan, during which they only received 0.1-mg intravenous heroin. There was no heroin injection during the third scan. Intravenous 50-mg heroin during the first scan induced pronounced effects leading to high levels of expectation at the second scan. There was no detectable increase in striatal dopamine levels to either heroin reward or expectation of reward. We believe this is the first human study to examine whether expectation of heroin reward increases striatal dopamine levels in opioid addiction. The absence of detectable increased dopamine levels to both the expectation and delivery of a heroin-related reward may have been due to the impact of substitute medication. It does however contrast with the changes seen in abstinent stimulant users, suggesting that striatal dopamine release alone may not play such a pivotal role in opioid-maintained individuals. © 2013 The Authors. Addiction Biology published by John Wiley & Sons Ltd on behalf of Society for the Study of Addiction.

A Neural Circuit Mechanism for the Involvements of Dopamine in Effort-Related Choices: Decay of Learned Values, Secondary Effects of Depletion, and Calculation of Temporal Difference Error

PubMed Central

2018-01-01

Abstract Dopamine has been suggested to be crucially involved in effort-related choices. Key findings are that dopamine depletion (i) changed preference for a high-cost, large-reward option to a low-cost, small-reward option, (ii) but not when the large-reward option was also low-cost or the small-reward option gave no reward, (iii) while increasing the latency in all the cases but only transiently, and (iv) that antagonism of either dopamine D1 or D2 receptors also specifically impaired selection of the high-cost, large-reward option. The underlying neural circuit mechanisms remain unclear. Here we show that findings i–iii can be explained by the dopaminergic representation of temporal-difference reward-prediction error (TD-RPE), whose mechanisms have now become clarified, if (1) the synaptic strengths storing the values of actions mildly decay in time and (2) the obtained-reward-representing excitatory input to dopamine neurons increases after dopamine depletion. The former is potentially caused by background neural activity–induced weak synaptic plasticity, and the latter is assumed to occur through post-depletion increase of neural activity in the pedunculopontine nucleus, where neurons representing obtained reward exist and presumably send excitatory projections to dopamine neurons. We further show that finding iv, which is nontrivial given the suggested distinct functions of the D1 and D2 corticostriatal pathways, can also be explained if we additionally assume a proposed mechanism of TD-RPE calculation, in which the D1 and D2 pathways encode the values of actions with a temporal difference. These results suggest a possible circuit mechanism for the involvements of dopamine in effort-related choices and, simultaneously, provide implications for the mechanisms of TD-RPE calculation. PMID:29468191

Dopamine dysregulation hypothesis: the common basis for motivational anhedonia in major depressive disorder and schizophrenia?

PubMed

Szczypiński, Jan Józef; Gola, Mateusz

2018-03-24

Abnormalities in reward processing are crucial symptoms of major depressive disorder (MDD) and schizophrenia (SCH). Recent neuroscientific findings regarding MDD have led to conclusions about two different symptoms related to reward processing: motivational and consummatory anhedonia, corresponding, respectively, to impaired motivation to obtain rewards ('wanting'), and diminished satisfaction from consuming them ('liking'). One can ask: which of these is common for MDD and SCH. In our review of the latest neuroscientific studies, we show that MDD and SCH do not share consummatory anhedonia, as SCH patients usually have unaltered liking. Therefore, we investigated whether motivational anhedonia is the common symptom across MDD and SCH. With regard to the similarities and differences between the neural mechanisms of MDD and SCH, here we expand the current knowledge of motivation deficits and present the common underlying mechanism of motivational anhedonia - the dopamine dysregulation hypothesis - stating that any prolonged dysregulation in tonic dopamine signaling that exceeds the given equilibrium can lead to striatal dysfunction and motivational anhedonia. The implications for further research and treatment of MDD and SCH are also discussed.

Temporal specificity of reward prediction errors signaled by putative dopamine neurons in rat VTA depends on ventral striatum

PubMed Central

Takahashi, Yuji K.; Langdon, Angela J.; Niv, Yael; Schoenbaum, Geoffrey

2016-01-01

Summary Dopamine neurons signal reward prediction errors. This requires accurate reward predictions. It has been suggested that the ventral striatum provides these predictions. Here we tested this hypothesis by recording from putative dopamine neurons in the VTA of rats performing a task in which prediction errors were induced by shifting reward timing or number. In controls, the neurons exhibited error signals in response to both manipulations. However, dopamine neurons in rats with ipsilateral ventral striatal lesions exhibited errors only to changes in number and failed to respond to changes in timing of reward. These results, supported by computational modeling, indicate that predictions about the temporal specificity and the number of expected rewards are dissociable, and that dopaminergic prediction-error signals rely on the ventral striatum for the former but not the latter. PMID:27292535

The effects of AMPA receptor blockade in the prelimbic cortex on systemic and ventral tegmental area opiate reward sensitivity.

PubMed

De Jaeger, Xavier; Bishop, Stephanie F; Ahmad, Tasha; Lyons, Danika; Ng, Garye Ami; Laviolette, Steven R

2013-02-01

The medial prefrontal cortex (mPFC) is a key neural region involved in opiate-related reward memory processing. AMPA receptor transmission in the mPFC modulates opiate-related reward memory processing, and chronic opiate exposure is associated with alterations in intra-mPFC AMPA receptor function. The objectives of this study were to examine how pharmacological blockade of AMPA receptor transmission in the prelimbic (PLC) division of the mPFC may modulate opiate reward memory acquisition and whether opiate exposure state may modulate the functional role of intra-PLC AMPA receptor transmission during opiate reward learning. Using an unbiased conditioned place preference (CPP) procedure in rats, we performed discrete, bilateral intra-PLC microinfusions of the AMPA receptor antagonist, 6,7-dinitroquinoxaline-2,3-dione, prior to behavioral morphine CPP conditioning, using sub-reward threshold conditioning doses of either systemic (0.05 mg/kg; i.p.) or intra-ventral tegmental area (VTA) morphine (250 ng/0.5 μl). We show that, in both opiate-naïve and opiate-dependent states, intra-PLC blockade of AMPA receptor transmission, but not the infralimbic cortex, increases the behavioral reward magnitude of systemic or intra-VTA morphine. This effect is dependent on dopamine (DA)ergic signaling because pre-administration of cis-(Z)-flupenthixol-dihydrochloride (α-flu), a broad-spectrum dopamine receptor antagonist, blocked the morphine-reward potentiating effects of AMPA receptor blockade. These findings suggest a critical role for intra-PLC AMPA receptor transmission in the processing of opiate reward signaling. Furthermore, blockade of AMPA transmission specifically within the PLC is capable of switching opiate reward processing to a DA-dependent reward system, independently of previous opiate exposure history.

The Mediating Effect of Prefrontal Asymmetry on the Relationship between the COMT Val158Met SNP and Trait Consummatory Positive Affect

PubMed Central

Katz, Andrea C.; Sarapas, Casey; Bishop, Jeffrey R.; Patel, Shitalben R.; Shankman, Stewart A.

2014-01-01

The Val158Met rs4680 polymorphism in the COMT gene regulates dopamine catabolism in the prefrontal cortex (PFC). Dopamine’s involvement in reward experience suggests those with the Met variant may exhibit trait-level sensitivity to reward due to more post-synaptic dopamine in the PFC. A physiological mediator of this association may be greater relative left asymmetry in the PFC, a putative biomarker for trait positive emotionality. Electroencephalograms of 120 participants were measured during a task that assesses two aspects of reward processing: pre-reward anticipation and post-reward consummatory affect. Participants provided genetics samples and completed the Temporal Experience of Pleasure Scale, which assesses trait-level anticipatory and consummatory positive affect. Met carriers had higher TEPS-Consummatory scores. This effect was mediated by greater relative left activation in the post-reward phase of the task. No effects were observed for the pre-reward phase. Results suggest that frontal asymmetry is an endophenotype between COMT genotype and trait reward responsivity. PMID:25195915

Layered reward signalling through octopamine and dopamine in Drosophila.

PubMed

Burke, Christopher J; Huetteroth, Wolf; Owald, David; Perisse, Emmanuel; Krashes, Michael J; Das, Gaurav; Gohl, Daryl; Silies, Marion; Certel, Sarah; Waddell, Scott

2012-12-20

Dopamine is synonymous with reward and motivation in mammals. However, only recently has dopamine been linked to motivated behaviour and rewarding reinforcement in fruitflies. Instead, octopamine has historically been considered to be the signal for reward in insects. Here we show, using temporal control of neural function in Drosophila, that only short-term appetitive memory is reinforced by octopamine. Moreover, octopamine-dependent memory formation requires signalling through dopamine neurons. Part of the octopamine signal requires the α-adrenergic-like OAMB receptor in an identified subset of mushroom-body-targeted dopamine neurons. Octopamine triggers an increase in intracellular calcium in these dopamine neurons, and their direct activation can substitute for sugar to form appetitive memory, even in flies lacking octopamine. Analysis of the β-adrenergic-like OCTβ2R receptor reveals that octopamine-dependent reinforcement also requires an interaction with dopamine neurons that control appetitive motivation. These data indicate that sweet taste engages a distributed octopamine signal that reinforces memory through discrete subsets of mushroom-body-targeted dopamine neurons. In addition, they reconcile previous findings with octopamine and dopamine and suggest that reinforcement systems in flies are more similar to mammals than previously thought.

Optogenetic mimicry of the transient activation of dopamine neurons by natural reward is sufficient for operant reinforcement.

PubMed

Kim, Kyung Man; Baratta, Michael V; Yang, Aimei; Lee, Doheon; Boyden, Edward S; Fiorillo, Christopher D

2012-01-01

Activation of dopamine receptors in forebrain regions, for minutes or longer, is known to be sufficient for positive reinforcement of stimuli and actions. However, the firing rate of dopamine neurons is increased for only about 200 milliseconds following natural reward events that are better than expected, a response which has been described as a "reward prediction error" (RPE). Although RPE drives reinforcement learning (RL) in computational models, it has not been possible to directly test whether the transient dopamine signal actually drives RL. Here we have performed optical stimulation of genetically targeted ventral tegmental area (VTA) dopamine neurons expressing Channelrhodopsin-2 (ChR2) in mice. We mimicked the transient activation of dopamine neurons that occurs in response to natural reward by applying a light pulse of 200 ms in VTA. When a single light pulse followed each self-initiated nose poke, it was sufficient in itself to cause operant reinforcement. Furthermore, when optical stimulation was delivered in separate sessions according to a predetermined pattern, it increased locomotion and contralateral rotations, behaviors that are known to result from activation of dopamine neurons. All three of the optically induced operant and locomotor behaviors were tightly correlated with the number of VTA dopamine neurons that expressed ChR2, providing additional evidence that the behavioral responses were caused by activation of dopamine neurons. These results provide strong evidence that the transient activation of dopamine neurons provides a functional reward signal that drives learning, in support of RL theories of dopamine function.

Dopamine Modulates Adaptive Prediction Error Coding in the Human Midbrain and Striatum.

PubMed

Diederen, Kelly M J; Ziauddeen, Hisham; Vestergaard, Martin D; Spencer, Tom; Schultz, Wolfram; Fletcher, Paul C

2017-02-15

Learning to optimally predict rewards requires agents to account for fluctuations in reward value. Recent work suggests that individuals can efficiently learn about variable rewards through adaptation of the learning rate, and coding of prediction errors relative to reward variability. Such adaptive coding has been linked to midbrain dopamine neurons in nonhuman primates, and evidence in support for a similar role of the dopaminergic system in humans is emerging from fMRI data. Here, we sought to investigate the effect of dopaminergic perturbations on adaptive prediction error coding in humans, using a between-subject, placebo-controlled pharmacological fMRI study with a dopaminergic agonist (bromocriptine) and antagonist (sulpiride). Participants performed a previously validated task in which they predicted the magnitude of upcoming rewards drawn from distributions with varying SDs. After each prediction, participants received a reward, yielding trial-by-trial prediction errors. Under placebo, we replicated previous observations of adaptive coding in the midbrain and ventral striatum. Treatment with sulpiride attenuated adaptive coding in both midbrain and ventral striatum, and was associated with a decrease in performance, whereas bromocriptine did not have a significant impact. Although we observed no differential effect of SD on performance between the groups, computational modeling suggested decreased behavioral adaptation in the sulpiride group. These results suggest that normal dopaminergic function is critical for adaptive prediction error coding, a key property of the brain thought to facilitate efficient learning in variable environments. Crucially, these results also offer potential insights for understanding the impact of disrupted dopamine function in mental illness. SIGNIFICANCE STATEMENT To choose optimally, we have to learn what to expect. Humans dampen learning when there is a great deal of variability in reward outcome, and two brain regions that are modulated by the brain chemical dopamine are sensitive to reward variability. Here, we aimed to directly relate dopamine to learning about variable rewards, and the neural encoding of associated teaching signals. We perturbed dopamine in healthy individuals using dopaminergic medication and asked them to predict variable rewards while we made brain scans. Dopamine perturbations impaired learning and the neural encoding of reward variability, thus establishing a direct link between dopamine and adaptation to reward variability. These results aid our understanding of clinical conditions associated with dopaminergic dysfunction, such as psychosis. Copyright © 2017 Diederen et al.

Dopamine in the Brain: Hypothesizing Surfeit or Deficit Links to Reward and Addiction.

PubMed

Blum, Kenneth; Thanos, Peter K; Oscar-Berman, Marlene; Febo, Marcelo; Baron, David; Badgaiyan, Rajendra D; Gardner, Eliot; Demetrovics, Zsolt; Fahlke, Claudia; Haberstick, Brett C; Dushaj, Kristina; Gold, Mark S

Recently there has been debate concerning the role of brain dopamine in reward and addiction. David Nutt and associates eloquently proposed that dopamine (DA) may be central to psycho stimulant dependence and some what important for alcohol, but not important for opiates, nicotine or even cannabis. Others have also argued that surfeit theories can explain for example cocaine seeking behavior as well as non-substance-related addictive behaviors. It seems prudent to distinguish between what constitutes "surfeit" compared to" deficit" in terms of short-term (acute) and long-term (chronic) brain reward circuitry responsivity. In an attempt to resolve controversy regarding the contributions of mesolimbic DA systems to reward, we review the three main competing explanatory categories: "liking", "learning", and "wanting". They are (a) the hedonic impact -liking reward, (b) the ability to predict rewarding effects-learning and (c) the incentive salience of reward-related stimuli -wanting. In terms of acute effects, most of the evidence seems to favor the "surfeit theory". Due to preferential dopamine release at mesolimbic-VTA-caudate-accumbens loci most drugs of abuse and Reward Deficiency Syndrome (RDS) behaviors have been linked to heightened feelings of well-being and hyperdopaminergic states.The "dopamine hypotheses" originally thought to be simple, is now believed to be quite complex and involves encoding the set point of hedonic tone, encoding attention, reward expectancy, and incentive motivation. Importantly, Willuhn et al. shows that in a self-administration paradigm, (chronic) excessive use of cocaine is caused by decreased phasic dopamine signaling in the striatum. In terms of chronic addictions, others have shown a blunted responsivity at brain reward sites with food, nicotine, and even gambling behavior. Finally, we are cognizant of the differences in dopaminergic function as addiction progresses and argue that relapse may be tied to dopamine deficiency. Vulnerability to addiction and relapse may be the result of the cumulative effects of dopaminergic and other neurotransmitter genetic variants and elevated stress levels. We therefore propose that dopamine homeostasis may be a preferred goal to combat relapse.

Dopamine selectively remediates 'model-based' reward learning: a computational approach.

PubMed

Sharp, Madeleine E; Foerde, Karin; Daw, Nathaniel D; Shohamy, Daphna

2016-02-01

Patients with loss of dopamine due to Parkinson's disease are impaired at learning from reward. However, it remains unknown precisely which aspect of learning is impaired. In particular, learning from reward, or reinforcement learning, can be driven by two distinct computational processes. One involves habitual stamping-in of stimulus-response associations, hypothesized to arise computationally from 'model-free' learning. The other, 'model-based' learning, involves learning a model of the world that is believed to support goal-directed behaviour. Much work has pointed to a role for dopamine in model-free learning. But recent work suggests model-based learning may also involve dopamine modulation, raising the possibility that model-based learning may contribute to the learning impairment in Parkinson's disease. To directly test this, we used a two-step reward-learning task which dissociates model-free versus model-based learning. We evaluated learning in patients with Parkinson's disease tested ON versus OFF their dopamine replacement medication and in healthy controls. Surprisingly, we found no effect of disease or medication on model-free learning. Instead, we found that patients tested OFF medication showed a marked impairment in model-based learning, and that this impairment was remediated by dopaminergic medication. Moreover, model-based learning was positively correlated with a separate measure of working memory performance, raising the possibility of common neural substrates. Our results suggest that some learning deficits in Parkinson's disease may be related to an inability to pursue reward based on complete representations of the environment. © The Author (2015). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

Dopamine D2 receptors mediate the increase in reinstatement of the conditioned rewarding effects of cocaine induced by acute social defeat.

PubMed

Reguilón, Marina Daiana; Montagud-Romero, Sandra; Ferrer-Pérez, Carmen; Roger-Sánchez, Concepción; Aguilar, María Asunción; Miñarro, José; Rodríguez-Arias, Marta

2017-03-15

Social stress modifies the activity of brain areas involved in the rewarding effects of psychostimulants, inducing neuroadaptations in the dopaminergic mesolimbic system and modifying the sensitivity of dopamine receptors. In the present study we evaluated the effect of the dopamine D 1 - and D 2 -like receptor antagonists (SCH23390 and raclopride, respectively) on the short-time effects of acute social defeat (ASD). Male OF1 mice were socially defeated before each conditioning session of the conditioned place preference (CPP) induced by 1mg/kg or 25mg/kg of cocaine plus the corresponding dopamine antagonist. A final experiment was designed to evaluate the effect of the dopamine antagonists on the CPP induced by 3mg/kg of cocaine with or without a stress experience. Mice exposed to ASD showed an increase in reinstatement of the conditioned reinforcing effects of cocaine that was blocked by all of the dopamine receptor antagonists. Blockade of dopamine D 2 -like receptors with raclopride specifically prevented the effects of stress without affecting the rewarding properties of cocaine. However, SCH23390 inhibited cocaine-induced preference in the control groups and even induced aversion in defeated mice conditioned with the lower dose of cocaine. Moreover, the lowest dose of SCH23390 blocked the rewarding effects of 3mg/kg of cocaine-induced CPP. Our results confirm that the dopamine D 2 receptor is involved in the short-term effects of ASD on the rewarding effects of cocaine. The dopamine D 1 receptor is clearly involved in the rewarding effects of cocaine, but its role in the effects of ASD remains to be demonstrated. Copyright © 2017 Elsevier B.V. All rights reserved.

Do dopaminergic gene polymorphisms affect mesolimbic reward activation of music listening response? Therapeutic impact on Reward Deficiency Syndrome (RDS).

PubMed

Blum, Kenneth; Chen, Thomas J H; Chen, Amanda L H; Madigan, Margaret; Downs, B William; Waite, Roger L; Braverman, Eric R; Kerner, Mallory; Bowirrat, Abdalla; Giordano, John; Henshaw, Harry; Gold, Mark S

2010-03-01

Using fMRI, Menon and Levitin [9] clearly found for the first time that listening to music strongly modulates activity in a network of mesolimbic structures involved in reward processing including the nucleus accumbens (NAc) and the ventral tegmental area (VTA), as well as the hypothalamus, and insula, which are thought to be involved in regulating autonomic and physiological responses to rewarding and emotional stimuli. Importantly, responses in the NAc and VTA were strongly correlated pointing to an association between dopamine release and NAc response to music. Listing to pleasant music induced a strong response and significant activation of the VTA-mediated interaction of the NAc with the hypothalamus, insula, and orbitofrontal cortex. Blum et al. [10] provided the first evidence that the dopamine D2 receptor gene (DRD2) Taq 1 A1 allele significantly associated with severe alcoholism whereby the author's suggested that they found the first "reward gene" located in the mesolimbic system. The enhanced functional and effective connectivity between brain regions mediating reward, autonomic, and cognitive processing provides insight into understanding why listening to music is one of the most rewarding and pleasurable human experiences. However, little is known about why some people have a more or less powerful mesolimbic experience when they are listening to music. It is well-known that music may induce an endorphinergic response that is blocked by naloxone, a known opioid antagonist (Goldstein [19]). Opioid transmission in the NAc is associated with dopamine release in the VTA. Moreover, dopamine release in the VTA is linked to polymorphisms of the DRD2 gene and even attention-deficit hyperactivity disorder (ADHD), whereby carriers of the DRD2 A1 allele show a reduced NAc release of dopamine (DA). Thus it is conjectured that similar mechanisms in terms of adequate dopamine release and subsequent activation of reward circuitry by listening to music might also be affected by an individual's D2 density in the VTA mediated interaction of the NAc. It is therefore hypothesized that carriers of DRD2 A1 allele may respond significantly differently to carriers of the DRD2 A2 genotype. In this regard, carriers of the D2 A1 allele have a blunted response to glucose and monetary rewards. In contrast powerful D2 agonists like bromocryptine show a heightened activation of the reward circuitry only in DRD2 A1 allele carriers. If music causes a powerful activation in spite of the DRD2 A1 allele due to a strong DA neuronal release which subsequently impinges on existing D2 receptors, then it is reasonable to assume that music is a strong indirect D2 agonist (by virtue of DA neuronal release in the NAc) and may have important therapeutic applicability in Reward Deficiency Syndrome (RDS) related behaviors including Substance Use Disorder (SUD). Ross et al. [18] found that music therapy appears to be a novel motivational tool in a severely impaired inpatient sample of patients with co-occurring mental illness and addiction. Copyright (c) 2009 Elsevier Ltd. All rights reserved.

Dynamic mesolimbic dopamine signaling during action sequence learning and expectation violation

PubMed Central

Collins, Anne L.; Greenfield, Venuz Y.; Bye, Jeffrey K.; Linker, Kay E.; Wang, Alice S.; Wassum, Kate M.

2016-01-01

Prolonged mesolimbic dopamine concentration changes have been detected during spatial navigation, but little is known about the conditions that engender this signaling profile or how it develops with learning. To address this, we monitored dopamine concentration changes in the nucleus accumbens core of rats throughout acquisition and performance of an instrumental action sequence task. Prolonged dopamine concentration changes were detected that ramped up as rats executed each action sequence and declined after earned reward collection. With learning, dopamine concentration began to rise increasingly earlier in the execution of the sequence and ultimately backpropagated away from stereotyped sequence actions, becoming only transiently elevated by the most distal and unexpected reward predictor. Action sequence-related dopamine signaling was reactivated in well-trained rats if they became disengaged in the task and in response to an unexpected change in the value, but not identity of the earned reward. Throughout training and test, dopamine signaling correlated with sequence performance. These results suggest that action sequences can engender a prolonged mode of dopamine signaling in the nucleus accumbens core and that such signaling relates to elements of the motivation underlying sequence execution and is dynamic with learning, overtraining and violations in reward expectation. PMID:26869075

Neuropharmacological mechanisms of drug reward: beyond dopamine in the nucleus accumbens.

PubMed

Bardo, M T

1998-01-01

Multiple lines of research have implicated the mesolimbic dopamine system in drug reward measured by either the drug self-administration or conditioned place preference paradigm. The present review summarizes recent work that examines the neuropharmacological mechanisms by which drugs impinge on this dopaminergic neural circuitry, as well as other systems that provide input and output circuits to the mesolimbic dopamine system. Studies examining the effect of selective agonist and antagonist drugs administered systemically have indicated that multiple neurotransmitters are involved, including dopamine, serotonin, acetylcholine, glutamate, GABA, and various peptides. Direct microinjection studies have also provided crucial evidence indicating that, in addition to the mesolimbic dopamine system, other structures play a role in drug reward, including the ventral pallidum, amygdala, hippocampus, hypothalamus, and pedunculopontine tegmental nucleus. GABAergic circuitry descending from the nucleus accumbens to the pedunculopontine tegmental nucleus via the ventral pallidum appears to be especially important in directing the behavioral sequelae associated with reward produced by various drugs of abuse. However, activation of the reward circuitry is achieved differently for various drugs of abuse. With amphetamine and cocaine, initiation of reward is controlled within the nucleus accumbens and prefrontal cortex, respectively. With opiates, initiation of reward involves the ventral tegmental area, nucleus accumbens, hippocampus, and hypothalamus. It is not clear presently if these multiple anatomical structures mediate opiate reward by converging on a single output system or multiple output systems.

Nucleus accumbens core dopamine signaling tracks the need-based motivational value of food-paired cues

PubMed Central

Aitken, Tara J.; Greenfield, Venuz Y.; Wassum, Kate M.

2016-01-01

Environmental reward-predictive stimuli provide a major source of motivation for instrumental reward-seeking activity and this has been linked to dopamine signaling in the nucleus accumbens (NAc). This cue-induced incentive motivation can be quite general, not restricted to instrumental actions that earn the same unique reward, and is also typically regulated by one’s current need state, such that cues only motivate actions when this is adaptive. But it is unknown whether cue-evoked dopamine signaling is similarly regulated by need state. Here we used fast-scan cyclic voltammetry to monitor dopamine concentration changes in the NAc core of rats during a Pavlovian-to-instrumental transfer (PIT) task in which the motivating influence of two cues, each signaling a distinct food reward (sucrose or food pellets), over an action earning a third unique food reward (grape-flavored polycose) was assessed in a state of hunger and of satiety. Both cues elicited a robust NAc dopamine response when hungry. The magnitude of the sucrose cue-evoked dopamine response correlated with the PIT effect that was selectively induced by this stimulus. Satiety attenuated these cue-evoked dopamine responses and behavioral responding, even though rats had never experienced the specific food rewards in this state. These data demonstrate that cue-evoked NAc core responses are sensitive to current need state, one critical variable that determines the current adaptive utility of cue-motivated behavior. PMID:26715366

A computational substrate for incentive salience.

PubMed

McClure, Samuel M; Daw, Nathaniel D; Montague, P Read

2003-08-01

Theories of dopamine function are at a crossroads. Computational models derived from single-unit recordings capture changes in dopaminergic neuron firing rate as a prediction error signal. These models employ the prediction error signal in two roles: learning to predict future rewarding events and biasing action choice. Conversely, pharmacological inhibition or lesion of dopaminergic neuron function diminishes the ability of an animal to motivate behaviors directed at acquiring rewards. These lesion experiments have raised the possibility that dopamine release encodes a measure of the incentive value of a contemplated behavioral act. The most complete psychological idea that captures this notion frames the dopamine signal as carrying 'incentive salience'. On the surface, these two competing accounts of dopamine function seem incommensurate. To the contrary, we demonstrate that both of these functions can be captured in a single computational model of the involvement of dopamine in reward prediction for the purpose of reward seeking.

Reward signal in a recurrent circuit drives appetitive long-term memory formation.

PubMed

Ichinose, Toshiharu; Aso, Yoshinori; Yamagata, Nobuhiro; Abe, Ayako; Rubin, Gerald M; Tanimoto, Hiromu

2015-11-17

Dopamine signals reward in animal brains. A single presentation of a sugar reward to Drosophila activates distinct subsets of dopamine neurons that independently induce short- and long-term olfactory memories (STM and LTM, respectively). In this study, we show that a recurrent reward circuit underlies the formation and consolidation of LTM. This feedback circuit is composed of a single class of reward-signaling dopamine neurons (PAM-α1) projecting to a restricted region of the mushroom body (MB), and a specific MB output cell type, MBON-α1, whose dendrites arborize that same MB compartment. Both MBON-α1 and PAM-α1 neurons are required during the acquisition and consolidation of appetitive LTM. MBON-α1 additionally mediates the retrieval of LTM, which is dependent on the dopamine receptor signaling in the MB α/β neurons. Our results suggest that a reward signal transforms a nascent memory trace into a stable LTM using a feedback circuit at the cost of memory specificity.

Dopamine dependency for acquisition and performance of Pavlovian conditioned response

PubMed Central

Darvas, Martin; Wunsch, Amanda M.; Gibbs, Jeffrey T.; Palmiter, Richard D.

2014-01-01

During Pavlovian conditioning, pairing of a neutral conditioned stimulus (CS) with a reward leads to conditioned reward-approach responses (CRs) that are elicited by presentation of the CS. CR behaviors can be sign tracking, in which animals engage the CS, or goal tracking, in which animals go to the reward location. We investigated CR behaviors in mice with only ∼5% of normal dopamine in the striatum using a Pavlovian conditioning paradigm. These mice had severely impaired acquisition of the CR, which was ameliorated by pharmacological restoration of dopamine synthesis with l-dopa. Surprisingly, after they had learned the CR, its expression decayed only gradually in following sessions that were conducted without l-dopa treatment. To assess specific contributions of dopamine signaling in the dorsal or ventral striatum, we performed virus-mediated restoration of dopamine synthesis in completely dopamine-deficient (DD) mice. Mice with dopamine signaling only in the dorsal striatum did not acquire a CR, whereas mice with dopamine signaling only in in the ventral striatum acquired a CR. The CR in mice with dopamine signaling only in the dorsal striatum was restored by subjecting the mice to instrumental training in which they had to interact with the CS to obtain rewards. We conclude that dopamine is essential for learning and performance of CR behavior that is predominantly goal tracking. Furthermore, although dopamine signaling in the ventral striatum is sufficient to support a CR, dopamine signaling only in the dorsal striatum can also support a CR under certain circumstances. PMID:24550305

Phasic dopamine release in the rat nucleus accumbens predicts approach and avoidance performance

PubMed Central

Gentry, Ronny N.; Lee, Brian; Roesch, Matthew R.

2016-01-01

Dopamine (DA) is critical for reward processing, but significantly less is known about its role in punishment avoidance. Using a combined approach-avoidance task, we measured phasic DA release in the nucleus accumbens (NAc) of rats during presentation of cues that predicted reward, punishment or neutral outcomes and investigated individual differences based on avoidance performance. Here we show that DA release within a single microenvironment is higher for reward and avoidance cues compared with neutral cues and positively correlated with poor avoidance behaviour. We found that DA release delineates trial-type during sessions with good avoidance but is non-selective during poor avoidance, with high release correlating with poor performance. These data demonstrate that phasic DA is released during cued approach and avoidance within the same microenvironment and abnormal processing of value signals is correlated with poor performance. PMID:27786172

The "Creative Right Brain" Revisited: Individual Creativity and Associative Priming in the Right Hemisphere Relate to Hemispheric Asymmetries in Reward Brain Function.

PubMed

Aberg, Kristoffer Carl; Doell, Kimberly C; Schwartz, Sophie

2017-10-01

The idea that creativity resides in the right cerebral hemisphere is persistent in popular science, but has been widely frowned upon by the scientific community due to little empirical support. Yet, creativity is believed to rely on the ability to combine remote concepts into novel and useful ideas, an ability which would depend on associative processing in the right hemisphere. Moreover, associative processing is modulated by dopamine, and asymmetries in dopamine functionality between hemispheres may imbalance the expression of their implemented cognitive functions. Here, by uniting these largely disconnected concepts, we hypothesize that relatively less dopamine function in the right hemisphere boosts creativity by releasing constraining effects of dopamine on remote associations. Indeed, participants with reduced neural responses in the dopaminergic system of the right hemisphere (estimated by functional MRI in a reward task with positive and negative feedback), displayed higher creativity (estimated by convergent and divergent tasks), and increased associative processing in the right hemisphere (estimated by a lateralized lexical decision task). Our findings offer unprecedented empirical support for a crucial and specific contribution of the right hemisphere to creativity. More importantly our study provides a comprehensive view on potential determinants of human creativity, namely dopamine-related activity and associative processing. © The Author 2016. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

The neurobiology of social play and its rewarding value in rats

PubMed Central

Vanderschuren, Louk J.M.J.; Achterberg, E.J. Marijke; Trezza, Viviana

2016-01-01

In the young of many mammalian species, including humans, a vigorous and highly rewarding social activity is abundantly expressed, known as social play behaviour. Social play is thought to be important for the development of social, cognitive and emotional processes and their neural underpinnings, and it is disrupted in pediatric psychiatric disorders. Here, we summarize recent progress in our understanding of the brain mechanisms of social play behaviour, with a focus on its rewarding properties. Opioid, endocannabinoid, dopamine and noradrenaline systems play a prominent role in the modulation of social play. Of these, dopamine is particularly important for the motivational properties of social play. The nucleus accumbens has been identified as a key site for opioid and dopamine modulation of social play. Endocannabinoid influences on social play rely on the basolateral amygdala, whereas noradrenaline modulates social play through the basolateral amygdala, habenula and prefrontal cortex. In sum, social play behaviour is the result of coordinated activity in a network of corticolimbic structures, and its monoamine, opioid and endocannabinoid innervation. PMID:27587003

Liking, wanting, and the incentive-sensitization theory of addiction.

PubMed

Berridge, Kent C; Robinson, Terry E

2016-11-01

Rewards are both "liked" and "wanted," and those 2 words seem almost interchangeable. However, the brain circuitry that mediates the psychological process of "wanting" a particular reward is dissociable from circuitry that mediates the degree to which it is "liked." Incentive salience or "wanting," a form of motivation, is generated by large and robust neural systems that include mesolimbic dopamine. By comparison, "liking," or the actual pleasurable impact of reward consumption, is mediated by smaller and fragile neural systems, and is not dependent on dopamine. The incentive-sensitization theory posits the essence of drug addiction to be excessive amplification specifically of psychological "wanting," especially triggered by cues, without necessarily an amplification of "liking." This is because of long-lasting changes in dopamine-related motivation systems of susceptible individuals, called "neural sensitization." A quarter-century after its proposal, evidence has continued to grow in support the incentive-sensitization theory. Further, its scope is now expanding to include diverse behavioral addictions and other psychopathologies. (PsycINFO Database Record (c) 2016 APA, all rights reserved).

Liking, Wanting and the Incentive-Sensitization Theory of Addiction

PubMed Central

Berridge, Kent C.; Robinson, Terry E.

2016-01-01

Rewards are both ‘liked’ and ‘wanted’, and those two words seem almost interchangeable. However, the brain circuitry that mediates the psychological process of ‘wanting’ a particular reward is dissociable from circuitry that mediates the degree to which it is ‘liked’. Incentive salience or ‘wanting’, a form of motivation, is generated by large and robust neural systems that include mesolimbic dopamine. By comparison, ‘liking’, or the actual pleasurable impact of reward consumption, is mediated by smaller and fragile neural systems, and is not dependent on dopamine. The incentive-sensitization theory posits the essence of drug addiction to be excessive amplification specifically of psychological ‘wanting’, especially triggered by cues, without necessarily an amplification of ‘liking’. This is due to long-lasting changes in dopamine-related motivation systems of susceptible individuals, called neural sensitization. A quarter-century after its proposal, evidence has continued to grow in support the incentive-sensitization theory. Further, its scope is now expanding to include diverse behavioral addictions and other psychopathologies. PMID:27977239

Dopaminergic Balance between Reward Maximization and Policy Complexity

PubMed Central

Parush, Naama; Tishby, Naftali; Bergman, Hagai

2011-01-01

Previous reinforcement-learning models of the basal ganglia network have highlighted the role of dopamine in encoding the mismatch between prediction and reality. Far less attention has been paid to the computational goals and algorithms of the main-axis (actor). Here, we construct a top-down model of the basal ganglia with emphasis on the role of dopamine as both a reinforcement learning signal and as a pseudo-temperature signal controlling the general level of basal ganglia excitability and motor vigilance of the acting agent. We argue that the basal ganglia endow the thalamic-cortical networks with the optimal dynamic tradeoff between two constraints: minimizing the policy complexity (cost) and maximizing the expected future reward (gain). We show that this multi-dimensional optimization processes results in an experience-modulated version of the softmax behavioral policy. Thus, as in classical softmax behavioral policies, probability of actions are selected according to their estimated values and the pseudo-temperature, but in addition also vary according to the frequency of previous choices of these actions. We conclude that the computational goal of the basal ganglia is not to maximize cumulative (positive and negative) reward. Rather, the basal ganglia aim at optimization of independent gain and cost functions. Unlike previously suggested single-variable maximization processes, this multi-dimensional optimization process leads naturally to a softmax-like behavioral policy. We suggest that beyond its role in the modulation of the efficacy of the cortico-striatal synapses, dopamine directly affects striatal excitability and thus provides a pseudo-temperature signal that modulates the tradeoff between gain and cost. The resulting experience and dopamine modulated softmax policy can then serve as a theoretical framework to account for the broad range of behaviors and clinical states governed by the basal ganglia and dopamine systems. PMID:21603228

Dopaminergic Modulation of Risky Decision-Making

PubMed Central

Simon, Nicholas W.; Montgomery, Karienn S.; Beas, Blanca S.; Mitchell, Marci R.; LaSarge, Candi L.; Mendez, Ian A.; Bañuelos, Cristina; Vokes, Colin M.; Taylor, Aaron B.; Haberman, Rebecca P.; Bizon, Jennifer L.; Setlow, Barry

2012-01-01

Many psychiatric disorders are characterized by abnormal risky decision-making and dysregulated dopamine receptor expression. The current study was designed to determine how different dopamine receptor subtypes modulate risk-taking in young adult rats, using a “Risky Decision-making Task” that involves choices between small “safe” rewards and large “risky” rewards accompanied by adverse consequences. Rats showed considerable, stable individual differences in risk preference in the task, which were not related to multiple measures of reward motivation, anxiety, or pain sensitivity. Systemic activation of D2-like receptors robustly attenuated risk-taking, whereas drugs acting on D1-like receptors had no effect. Systemic amphetamine also reduced risk-taking, an effect which was attenuated by D2-like (but not D1-like) receptor blockade. Dopamine receptor mRNA expression was evaluated in a separate cohort of drug-naive rats characterized in the task. D1 mRNA expression in both nucleus accumbens shell and insular cortex was positively associated with risk-taking, while D2 mRNA expression in orbitofrontal and medial prefrontal cortex predicted risk preference in opposing nonlinear patterns. Additionally, lower levels of D2 mRNA in dorsal striatum were associated with greater risk-taking. These data strongly implicate dopamine signaling in prefrontal corticalstriatal circuitry in modulating decision-making processes involving integration of reward information with risks of adverse consequences. PMID:22131407

Leptin Suppresses the Rewarding Effects of Running via STAT3 Signaling in Dopamine Neurons.

PubMed

Fernandes, Maria Fernanda A; Matthys, Dominique; Hryhorczuk, Cécile; Sharma, Sandeep; Mogra, Shabana; Alquier, Thierry; Fulton, Stephanie

2015-10-06

The adipose hormone leptin potently influences physical activity. Leptin can decrease locomotion and running, yet the mechanisms involved and the influence of leptin on the rewarding effects of running ("runner's high") are unknown. Leptin receptor (LepR) signaling involves activation of signal transducer and activator of transcription-3 (STAT3), including in dopamine neurons of the ventral tegmental area (VTA) that are essential for reward-relevant behavior. We found that mice lacking STAT3 in dopamine neurons exhibit greater voluntary running, an effect reversed by viral-mediated STAT3 restoration. STAT3 deletion increased the rewarding effects of running whereas intra-VTA leptin blocked it in a STAT3-dependent manner. Finally, STAT3 loss-of-function reduced mesolimbic dopamine overflow and function. Findings suggest that leptin influences the motivational effects of running via LepR-STAT3 modulation of dopamine tone. Falling leptin is hypothesized to increase stamina and the rewarding effects of running as an adaptive means to enhance the pursuit and procurement of food. Copyright © 2015 Elsevier Inc. All rights reserved.

Reward Prediction Errors in Drug Addiction and Parkinson's Disease: from Neurophysiology to Neuroimaging.

PubMed

García-García, Isabel; Zeighami, Yashar; Dagher, Alain

2017-06-01

Surprises are important sources of learning. Cognitive scientists often refer to surprises as "reward prediction errors," a parameter that captures discrepancies between expectations and actual outcomes. Here, we integrate neurophysiological and functional magnetic resonance imaging (fMRI) results addressing the processing of reward prediction errors and how they might be altered in drug addiction and Parkinson's disease. By increasing phasic dopamine responses, drugs might accentuate prediction error signals, causing increases in fMRI activity in mesolimbic areas in response to drugs. Chronic substance dependence, by contrast, has been linked with compromised dopaminergic function, which might be associated with blunted fMRI responses to pleasant non-drug stimuli in mesocorticolimbic areas. In Parkinson's disease, dopamine replacement therapies seem to induce impairments in learning from negative outcomes. The present review provides a holistic overview of reward prediction errors across different pathologies and might inform future clinical strategies targeting impulsive/compulsive disorders.

NMDA receptor blockade in the prelimbic cortex activates the mesolimbic system and dopamine-dependent opiate reward signaling.

PubMed

Tan, Huibing; Rosen, Laura G; Ng, Garye A; Rushlow, Walter J; Laviolette, Steven R

2014-12-01

N-Methyl-D-aspartate (NMDA) receptors in the medial prefrontal cortex (mPFC) are involved in opiate reward processing and modulate sub-cortical dopamine (DA) activity. NMDA receptor blockade in the prelimbic (PLC) division of the mPFC strongly potentiates the rewarding behavioural properties of normally sub-reward threshold doses of opiates. However, the possible functional interactions between cortical NMDA and sub-cortical DAergic motivational neural pathways underlying these effects are not understood. This study examines how NMDA receptor modulation in the PLC influences opiate reward processing via interactions with sub-cortical DAergic transmission. We further examined whether direct intra-PLC NMDA receptor modulation may activate DA-dependent opiate reward signaling via interactions with the ventral tegmental area (VTA). Using an unbiased place conditioning procedure (CPP) in rats, we performed bilateral intra-PLC microinfusions of the competitive NMDA receptor antagonist, (2R)-amino-5-phosphonovaleric acid (AP-5), prior to behavioural morphine place conditioning and challenged the rewarding effects of morphine with DA receptor blockade. We next examined the effects of intra-PLC NMDA receptor blockade on the spontaneous activity patterns of presumptive VTA DA or GABAergic neurons, using single-unit, extracellular in vivo neuronal recordings. We show that intra-PLC NMDA receptor blockade strongly activates sub-cortical DA neurons within the VTA while inhibiting presumptive non-DA GABAergic neurons. Behaviourally, NMDA receptor blockade activates a DA-dependent opiate reward system, as pharmacological blockade of DA transmission blocked morphine reward only in the presence of intra-PLC NMDA receptor antagonism. These findings demonstrate a cortical NMDA-mediated mechanism controlling mesolimbic DAergic modulation of opiate reward processing.

The Dopamine Prediction Error: Contributions to Associative Models of Reward Learning

PubMed Central

Nasser, Helen M.; Calu, Donna J.; Schoenbaum, Geoffrey; Sharpe, Melissa J.

2017-01-01

Phasic activity of midbrain dopamine neurons is currently thought to encapsulate the prediction-error signal described in Sutton and Barto’s (1981) model-free reinforcement learning algorithm. This phasic signal is thought to contain information about the quantitative value of reward, which transfers to the reward-predictive cue after learning. This is argued to endow the reward-predictive cue with the value inherent in the reward, motivating behavior toward cues signaling the presence of reward. Yet theoretical and empirical research has implicated prediction-error signaling in learning that extends far beyond a transfer of quantitative value to a reward-predictive cue. Here, we review the research which demonstrates the complexity of how dopaminergic prediction errors facilitate learning. After briefly discussing the literature demonstrating that phasic dopaminergic signals can act in the manner described by Sutton and Barto (1981), we consider how these signals may also influence attentional processing across multiple attentional systems in distinct brain circuits. Then, we discuss how prediction errors encode and promote the development of context-specific associations between cues and rewards. Finally, we consider recent evidence that shows dopaminergic activity contains information about causal relationships between cues and rewards that reflect information garnered from rich associative models of the world that can be adapted in the absence of direct experience. In discussing this research we hope to support the expansion of how dopaminergic prediction errors are thought to contribute to the learning process beyond the traditional concept of transferring quantitative value. PMID:28275359

Effects of an acute therapeutic or rewarding dose of amphetamine on acquisition of Pavlovian autoshaping and ventral striatal dopamine signaling.

PubMed

Schuweiler, D R; Athens, J M; Thompson, J M; Vazhayil, S T; Garris, P A

2018-01-15

Rewarding doses of amphetamine increase the amplitude, duration, and frequency of dopamine transients in the ventral striatum. Debate continues at the behavioral level about which component of reward, learning or incentive salience, is signaled by these dopamine transients and thus altered in addiction. The learning hypothesis proposes that rewarding drugs result in pathological overlearning of drug-predictive cues, while the incentive sensitization hypothesis suggests that rewarding drugs result in sensitized attribution of incentive salience to drug-predictive cues. Therapeutic doses of amphetamine, such as those used to treat attention-deficit hyperactivity disorder, are hypothesized to enhance the ventral striatal dopamine transients that are critical for reward-related learning and to enhance Pavlovian learning. However, the effects of therapeutic doses of amphetamine on Pavlovian learning are poorly understood, and the effects on dopamine transients are completely unknown. We determined the effects of an acute pre-training therapeutic or rewarding amphetamine injection on the acquisition of Pavlovian autoshaping in the intact rat. We also determined the effects of these doses on electrically evoked transient-like dopamine signals using fast-scan cyclic voltammetry in the anesthetized rat. The rewarding dose enhanced the amplitude and duration of DA signals, caused acute task disengagement, impaired learning for several days, and triggered incentive sensitization. The therapeutic dose produced smaller enhancements in DA signals but did not have similar behavioral effects. These results underscore the necessity of more studies using therapeutic doses, and suggest a hybrid learning/incentive sensitization model may be required to explain the development of addiction. Copyright © 2017 Elsevier B.V. All rights reserved.

Common Neurogenetic Diagnosis and Meso-Limbic Manipulation of Hypodopaminergic Function in Reward Deficiency Syndrome (RDS): Changing the Recovery Landscape.

PubMed

Blum, Kenneth; Febo, Marcelo; Badgaiyan, Rajendra D; Demetrovics, Zsolt; Simpatico, Thomas; Fahlke, Claudia; M, Oscar-Berman; Li, Mona; Dushaj, Kristina; Gold, Mark S

2017-01-01

In 1990, Blum and associates provided the first confirmed genetic link between the DRD2 polymorphisms and alcoholism. This finding was based on an earlier conceptual framework, which served as a blueprint for their seminal genetic association discovery they termed "Brain Reward Cascade." These findings were followed by a new way of understanding all addictive behaviors (substance and non-substance) termed "Reward Deficiency Syndrome" (RDS). RDS incorporates a complex multifaceted array of inheritable behaviors that are polygenic. In this review article, we attempt to clarify these terms and provide a working model to accurately diagnose and treat these unwanted behaviors. We are hereby proposing the development of a translational model we term "Reward Deficiency Solution System™" that incorporates neurogenetic testing and meso-limbic manipulation of a "hypodopaminergic" trait/state, which provides dopamine agonistic therapy (DAT) as well as reduced "dopamine resistance," while embracing "dopamine homeostasis." The result is better recovery and relapse prevention, despite DNA antecedents, which could impact the recovery process and relapse. Understanding the commonality of mental illness will transform erroneous labeling based on symptomatology, into a genetic and anatomical etiology. WC: 184.

Distinctive striatal dopamine signaling after dieting and gastric bypass.

PubMed

Hankir, Mohammed K; Ashrafian, Hutan; Hesse, Swen; Horstmann, Annette; Fenske, Wiebke K

2015-05-01

Highly palatable and/or calorically dense foods, such as those rich in fat, engage the striatum to govern and set complex behaviors. Striatal dopamine signaling has been implicated in hedonic feeding and the development of obesity. Dieting and bariatric surgery have markedly different outcomes on weight loss, yet how these interventions affect central homeostatic and food reward processing remains poorly understood. Here, we propose that dieting and gastric bypass produce distinct changes in peripheral factors with known roles in regulating energy homeostasis, resulting in differential modulation of nigrostriatal and mesolimbic dopaminergic reward circuits. Enhancement of intestinal fat metabolism after gastric bypass may also modify striatal dopamine signaling contributing to its unique long-term effects on feeding behavior and body weight in obese individuals. Copyright © 2015 Elsevier Ltd. All rights reserved.

Cannabinoid modulation of drug reward and the implications of marijuana legalization.

PubMed

Covey, Dan P; Wenzel, Jennifer M; Cheer, Joseph F

2015-12-02

Marijuana is the most popular illegal drug worldwide. Recent trends indicate that this may soon change; not due to decreased marijuana use, but to an amendment in marijuana's illegal status. The cannabinoid type 1 (CB1) receptor mediates marijuana's psychoactive and reinforcing properties. CB1 receptors are also part of the brain endocannabinoid (eCB) system and support numerous forms of learning and memory, including the conditioned reinforcing properties of cues predicting reward or punishment. This is accomplished via eCB-dependent alterations in mesolimbic dopamine function, which plays an obligatory role in reward learning and motivation. Presynaptic CB1 receptors control midbrain dopamine neuron activity and thereby shape phasic dopamine release in target regions, particularly the nucleus accumbens (NAc). By also regulating synaptic input to the NAc, CB1 receptors modulate NAc output onto downstream neurons of the basal ganglia motor circuit, and thereby support goal-directed behaviors. Abused drugs promote short- and long-term adaptations in eCB-regulation of mesolimbic dopamine function, and thereby hijack neural systems related to the pursuit of rewards to promote drug abuse. By pharmacologically targeting the CB1 receptors, marijuana has preferential access to this neuronal system and can potently alter eCB-dependent processing of reward-related stimuli. As marijuana legalization progresses, greater access to this drug should increase the utility of marijuana as a research tool to better understand the eCB system, which has the potential to advance cannabinoid-based treatments for drug addiction. Copyright © 2014 Elsevier B.V. All rights reserved.

The role of dopamine in risk taking: a specific look at Parkinson’s disease and gambling

PubMed Central

Clark, Crystal A.; Dagher, Alain

2014-01-01

An influential model suggests that dopamine signals the difference between predicted and experienced reward. In this way, dopamine can act as a learning signal that can shape behaviors to maximize rewards and avoid punishments. Dopamine is also thought to invigorate reward seeking behavior. Loss of dopamine signaling is the major abnormality in Parkinson’s disease. Dopamine agonists have been implicated in the occurrence of impulse control disorders in Parkinson’s disease patients, the most common being pathological gambling, compulsive sexual behavior, and compulsive buying. Recently, a number of functional imaging studies investigating impulse control disorders in Parkinson’s disease have been published. Here we review this literature, and attempt to place it within a decision-making framework in which potential gains and losses are evaluated to arrive at optimum choices. We also provide a hypothetical but still incomplete model on the effect of dopamine agonist treatment on these value and risk assessments. Two of the main brain structures thought to be involved in computing aspects of reward and loss are the ventral striatum (VStr) and the insula, both dopamine projection sites. Both structures are consistently implicated in functional brain imaging studies of pathological gambling in Parkinson’s disease. PMID:24910600

The Neurobiology of Opiate Motivation

PubMed Central

Ting-A-Kee, Ryan; van der Kooy, Derek

2012-01-01

Opiates are a highly addictive class of drugs that have been reported to possess both dopamine-dependent and dopamine-independent rewarding properties. The search for how, if at all, these distinct mechanisms of motivation are related is of great interest in drug addiction research. Recent electrophysiological, molecular, and behavioral work has greatly improved our understanding of this process. In particular, the signaling properties of GABAA receptors located on GABA neurons in the ventral tegmental area (VTA) appear to be crucial to understanding the interplay between dopamine-dependent and dopamine-independent mechanisms of opiate motivation. PMID:23028134

Hedonic Eating and the “Delicious Circle”: From Lipid-Derived Mediators to Brain Dopamine and Back

PubMed Central

Coccurello, Roberto; Maccarrone, Mauro

2018-01-01

Palatable food can be seductive and hedonic eating can become irresistible beyond hunger and negative consequences. This is witnessed by the subtle equilibrium between eating to provide energy intake for homeostatic functions, and reward-induced overeating. In recent years, considerable efforts have been devoted to study neural circuits, and to identify potential factors responsible for the derangement of homeostatic eating toward hedonic eating and addiction-like feeding behavior. Here, we examined recent literature on “old” and “new” players accountable for reward-induced overeating and possible liability to eating addiction. Thus, the role of midbrain dopamine is positioned at the intersection between selected hormonal signals involved in food reward information processing (namely, leptin, ghrelin, and insulin), and lipid-derived neural mediators such as endocannabinoids. The impact of high fat palatable food and dietary lipids on endocannabinoid formation is reviewed in its pathogenetic potential for the derangement of feeding homeostasis. Next, endocannabinoid signaling that regulates synaptic plasticity is discussed as a key mechanism acting both at hypothalamic and mesolimbic circuits, and affecting both dopamine function and interplay between leptin and ghrelin signaling. Outside the canonical hypothalamic feeding circuits involved in energy homeostasis and the notion of “feeding center,” we focused on lateral hypothalamus as neural substrate able to confront food-associated homeostatic information with food salience, motivation to eat, reward-seeking, and development of compulsive eating. Thus, the lateral hypothalamus-ventral tegmental area-nucleus accumbens neural circuitry is reexamined in order to interrogate the functional interplay between ghrelin, dopamine, orexin, and endocannabinoid signaling. We suggested a pivotal role for endocannabinoids in food reward processing within the lateral hypothalamus, and for orexin neurons to integrate endocrine signals with food reinforcement and hedonic eating. In addition, the role played by different stressors in the reinstatement of preference for palatable food and food-seeking behavior is also considered in the light of endocannabinoid production, activation of orexin receptors and disinhibition of dopamine neurons. Finally, type-1 cannabinoid receptor-dependent inhibition of GABA-ergic release and relapse to reward-associated stimuli is linked to ghrelin and orexin signaling in the lateral hypothalamus-ventral tegmental area-nucleus accumbens network to highlight its pathological potential for food addiction-like behavior. PMID:29740277

Reward-based hypertension control by a synthetic brain-dopamine interface.

PubMed

Rössger, Katrin; Charpin-El Hamri, Ghislaine; Fussenegger, Martin

2013-11-05

Synthetic biology has significantly advanced the design of synthetic trigger-controlled devices that can reprogram mammalian cells to interface with complex metabolic activities. In the brain, the neurotransmitter dopamine coordinates communication with target neurons via a set of dopamine receptors that control behavior associated with reward-driven learning. This dopamine transmission has recently been suggested to increase central sympathetic outflow, resulting in plasma dopamine levels that correlate with corresponding brain activities. By functionally rewiring the human dopamine receptor D1 (DRD1) via the second messenger cyclic adenosine monophosphate (cAMP) to synthetic promoters containing cAMP response element-binding protein 1(CREB1)-specific cAMP-responsive operator modules, we have designed a synthetic dopamine-sensitive transcription controller that reversibly fine-tunes specific target gene expression at physiologically relevant brain-derived plasma dopamine levels. Following implantation of circuit-transgenic human cell lines insulated by semipermeable immunoprotective microcontainers into mice, the designer device interfaced with dopamine-specific brain activities and produced a systemic expression response when the animal's reward system was stimulated by food, sexual arousal, or addictive drugs. Reward-triggered brain activities were able to remotely program peripheral therapeutic implants to produce sufficient amounts of the atrial natriuretic peptide, which reduced the blood pressure of hypertensive mice to the normal physiologic range. Seamless control of therapeutic transgenes by subconscious behavior may provide opportunities for treatment strategies of the future.

Independent effects of age and levodopa on reversal learning in healthy volunteers.

PubMed

Vo, Andrew; Seergobin, Ken N; MacDonald, Penny A

2018-05-18

The dopamine overdose hypothesis has provided an important theoretical framework for understanding cognition in Parkinson's disease. It posits that effects of dopaminergic therapy on cognition in Parkinson's disease depend on baseline dopamine levels in brain regions that support different functions. Although functions performed by more severely dopamine-depleted brain regions improve with medication, those associated with less dopamine deficient areas are actually worsened. It is presumed that medication-related worsening of cognition owes to dopamine overdose. We investigated whether age-related changes in baseline dopamine levels would modulate effects of dopaminergic therapy on reward learning in healthy volunteers. In a double-blind, crossover design, healthy younger and older adults completed a probabilistic reversal learning task after treatment with 100/25 mg of levodopa/carbidopa versus placebo. Older adults learned more poorly than younger adults at baseline, being more likely to shift responses after misleading punishment. Levodopa worsened stimulus-reward learning relative to placebo to the same extent in both groups, irrespective of differences in baseline performance and expected dopamine levels. When order effects were eliminated, levodopa induced response shifts after reward more often than placebo. Our results reveal independent deleterious effects of age group and exogenous dopamine on reward learning, suggesting a more complex scenario than predicted by the dopamine overdose hypothesis. Copyright © 2018 Elsevier Inc. All rights reserved.

Abnormal Striatal BOLD Responses to Reward Anticipation and Reward Delivery in ADHD

PubMed Central

Furukawa, Emi; Bado, Patricia; Tripp, Gail; Mattos, Paulo; Wickens, Jeff R.; Bramati, Ivanei E.; Alsop, Brent; Ferreira, Fernanda Meireles; Lima, Debora; Tovar-Moll, Fernanda; Sergeant, Joseph A.; Moll, Jorge

2014-01-01

Altered reward processing has been proposed to contribute to the symptoms of attention deficit hyperactivity disorder (ADHD). The neurobiological mechanism underlying this alteration remains unclear. We hypothesize that the transfer of dopamine release from reward to reward-predicting cues, as normally observed in animal studies, may be deficient in ADHD. Functional magnetic resonance imaging (fMRI) was used to investigate striatal responses to reward-predicting cues and reward delivery in a classical conditioning paradigm. Data from 14 high-functioning and stimulant-naïve young adults with elevated lifetime symptoms of ADHD (8 males, 6 females) and 15 well-matched controls (8 males, 7 females) were included in the analyses. During reward anticipation, increased blood-oxygen-level-dependent (BOLD) responses in the right ventral and left dorsal striatum were observed in controls, but not in the ADHD group. The opposite pattern was observed in response to reward delivery; the ADHD group demonstrated significantly greater BOLD responses in the ventral striatum bilaterally and the left dorsal striatum relative to controls. In the ADHD group, the number of current hyperactivity/impulsivity symptoms was inversely related to ventral striatal responses during reward anticipation and positively associated with responses to reward. The BOLD response patterns observed in the striatum are consistent with impaired predictive dopamine signaling in ADHD, which may explain altered reward-contingent behaviors and symptoms of ADHD. PMID:24586543

Chronic cocaine disrupts mesocortical learning mechanisms

PubMed Central

Buchta, William C.; Riegel, Arthur C.

2016-01-01

The addictive power of drugs of abuse such as cocaine comes from their ability to hijack natural reward and plasticity mechanisms mediated by dopamine signaling in the brain. Reward learning involves burst firing of midbrain dopamine neurons in response to rewards and cues predictive of reward. The resulting release of dopamine in terminal regions is thought to act as a teaching signaling to areas such as the prefrontal cortex and striatum. In this review, we posit that a pool of extrasynaptic dopaminergic D1-like receptors activated in response to dopamine neuron burst firing serve to enable synaptic plasticity in the prefrontal cortex in response to rewards and their cues. We propose that disruptions in these mechanisms following chronic cocaine use contribute to addiction pathology, in part due to the unique architecture of the mesocortical pathway. By blocking dopamine reuptake in the cortex, cocaine elevates dopamine signaling at these extra-synaptic receptors, prolonging D1-receptor activation and the subsequent activation of intracellular signaling cascades, and thus inducing long-lasting maladaptive plasticity. These cellular adaptations may account for many of the changes in cortical function observed in drug addicts, including an enduring vulnerability to relapse. Therefore, understanding and targeting these neuroadaptations may provide cognitive benefits and help prevent relapse in human drug addicts. PMID:25704202

Electrophysiological Evidence of Atypical Motivation and Reward Processing in Children with Attention-Deficit Hyperactivity Disorder

ERIC Educational Resources Information Center

Holroyd, Clay B.; Baker, Travis E.; Kerns, Kimberly A.; Muller, Ulrich

2008-01-01

Behavioral and neurophysiological evidence suggest that attention-deficit hyperactivity disorder (ADHD) is characterized by the impact of abnormal reward prediction error signals carried by the midbrain dopamine system on frontal brain areas that implement cognitive control. To investigate this issue, we recorded the event-related brain potential…

Attenuation of dopamine-modulated prefrontal value signals underlies probabilistic reward learning deficits in old age

PubMed Central

Axelsson, Jan; Riklund, Katrine; Nyberg, Lars; Dayan, Peter; Bäckman, Lars

2017-01-01

Probabilistic reward learning is characterised by individual differences that become acute in aging. This may be due to age-related dopamine (DA) decline affecting neural processing in striatum, prefrontal cortex, or both. We examined this by administering a probabilistic reward learning task to younger and older adults, and combining computational modelling of behaviour, fMRI and PET measurements of DA D1 availability. We found that anticipatory value signals in ventromedial prefrontal cortex (vmPFC) were attenuated in older adults. The strength of this signal predicted performance beyond age and was modulated by D1 availability in nucleus accumbens. These results uncover that a value-anticipation mechanism in vmPFC declines in aging, and that this mechanism is associated with DA D1 receptor availability. PMID:28870286

Attenuating GABAA Receptor Signaling in Dopamine Neurons Selectively Enhances Reward Learning and Alters Risk Preference in Mice

PubMed Central

Parker, Jones G.; Wanat, Matthew J.; Soden, Marta E.; Ahmad, Kinza; Zweifel, Larry S.; Bamford, Nigel S.; Palmiter, Richard D.

2011-01-01

Phasic dopamine transmission encodes the value of reward-predictive stimuli and influences both learning and decision-making. Altered dopamine signaling is associated with psychiatric conditions characterized by risky choices such as pathological gambling. These observations highlight the importance of understanding how dopamine neuron activity is modulated. While excitatory drive onto dopamine neurons is critical for generating phasic dopamine responses, emerging evidence suggests that inhibitory signaling also modulates these responses. To address the functional importance of inhibitory signaling in dopamine neurons, we generated mice lacking the β3 subunit of the GABAA receptor specifically in dopamine neurons (β3-KO mice) and examined their behavior in tasks that assessed appetitive learning, aversive learning, and risk preference. Dopamine neurons in midbrain slices from β3-KO mice exhibited attenuated GABA-evoked inhibitory post-synaptic currents. Furthermore, electrical stimulation of excitatory afferents to dopamine neurons elicited more dopamine release in the nucleus accumbens of β3-KO mice as measured by fast-scan cyclic voltammetry. β3-KO mice were more active than controls when given morphine, which correlated with potential compensatory upregulation of GABAergic tone onto dopamine neurons. β3-KO mice learned faster in two food-reinforced learning paradigms, but extinguished their learned behavior normally. Enhanced learning was specific for appetitive tasks, as aversive learning was unaffected in β3-KO mice. Finally, we found that β3-KO mice had enhanced risk preference in a probabilistic selection task that required mice to choose between a small certain reward and a larger uncertain reward. Collectively, these findings identify a selective role for GABAA signaling in dopamine neurons in appetitive learning and decision-making. PMID:22114279

Phasic dopamine as a prediction error of intrinsic and extrinsic reinforcements driving both action acquisition and reward maximization: a simulated robotic study.

PubMed

Mirolli, Marco; Santucci, Vieri G; Baldassarre, Gianluca

2013-03-01

An important issue of recent neuroscientific research is to understand the functional role of the phasic release of dopamine in the striatum, and in particular its relation to reinforcement learning. The literature is split between two alternative hypotheses: one considers phasic dopamine as a reward prediction error similar to the computational TD-error, whose function is to guide an animal to maximize future rewards; the other holds that phasic dopamine is a sensory prediction error signal that lets the animal discover and acquire novel actions. In this paper we propose an original hypothesis that integrates these two contrasting positions: according to our view phasic dopamine represents a TD-like reinforcement prediction error learning signal determined by both unexpected changes in the environment (temporary, intrinsic reinforcements) and biological rewards (permanent, extrinsic reinforcements). Accordingly, dopamine plays the functional role of driving both the discovery and acquisition of novel actions and the maximization of future rewards. To validate our hypothesis we perform a series of experiments with a simulated robotic system that has to learn different skills in order to get rewards. We compare different versions of the system in which we vary the composition of the learning signal. The results show that only the system reinforced by both extrinsic and intrinsic reinforcements is able to reach high performance in sufficiently complex conditions. Copyright © 2013 Elsevier Ltd. All rights reserved.

Nucleus Accumbens Acetylcholine Receptors Modulate Dopamine and Motivation.

PubMed

Collins, Anne L; Aitken, Tara J; Greenfield, Venuz Y; Ostlund, Sean B; Wassum, Kate M

2016-11-01

Environmental reward-predictive cues can motivate reward-seeking behaviors. Although this influence is normally adaptive, it can become maladaptive in disordered states, such as addiction. Dopamine release in the nucleus accumbens core (NAc) is known to mediate the motivational impact of reward-predictive cues, but little is known about how other neuromodulatory systems contribute to cue-motivated behavior. Here, we examined the role of the NAc cholinergic receptor system in cue-motivated behavior using a Pavlovian-to-instrumental transfer task designed to assess the motivating influence of a reward-predictive cue over an independently-trained instrumental action. Disruption of NAc muscarinic acetylcholine receptor activity attenuated, whereas blockade of nicotinic receptors augmented cue-induced invigoration of reward seeking. We next examined a potential dopaminergic mechanism for this behavioral effect by combining fast-scan cyclic voltammetry with local pharmacological acetylcholine receptor manipulation. The data show evidence of opposing modulation of cue-evoked dopamine release, with muscarinic and nicotinic receptor antagonists causing suppression and augmentation, respectively, consistent with the behavioral effects of these manipulations. In addition to demonstrating cholinergic modulation of naturally-evoked and behaviorally-relevant dopamine signaling, these data suggest that NAc cholinergic receptors may gate the expression of cue-motivated behavior through modulation of phasic dopamine release.

Distinct patterns of outcome valuation and amygdala-prefrontal cortex synaptic remodeling in adolescence and adulthood

PubMed Central

Stolyarova, Alexandra; Izquierdo, Alicia

2015-01-01

Adolescent behavior is typified by increased risk-taking, reward- and novelty-seeking, as well as an augmented need for social and environmental stimulation. This behavioral phenotype may result from alterations in outcome valuation or reward learning. In the present set of experiments, we directly compared adult and adolescent animals on tasks measuring both of these processes. Additionally, we examined developmental differences in dopamine D1-like receptor (D1R), dopamine D2-like receptor (D2R), and polysialylated neural cell adhesion molecule (PSA-NCAM) expression in animals that were trained on an effortful reward valuation task, given that these proteins play an important role in the functional development of the amygdala-prefrontocortical (PFC) circuit and mesocorticolimbic dopamine system. We found that adolescent animals were not different from adults in appetitive associative learning, but exhibited distinct pattern of responses to differences in outcome values, which was paralleled by an enhanced motivation to invest effort to obtain larger rewards. There were no differences in D2 receptor expression, but D1 receptor expression was significantly reduced in the striatum of animals that had experiences with reward learning during adolescence compared to animals that went through the same experiences in adulthood. We observed increased levels of PSA-NCAM expression in both PFC and amygdala of late adolescents compared to adults that were previously trained on an effortful reward valuation task. PSA-NCAM levels in PFC were strongly and positively associated with high effort/reward (HER) choices in adolescents, but not in adult animals. Increased levels of PSA-NCAM expression in adolescents may index increased structural plasticity and represent a neural correlate of a reward sensitive endophenotype. PMID:25999830

Dopaminergic modulation of the trade-off between probability and time in economic decision-making.

PubMed

Arrondo, Gonzalo; Aznárez-Sanado, Maite; Fernández-Seara, Maria A; Goñi, Joaquín; Loayza, Francis R; Salamon-Klobut, Ewa; Heukamp, Franz H; Pastor, Maria A

2015-06-01

Studies on animals and humans have demonstrated the importance of dopamine in modulating decision-making processes. In this work, we have tested dopaminergic modulation of economic decision-making and its neural correlates by administering either placebo or metoclopramide, a dopamine D2-receptor antagonist, to healthy subjects, during a functional MRI study. The decision-making task combined probability and time delay with a fixed monetary reward. For individual behavioral characterization, we used the Probability Time Trade-off (PTT) economic model, which integrates the traditional trade-offs of reward magnitude-time and reward magnitude-probability into a single measurement, thereby quantifying the subjective value of a delayed and probabilistic outcome. A regression analysis between BOLD signal and the PTT model index permitted to identify the neural substrate encoding the subjective reward-value. Behaviorally, medication reduced the rate of temporal discounting over probability, reflected in medicated subjects being more prone to postpone the reward in order to increase the outcome probability. In addition, medicated subjects showed less activity during the task in the postcentral gyrus as well as frontomedian areas, whereas there were no differences in the ventromedial orbitofrontal cortex (VMOFC) between groups when coding the subjective value. The present study demonstrates by means of behavior and imaging that dopamine modulation alters the probability-time trade-off in human economic decision-making. Copyright © 2015 Elsevier B.V. and ECNP. All rights reserved.

Encoding of aversion by dopamine and the nucleus accumbens.

PubMed

McCutcheon, James E; Ebner, Stephanie R; Loriaux, Amy L; Roitman, Mitchell F

2012-01-01

Adaptive motivated behavior requires rapid discrimination between beneficial and harmful stimuli. Such discrimination leads to the generation of either an approach or rejection response, as appropriate, and enables organisms to maximize reward and minimize punishment. Classically, the nucleus accumbens (NAc) and the dopamine projection to it are considered an integral part of the brain's reward circuit, i.e., they direct approach and consumption behaviors and underlie positive reinforcement. This reward-centered framing ignores important evidence about the role of this system in encoding aversive events. One reason for bias toward reward is the difficulty in designing experiments in which animals repeatedly experience punishments; another is the challenge in dissociating the response to an aversive stimulus itself from the reward/relief experienced when an aversive stimulus is terminated. Here, we review studies that employ techniques with sufficient time resolution to measure responses in ventral tegmental area and NAc to aversive stimuli as they are delivered. We also present novel findings showing that the same stimulus - intra-oral infusion of sucrose - has differing effects on NAc shell dopamine release depending on the prior experience. Here, for some rats, sucrose was rendered aversive by explicitly pairing it with malaise in a conditioned taste aversion paradigm. Thereafter, sucrose infusions led to a suppression of dopamine with a similar magnitude and time course to intra-oral infusions of a bitter quinine solution. The results are discussed in the context of regional differences in dopamine signaling and the implications of a pause in phasic dopamine release within the NAc shell. Together with our data, the emerging literature suggests an important role for differential phasic dopamine signaling in aversion vs. reward.

METHAMPHETAMINE-INDUCED DOPAMINE TERMINAL DEFICITS IN THE NUCLEUS ACCUMBENS ARE EXACERBATED BY REWARD-ASSOCIATED CUES AND ATTENUATED BY CB1 RECEPTOR ANTAGONISM

PubMed Central

Loewinger, Gabriel C.; Beckert, Michael V.; Tejeda, Hugo A.; Cheer, Joseph F.

2012-01-01

Methamphetamine (METH) exposure is primarily associated with deleterious effects to dopaminergic neurons. While several studies have implicated the endocannabinoid system in METH’s locomotor, rewarding and neurochemical effects, a role for this signaling system in METH’s effects on dopamine terminal dynamics has not been elucidated. Given that CB1 receptor blockade reduces the acute potentiation of phasic extracellular dopamine release from other psychomotor stimulant drugs and that the degree of acute METH-induced increases in extracellular dopamine levels is related to the severity of dopamine depletion, we predicted that pretreatment with the CB1 receptor antagonist rimonabant would reduce METH-induced alterations at dopamine terminals. Furthermore, we hypothesized that administration of METH in environments where reward associated-cues were present would potentiate METH’s acute effects on dopamine release in the nucleus accumbens and exacerbate changes in dopamine terminal activity. Fast-scan cyclic voltammetry was used to measure electrically-evoked dopamine release in the nucleus accumbens and revealed markers of compromised dopamine terminal integrity nine days after a single dose of METH. These were exacerbated in animals that received METH in the presence of reward-associated cues, and attenuated in rimonabant-pretreated animals. While these deficits in dopamine dynamics were associated with reduced operant responding on days following METH administration in animals treated with only METH, rimonabant-pretreated animals exhibited levels of operant responding comparable to control. Moreover, dopamine release correlated significantly with changes in lever pressing behavior that occurred on days following METH administration. Together these data suggest that the endocannabinoid system is involved in the subsecond dopaminergic response to METH. PMID:22306525

The neuromodulator of exploration: A unifying theory of the role of dopamine in personality

PubMed Central

DeYoung, Colin G.

2013-01-01

The neuromodulator dopamine is centrally involved in reward, approach behavior, exploration, and various aspects of cognition. Variations in dopaminergic function appear to be associated with variations in personality, but exactly which traits are influenced by dopamine remains an open question. This paper proposes a theory of the role of dopamine in personality that organizes and explains the diversity of findings, utilizing the division of the dopaminergic system into value coding and salience coding neurons (Bromberg-Martin et al., 2010). The value coding system is proposed to be related primarily to Extraversion and the salience coding system to Openness/Intellect. Global levels of dopamine influence the higher order personality factor, Plasticity, which comprises the shared variance of Extraversion and Openness/Intellect. All other traits related to dopamine are linked to Plasticity or its subtraits. The general function of dopamine is to promote exploration, by facilitating engagement with cues of specific reward (value) and cues of the reward value of information (salience). This theory constitutes an extension of the entropy model of uncertainty (EMU; Hirsh et al., 2012), enabling EMU to account for the fact that uncertainty is an innate incentive reward as well as an innate threat. The theory accounts for the association of dopamine with traits ranging from sensation and novelty seeking, to impulsivity and aggression, to achievement striving, creativity, and cognitive abilities, to the overinclusive thinking characteristic of schizotypy. PMID:24294198

Dopamine reward prediction errors reflect hidden state inference across time

PubMed Central

Starkweather, Clara Kwon; Babayan, Benedicte M.; Uchida, Naoshige; Gershman, Samuel J.

2017-01-01

Midbrain dopamine neurons signal reward prediction error (RPE), or actual minus expected reward. The temporal difference (TD) learning model has been a cornerstone in understanding how dopamine RPEs could drive associative learning. Classically, TD learning imparts value to features that serially track elapsed time relative to observable stimuli. In the real world, however, sensory stimuli provide ambiguous information about the hidden state of the environment, leading to the proposal that TD learning might instead compute a value signal based on an inferred distribution of hidden states (a ‘belief state’). In this work, we asked whether dopaminergic signaling supports a TD learning framework that operates over hidden states. We found that dopamine signaling exhibited a striking difference between two tasks that differed only with respect to whether reward was delivered deterministically. Our results favor an associative learning rule that combines cached values with hidden state inference. PMID:28263301

Dopamine reward prediction errors reflect hidden-state inference across time.

PubMed

Starkweather, Clara Kwon; Babayan, Benedicte M; Uchida, Naoshige; Gershman, Samuel J

2017-04-01

Midbrain dopamine neurons signal reward prediction error (RPE), or actual minus expected reward. The temporal difference (TD) learning model has been a cornerstone in understanding how dopamine RPEs could drive associative learning. Classically, TD learning imparts value to features that serially track elapsed time relative to observable stimuli. In the real world, however, sensory stimuli provide ambiguous information about the hidden state of the environment, leading to the proposal that TD learning might instead compute a value signal based on an inferred distribution of hidden states (a 'belief state'). Here we asked whether dopaminergic signaling supports a TD learning framework that operates over hidden states. We found that dopamine signaling showed a notable difference between two tasks that differed only with respect to whether reward was delivered in a deterministic manner. Our results favor an associative learning rule that combines cached values with hidden-state inference.

Lesion to the nigrostriatal dopamine system disrupts stimulus-response habit formation.

PubMed

Faure, Alexis; Haberland, Ulrike; Condé, Françoise; El Massioui, Nicole

2005-03-16

Acquisition and performance of instrumental actions are assumed to require both action-outcome and stimulus-response (S-R) habit processes. Over the course of extended training, control over instrumental performance shifts from goal-directed action-outcome associations to S-R associations that progressively gain domination over behavior. Lesions of the lateral part of the dorsal striatum disrupt this process, and rats with lesions to the lateral striatum showed selective sensitivity to devaluation of the instrumental outcome (Yin et al., 2004), indicating that this area is necessary for habit formation. The present experiment further explored the basis of this dysfunction by examining the ability of rats subjected to bilateral 6-hydroxydopamine lesions of the nigrostriatal dopaminergic pathway to develop behavioral autonomy with overtraining. Rats were given extended training on two cued instrumental tasks associating a stimulus (a tone or a light) with an instrumental action (lever press or chain pull) and a food reward (pellets or sucrose). Both tasks were run daily in separate sessions. Overtraining was followed by a test of goal sensitivity by satiety-specific devaluation of the reward. In control animals, one action (lever press) was insensitive to reward devaluation, indicating that it became a habit, whereas the second action (chain pull) was still sensitive to goal devaluation. This result provides evidence that the development of habit learning may depend on the characteristics of the response. In dopamine-depleted rats, lever press and chain pull remained sensitive to reward devaluation, evidencing a role of striatal dopamine transmission in habit formation.

Histidine-decarboxylase knockout mice show deficient nonreinforced episodic object memory, improved negatively reinforced water-maze performance, and increased neo- and ventro-striatal dopamine turnover.

PubMed

Dere, Ekrem; De Souza-Silva, Maria A; Topic, Bianca; Spieler, Richard E; Haas, Helmut L; Huston, Joseph P

2003-01-01

The brain's histaminergic system has been implicated in hippocampal synaptic plasticity, learning, and memory, as well as brain reward and reinforcement. Our past pharmacological and lesion studies indicated that the brain's histamine system exerts inhibitory effects on the brain's reinforcement respective reward system reciprocal to mesolimbic dopamine systems, thereby modulating learning and memory performance. Given the close functional relationship between brain reinforcement and memory processes, the total disruption of brain histamine synthesis via genetic disruption of its synthesizing enzyme, histidine decarboxylase (HDC), in the mouse might have differential effects on learning dependent on the task-inherent reinforcement contingencies. Here, we investigated the effects of an HDC gene disruption in the mouse in a nonreinforced object exploration task and a negatively reinforced water-maze task as well as on neo- and ventro-striatal dopamine systems known to be involved in brain reward and reinforcement. Histidine decarboxylase knockout (HDC-KO) mice had higher dihydrophenylacetic acid concentrations and a higher dihydrophenylacetic acid/dopamine ratio in the neostriatum. In the ventral striatum, dihydrophenylacetic acid/dopamine and 3-methoxytyramine/dopamine ratios were higher in HDC-KO mice. Furthermore, the HDC-KO mice showed improved water-maze performance during both hidden and cued platform tasks, but deficient object discrimination based on temporal relationships. Our data imply that disruption of brain histamine synthesis can have both memory promoting and suppressive effects via distinct and independent mechanisms and further indicate that these opposed effects are related to the task-inherent reinforcement contingencies.

Neurobiological constraints on behavioral models of motivation.

PubMed

Nader, K; Bechara, A; van der Kooy, D

1997-01-01

The application of neurobiological tools to behavioral questions has produced a number of working models of the mechanisms mediating the rewarding and aversive properties of stimuli. The authors review and compare three models that differ in the nature and number of the processes identified. The dopamine hypothesis, a single system model, posits that the neurotransmitter dopamine plays a fundamental role in mediating the rewarding properties of all classes of stimuli. In contrast, both nondeprived/deprived and saliency attribution models claim that separate systems make independent contributions to reward. The former identifies the psychological boundary defined by the two systems as being between states of nondeprivation (e.g. food sated) and deprivation (e.g. hunger). The latter identifies a boundary between liking and wanting systems. Neurobiological dissociations provide tests of and explanatory power for behavioral theories of goal-directed behavior.

Depletion of nucleus accumbens dopamine leads to impaired reward and aversion processing in mice: Relevance to motivation pathologies.

PubMed

Bergamini, Giorgio; Sigrist, Hannes; Ferger, Boris; Singewald, Nicolas; Seifritz, Erich; Pryce, Christopher R

2016-10-01

Dopamine (DA) neurotransmission, particularly the ventral tegmental area-nucleus accumbens (VTA-NAcc) projection, underlies reward and aversion processing, and deficient DA function could underlie motivational impairments in psychiatric disorders. 6-hydroxydopamine (6-OHDA) injection is an established method for chronic DA depletion, principally applied in rat to study NAcc DA regulation of reward motivation. Given the increasing focus on studying environmental and genetic regulation of DA function in mouse models, it is important to establish the effects of 6-OHDA DA depletion in mice, in terms of reward and aversion processing. This mouse study investigated effects of 6-OHDA-induced NAcc DA depletion using the operant behavioural test battery of progressive ratio schedule (PRS), learned non-reward (LNR), learned helplessness (LH), treadmill, and in addition Pavlovian fear conditioning. 6-OHDA NAcc DA depletion, confirmed by ex vivo HPLC-ED, reduced operant responding: for gustatory reward under effortful conditions in the PRS test; to a stimulus recently associated with gustatory non-reward in the LNR test; to escape footshock recently experienced as uncontrollable in the LH test; and to avoid footshock by physical effort in the treadmill test. Evidence for specificity of effects to NAcc DA was provided by lack of effect of medial prefrontal cortex DA depletion in the LNR and LH tests. These findings add significantly to the evidence that NAcc DA is a major regulator of behavioural responding, particularly at the motivational level, to both reward and aversion. They demonstrate the suitability of mouse models for translational study of causation and reversal of pathophysiological DA function underlying motivation psychopathologies. Copyright © 2016 Elsevier Ltd. All rights reserved.

Effects of dopamine and glutamate on synaptic plasticity: a computational modeling approach for drug abuse as comorbidity in mood disorders.

PubMed

Qi, Z; Kikuchi, S; Tretter, F; Voit, E O

2011-05-01

Major depressive disorder (MDD) affects about 16% of the general population and is a leading cause of death in the United States and around the world. Aggravating the situation is the fact that "drug use disorders" are highly comorbid in MDD patients, and VICE VERSA. Drug use and MDD share a common component, the dopamine system, which is critical in many motivation and reward processes, as well as in the regulation of stress responses in MDD. A potentiating mechanism in drug use disorders appears to be synaptic plasticity, which is regulated by dopamine transmission. In this article, we describe a computational model of the synaptic plasticity of GABAergic medium spiny neurons in the nucleus accumbens, which is critical in the reward system. The model accounts for effects of both dopamine and glutamate transmission. Model simulations show that GABAergic medium spiny neurons tend to respond to dopamine stimuli with synaptic potentiation and to glutamate signals with synaptic depression. Concurrent dopamine and glutamate signals cause various types of synaptic plasticity, depending on input scenarios. Interestingly, the model shows that a single 0.5 mg/kg dose of amphetamine can cause synaptic potentiation for over 2 h, a phenomenon that makes synaptic plasticity of medium spiny neurons behave quasi as a bistable system. The model also identifies mechanisms that could potentially be critical to correcting modifications of synaptic plasticity caused by drugs in MDD patients. An example is the feedback loop between protein kinase A, phosphodiesterase, and the second messenger cAMP in the postsynapse. Since reward mechanisms activated by psychostimulants could be crucial in establishing addiction comorbidity in patients with MDD, this model might become an aid for identifying and targeting specific modules within the reward system and lead to a better understanding and potential treatment of comorbid drug use disorders in MDD. © Georg Thieme Verlag KG Stuttgart · New York.

Common Neurogenetic Diagnosis and Meso-Limbic Manipulation of Hypodopaminergic Function in Reward Deficiency Syndrome (RDS): Changing the Recovery Landscape

PubMed Central

Blum, Kenneth; Febo, Marcelo; Badgaiyan, Rajendra D.; Demetrovics, Zsolt; Simpatico, Thomas; Fahlke, Claudia; Li, Mona; Dushaj, Kristina; Gold, Mark S.

2017-01-01

Abstract: Background: In 1990, Blum and associates provided the first confirmed genetic link between the DRD2 polymorphisms and alcoholism. This finding was based on an earlier conceptual framework, which served as a blueprint for their seminal genetic association discovery they termed “Brain Reward Cascade.” These findings were followed by a new way of understanding all addictive behaviors (substance and non-substance) termed “Reward Deficiency Syndrome” (RDS). RDS incorporates a complex multifaceted array of inheritable behaviors that are polygenic. Objective: In this review article, we attempt to clarify these terms and provide a working model to accurately diagnose and treat these unwanted behaviors. Method: We are hereby proposing the development of a translational model we term “Reward Deficiency Solution System™” that incorporates neurogenetic testing and meso-limbic manipulation of a “hypodopaminergic” trait/state, which provides dopamine agonistic therapy (DAT) as well as reduced “dopamine resistance,” while embracing “dopamine homeostasis.” Result: The result is better recovery and relapse prevention, despite DNA antecedents, which could impact the recovery process and relapse. Understanding the commonality of mental illness will transform erroneous labeling based on symptomatology, into a genetic and anatomical etiology. WC: 184. PMID:27174576

Brain reward circuitry beyond the mesolimbic dopamine system: a neurobiological theory.

PubMed

Ikemoto, Satoshi

2010-11-01

Reductionist attempts to dissect complex mechanisms into simpler elements are necessary, but not sufficient for understanding how biological properties like reward emerge out of neuronal activity. Recent studies on intracranial self-administration of neurochemicals (drugs) found that rats learn to self-administer various drugs into the mesolimbic dopamine structures-the posterior ventral tegmental area, medial shell nucleus accumbens and medial olfactory tubercle. In addition, studies found roles of non-dopaminergic mechanisms of the supramammillary, rostromedial tegmental and midbrain raphe nuclei in reward. To explain intracranial self-administration and related effects of various drug manipulations, I outlined a neurobiological theory claiming that there is an intrinsic central process that coordinates various selective functions (including perceptual, visceral, and reinforcement processes) into a global function of approach. Further, this coordinating process for approach arises from interactions between brain structures including those structures mentioned above and their closely linked regions: the medial prefrontal cortex, septal area, ventral pallidum, bed nucleus of stria terminalis, preoptic area, lateral hypothalamic areas, lateral habenula, periaqueductal gray, laterodorsal tegmental nucleus and parabrachical area. Published by Elsevier Ltd.

Molecular Genetic Testing in Reward Deficiency Syndrome (RDS): Facts and Fiction.

PubMed

Blum, Kenneth; Badgaiyan, Rajendra D; Agan, Gozde; Fratantonio, James; Simpatico, Thomas; Febo, Marcelo; Haberstick, Brett C; Smolen, Andrew; Gold, Mark S

The Brain Reward Cascade (BRC) is an interaction of neurotransmitters and their respective genes to control the amount of dopamine released within the brain. Any variations within this pathway, whether genetic or environmental (epigenetic), may result in addictive behaviors or RDS, which was coined to define addictive behaviors and their genetic components. To carry out this review we searched a number of important databases including: Filtered: Cochrane Systematic reviews; DARE; Pubmed Central Clinical Quaries; National Guideline Clearinghouse and unfiltered resources: PsychINFO; ACP PIER; PsychSage; Pubmed/Medline. The major search terms included: dopamine agonist therapy for Addiction; dopamine agonist therapy for Reward dependence; dopamine antagonistic therapy for addiction; dopamine antagonistic therapy for reward dependence and neurogenetics of RDS. While there are many studies claiming a genetic association with RDS behavior, not all are scientifically accurate. Albeit our bias, this Clinical Pearl discusses the facts and fictions behind molecular genetic testing in RDS and the significance behind the development of the Genetic Addiction Risk Score (GARS PREDX ™), the first test to accurately predict one's genetic risk for RDS.

Effort, anhedonia, and function in schizophrenia: reduced effort allocation predicts amotivation and functional impairment.

PubMed

Barch, Deanna M; Treadway, Michael T; Schoen, Nathan

2014-05-01

One of the most debilitating aspects of schizophrenia is an apparent interest in or ability to exert effort for rewards. Such "negative symptoms" may prevent individuals from obtaining potentially beneficial outcomes in educational, occupational, or social domains. In animal models, dopamine abnormalities decrease willingness to work for rewards, implicating dopamine (DA) function as a candidate substrate for negative symptoms given that schizophrenia involves dysregulation of the dopamine system. We used the effort-expenditure for rewards task (EEfRT) to assess the degree to which individuals with schizophrenia were wiling to exert increased effort for either larger magnitude rewards or for rewards that were more probable. Fifty-nine individuals with schizophrenia and 39 demographically similar controls performed the EEfRT task, which involves making choices between "easy" and "hard" tasks to earn potential rewards. Individuals with schizophrenia showed less of an increase in effort allocation as either reward magnitude or probability increased. In controls, the frequency of choosing the hard task in high reward magnitude and probability conditions was negatively correlated with depression severity and anhedonia. In schizophrenia, fewer hard task choices were associated with more severe negative symptoms and worse community and work function as assessed by a caretaker. Consistent with patterns of disrupted dopamine functioning observed in animal models of schizophrenia, these results suggest that 1 mechanism contributing to impaired function and motivational drive in schizophrenia may be a reduced allocation of greater effort for higher magnitude or higher probability rewards.

Dopamine Reward Prediction Error Responses Reflect Marginal Utility

PubMed Central

Stauffer, William R.; Lak, Armin; Schultz, Wolfram

2014-01-01

Summary Background Optimal choices require an accurate neuronal representation of economic value. In economics, utility functions are mathematical representations of subjective value that can be constructed from choices under risk. Utility usually exhibits a nonlinear relationship to physical reward value that corresponds to risk attitudes and reflects the increasing or decreasing marginal utility obtained with each additional unit of reward. Accordingly, neuronal reward responses coding utility should robustly reflect this nonlinearity. Results In two monkeys, we measured utility as a function of physical reward value from meaningful choices under risk (that adhered to first- and second-order stochastic dominance). The resulting nonlinear utility functions predicted the certainty equivalents for new gambles, indicating that the functions’ shapes were meaningful. The monkeys were risk seeking (convex utility function) for low reward and risk avoiding (concave utility function) with higher amounts. Critically, the dopamine prediction error responses at the time of reward itself reflected the nonlinear utility functions measured at the time of choices. In particular, the reward response magnitude depended on the first derivative of the utility function and thus reflected the marginal utility. Furthermore, dopamine responses recorded outside of the task reflected the marginal utility of unpredicted reward. Accordingly, these responses were sufficient to train reinforcement learning models to predict the behaviorally defined expected utility of gambles. Conclusions These data suggest a neuronal manifestation of marginal utility in dopamine neurons and indicate a common neuronal basis for fundamental explanatory constructs in animal learning theory (prediction error) and economic decision theory (marginal utility). PMID:25283778

Mapping anhedonia onto reinforcement learning: a behavioural meta-analysis

PubMed Central

2013-01-01

Background Depression is characterised partly by blunted reactions to reward. However, tasks probing this deficiency have not distinguished insensitivity to reward from insensitivity to the prediction errors for reward that determine learning and are putatively reported by the phasic activity of dopamine neurons. We attempted to disentangle these factors with respect to anhedonia in the context of stress, Major Depressive Disorder (MDD), Bipolar Disorder (BPD) and a dopaminergic challenge. Methods Six behavioural datasets involving 392 experimental sessions were subjected to a model-based, Bayesian meta-analysis. Participants across all six studies performed a probabilistic reward task that used an asymmetric reinforcement schedule to assess reward learning. Healthy controls were tested under baseline conditions, stress or after receiving the dopamine D2 agonist pramipexole. In addition, participants with current or past MDD or BPD were evaluated. Reinforcement learning models isolated the contributions of variation in reward sensitivity and learning rate. Results MDD and anhedonia reduced reward sensitivity more than they affected the learning rate, while a low dose of the dopamine D2 agonist pramipexole showed the opposite pattern. Stress led to a pattern consistent with a mixed effect on reward sensitivity and learning rate. Conclusion Reward-related learning reflected at least two partially separable contributions. The first related to phasic prediction error signalling, and was preferentially modulated by a low dose of the dopamine agonist pramipexole. The second related directly to reward sensitivity, and was preferentially reduced in MDD and anhedonia. Stress altered both components. Collectively, these findings highlight the contribution of model-based reinforcement learning meta-analysis for dissecting anhedonic behavior. PMID:23782813

Dopaminergic inputs in the dentate gyrus direct the choice of memory encoding.

PubMed

Du, Huiyun; Deng, Wei; Aimone, James B; Ge, Minyan; Parylak, Sarah; Walch, Keenan; Zhang, Wei; Cook, Jonathan; Song, Huina; Wang, Liping; Gage, Fred H; Mu, Yangling

2016-09-13

Rewarding experiences are often well remembered, and such memory formation is known to be dependent on dopamine modulation of the neural substrates engaged in learning and memory; however, it is unknown how and where in the brain dopamine signals bias episodic memory toward preceding rather than subsequent events. Here we found that photostimulation of channelrhodopsin-2-expressing dopaminergic fibers in the dentate gyrus induced a long-term depression of cortical inputs, diminished theta oscillations, and impaired subsequent contextual learning. Computational modeling based on this dopamine modulation indicated an asymmetric association of events occurring before and after reward in memory tasks. In subsequent behavioral experiments, preexposure to a natural reward suppressed hippocampus-dependent memory formation, with an effective time window consistent with the duration of dopamine-induced changes of dentate activity. Overall, our results suggest a mechanism by which dopamine enables the hippocampus to encode memory with reduced interference from subsequent experience.

Dopaminergic inputs in the dentate gyrus direct the choice of memory encoding

PubMed Central

Du, Huiyun; Deng, Wei; Aimone, James B.; Ge, Minyan; Parylak, Sarah; Walch, Keenan; Zhang, Wei; Cook, Jonathan; Song, Huina; Wang, Liping; Gage, Fred H.; Mu, Yangling

2016-01-01

Rewarding experiences are often well remembered, and such memory formation is known to be dependent on dopamine modulation of the neural substrates engaged in learning and memory; however, it is unknown how and where in the brain dopamine signals bias episodic memory toward preceding rather than subsequent events. Here we found that photostimulation of channelrhodopsin-2–expressing dopaminergic fibers in the dentate gyrus induced a long-term depression of cortical inputs, diminished theta oscillations, and impaired subsequent contextual learning. Computational modeling based on this dopamine modulation indicated an asymmetric association of events occurring before and after reward in memory tasks. In subsequent behavioral experiments, preexposure to a natural reward suppressed hippocampus-dependent memory formation, with an effective time window consistent with the duration of dopamine-induced changes of dentate activity. Overall, our results suggest a mechanism by which dopamine enables the hippocampus to encode memory with reduced interference from subsequent experience. PMID:27573822

Reward system and addiction: what dopamine does and doesn't do.

PubMed

Di Chiara, Gaetano; Bassareo, Valentina

2007-02-01

Addictive drugs share with palatable food the property of increasing extracellular dopamine (DA), preferentially in the nucleus accumbens shell rather than in the core. However, by acting directly on the brain, drugs bypass the adaptive mechanisms (habituation) that constrain the responsiveness of accumbens shell DA to food reward, abnormally facilitating Pavlovian incentive learning and promoting the acquisition of abnormal DA-releasing properties by drug conditioned stimuli. Thus, whereas Pavlovian food conditioned stimuli release core but not shell DA, drug conditioned stimuli do the opposite, releasing shell but not core DA. This process, which results in the acquisition of excessive incentive-motivational properties by drug conditioned stimuli, initiates the drug addiction process. Neuroadaptive processes related to the chronic influence of drugs on subcortical DA might secondarily impair the function of prefronto-striatal loops, resulting in impairments in impulse control and decision making that form the basis for the compulsive feature of drug seeking and its relapsing character.

Looking for reward in all the wrong places: dopamine receptor gene polymorphisms indirectly affect aggression through sensation-seeking.

PubMed

Chester, David S; DeWall, C Nathan; Derefinko, Karen J; Estus, Steven; Lynam, Donald R; Peters, Jessica R; Jiang, Yang

2016-10-01

Individuals with genotypes that code for reduced dopaminergic brain activity often exhibit a predisposition toward aggression. However, it remains largely unknown how dopaminergic genotypes may increase aggression. Lower-functioning dopamine systems motivate individuals to seek reward from external sources such as illicit drugs and other risky experiences. Based on emerging evidence that aggression is a rewarding experience, we predicted that the effect of lower-functioning dopaminergic functioning on aggression would be mediated by tendencies to seek the environment for rewards. Caucasian female and male undergraduates (N = 277) were genotyped for five polymorphisms of the dopamine D2 receptor (DRD2) gene; they reported their previous history of aggression and their dispositional reward-seeking. Lower-functioning DRD2 profiles were associated with greater sensation-seeking, which then predicted greater aggression. Our findings suggest that lower-functioning dopaminergic activity puts individuals at risk for violence because it motivates them to experience aggression's hedonically rewarding qualities.

Morphological elucidation of basal ganglia circuits contributing reward prediction

PubMed Central

Fujiyama, Fumino; Takahashi, Susumu; Karube, Fuyuki

2015-01-01

Electrophysiological studies in monkeys have shown that dopaminergic neurons respond to the reward prediction error. In addition, striatal neurons alter their responsiveness to cortical or thalamic inputs in response to the dopamine signal, via the mechanism of dopamine-regulated synaptic plasticity. These findings have led to the hypothesis that the striatum exhibits synaptic plasticity under the influence of the reward prediction error and conduct reinforcement learning throughout the basal ganglia circuits. The reinforcement learning model is useful; however, the mechanism by which such a process emerges in the basal ganglia needs to be anatomically explained. The actor–critic model has been previously proposed and extended by the existence of role sharing within the striatum, focusing on the striosome/matrix compartments. However, this hypothesis has been difficult to confirm morphologically, partly because of the complex structure of the striosome/matrix compartments. Here, we review recent morphological studies that elucidate the input/output organization of the striatal compartments. PMID:25698913

Probabilistic reversal learning is impaired in Parkinson's disease

PubMed Central

Peterson, David A.; Elliott, Christian; Song, David D.; Makeig, Scott; Sejnowski, Terrence J.; Poizner, Howard

2009-01-01

In many everyday settings, the relationship between our choices and their potentially rewarding outcomes is probabilistic and dynamic. In addition, the difficulty of the choices can vary widely. Although a large body of theoretical and empirical evidence suggests that dopamine mediates rewarded learning, the influence of dopamine in probabilistic and dynamic rewarded learning remains unclear. We adapted a probabilistic rewarded learning task originally used to study firing rates of dopamine cells in primate substantia nigra pars compacta (Morris et al. 2006) for use as a reversal learning task with humans. We sought to investigate how the dopamine depletion in Parkinson's disease (PD) affects probabilistic reward learning and adaptation to a reversal in reward contingencies. Over the course of 256 trials subjects learned to choose the more favorable from among pairs of images with small or large differences in reward probabilities. During a subsequent otherwise identical reversal phase, the reward probability contingencies for the stimuli were reversed. Seventeen Parkinson's disease (PD) patients of mild to moderate severity were studied off of their dopaminergic medications and compared to 15 age-matched controls. Compared to controls, PD patients had distinct pre- and post-reversal deficiencies depending upon the difficulty of the choices they had to learn. The patients also exhibited compromised adaptability to the reversal. A computational model of the subjects’ trial-by-trial choices demonstrated that the adaptability was sensitive to the gain with which patients weighted pre-reversal feedback. Collectively, the results implicate the nigral dopaminergic system in learning to make choices in environments with probabilistic and dynamic reward contingencies. PMID:19628022

Dopamine reward prediction error responses reflect marginal utility.

PubMed

Stauffer, William R; Lak, Armin; Schultz, Wolfram

2014-11-03

Optimal choices require an accurate neuronal representation of economic value. In economics, utility functions are mathematical representations of subjective value that can be constructed from choices under risk. Utility usually exhibits a nonlinear relationship to physical reward value that corresponds to risk attitudes and reflects the increasing or decreasing marginal utility obtained with each additional unit of reward. Accordingly, neuronal reward responses coding utility should robustly reflect this nonlinearity. In two monkeys, we measured utility as a function of physical reward value from meaningful choices under risk (that adhered to first- and second-order stochastic dominance). The resulting nonlinear utility functions predicted the certainty equivalents for new gambles, indicating that the functions' shapes were meaningful. The monkeys were risk seeking (convex utility function) for low reward and risk avoiding (concave utility function) with higher amounts. Critically, the dopamine prediction error responses at the time of reward itself reflected the nonlinear utility functions measured at the time of choices. In particular, the reward response magnitude depended on the first derivative of the utility function and thus reflected the marginal utility. Furthermore, dopamine responses recorded outside of the task reflected the marginal utility of unpredicted reward. Accordingly, these responses were sufficient to train reinforcement learning models to predict the behaviorally defined expected utility of gambles. These data suggest a neuronal manifestation of marginal utility in dopamine neurons and indicate a common neuronal basis for fundamental explanatory constructs in animal learning theory (prediction error) and economic decision theory (marginal utility). Copyright © 2014 The Authors. Published by Elsevier Inc. All rights reserved.

Regulatory processes of hunger motivated behavior.

PubMed

Lénárd, L; Karádi, Z

2012-01-01

While food intake and body weight are under homeostatic regulation, eating is a highly motivated and reinforced behavior that induces feelings of gratification and pleasure. The chemical senses (taste and odor) and their evaluation are essential to these functions. Brainstem and limbic glucose-monitoring (GM) neurons receiving neurochemical information from the periphery and from the local brain milieu are important controlling hunger motivation, and brain gut peptides have a modulatory role on this function. The hypothalamic and limbic forebrain areas are responsible for evaluation of reward quality and related emotions. They are innervated by the mesolimbic dopaminergic system (MLDS) and majority of GM neurons are also influenced by dopamine. Via dopamine release, the MLDS plays an essential role in rewarding-reinforcing processes of feeding and addiction. The GM network and the MLDS in the limbic system represent essential elements in the neural substrate of motivation.

Peril and Pleasure: An RDoC-inspired examination of threat responses and reward processing in anxiety and depression

PubMed Central

Dillon, Daniel G.; Rosso, Isabelle M.; Pechtel, Pia; Killgore, William D. S.; Rauch, Scott L.; Pizzagalli, Diego A.

2014-01-01

As a step toward addressing limitations in the current psychiatric diagnostic system, the NIMH recently developed the Research Domain Criteria (RDoC) to stimulate integrative research—spanning self-report, behavior, neural circuitry, and molecular/genetic mechanisms—on core psychological processes implicated in mental illness. Here, we use the RDoC conceptualization to review research on threat responses, reward processing, and their interaction. The first section of the manuscript highlights the pivotal role of exaggerated threat responses—mediated by circuits connecting the frontal cortex, amygdala, and midbrain—in anxiety, and reviews data indicating that genotypic variation in the serotonin system is associated with hyperactivity in this circuitry, which elevates the risk for anxiety and mood disorders. In the second section, we describe mounting evidence linking anhedonic behavior to deficits in psychological functions that rely heavily on dopamine signaling, especially cost/benefit decision-making and reward learning. The third section covers recent studies that document negative effects of acute threats and chronic stress on reward responses in humans. The mechanisms underlying such effects are unclear, but new optogenetic data in rodents indicate that GABAergic inhibition of midbrain dopamine neurons, driven by activation of the habenula, may play a fundamental role in stress-induced anhedonia. In addition to its basic scientific value, a better understanding of interactions between the neural systems that mediate threat and reward responses may offer relief from the burdensome condition of anxious depression. PMID:24151118

Optimized in vivo detection of dopamine release using 18F-fallypride PET.

PubMed

Ceccarini, Jenny; Vrieze, Elske; Koole, Michel; Muylle, Tom; Bormans, Guy; Claes, Stephan; Van Laere, Koen

2012-10-01

The high-affinity D(2/3) PET radioligand (18)F-fallypride offers the possibility of measuring both striatal and extrastriatal dopamine release during activation paradigms. When a single (18)F-fallypride scanning protocol is used, task timing is critical to the ability to explore both striatal and extrastriatal dopamine release simultaneously. We evaluated the sensitivity and optimal timing of task administration for a single (18)F-fallypride PET protocol and the linearized simplified reference region kinetic model in detecting both striatal and extrastriatal reward-induced dopamine release, using human and simulation studies. Ten healthy volunteers underwent a single-bolus (18)F-fallypride PET protocol. A reward responsiveness learning task was initiated at 100 min after injection. PET data were analyzed using the linearized simplified reference region model, which accounts for time-dependent changes in (18)F-fallypride displacement. Voxel-based statistical maps, reflecting task-induced D(2/3) ligand displacement, and volume-of-interest-based analysis were performed to localize areas with increased ligand displacement after task initiation, thought to be proportional to changes in endogenous dopamine release (γ parameter). Simulated time-activity curves for baseline and hypothetical dopamine release functions (different peak heights of dopamine and task timings) were generated using the enhanced receptor-binding kinetic model to investigate γ as a function of these parameters. The reward task induced increased ligand displacement in extrastriatal regions of the reward circuit, including the medial orbitofrontal cortex, ventromedial prefrontal cortex, and dorsal anterior cingulate cortex. For task timing of 100 min, ligand displacement was found for the striatum only when peak height of dopamine was greater than 240 nM, whereas for frontal regions, γ was always positive for all task timings and peak heights of dopamine. Simulation results for a peak height of dopamine of 200 nM showed that an effect of striatal ligand displacement could be detected only when task timing was greater than 120 min. The prefrontal and anterior cingulate cortices are involved in reward responsiveness that can be measured using (18)F-fallypride PET in a single scanning session. To measure both striatal and extrastriatal dopamine release, the height of dopamine released and task timing need to be considered in designing activation studies depending on regional D(2/3) density.

Ventral striatal prediction error signaling is associated with dopamine synthesis capacity and fluid intelligence

PubMed Central

Schlagenhauf, Florian; Rapp, Michael A.; Huys, Quentin J. M.; Beck, Anne; Wüstenberg, Torsten; Deserno, Lorenz; Buchholz, Hans-Georg; Kalbitzer, Jan; Buchert, Ralph; Kienast, Thorsten; Cumming, Paul; Plotkin, Michail; Kumakura, Yoshitaka; Grace, Anthony A.; Dolan, Raymond J.; Heinz, Andreas

2013-01-01

Fluid intelligence represents the capacity for flexible problem solving and rapid behavioral adaptation. Rewards drive flexible behavioral adaptation, in part via a teaching signal expressed as reward prediction errors in the ventral striatum, which has been associated with phasic dopamine release in animal studies. We examined a sample of 28 healthy male adults using multimodal imaging and biological parametric mapping with 1) functional magnetic resonance imaging during a reversal learning task and 2) in a subsample of 17 subjects also with positron emission tomography using 6-[18F]fluoro-L-DOPA to assess dopamine synthesis capacity. Fluid intelligence was measured using a battery of nine standard neuropsychological tests. Ventral striatal BOLD correlates of reward prediction errors were positively correlated with fluid intelligence and, in the right ventral striatum, also inversely correlated with dopamine synthesis capacity (FDOPA Kinapp). When exploring aspects of fluid intelligence, we observed that prediction error signaling correlates with complex attention and reasoning. These findings indicate that individual differences in the capacity for flexible problem solving may be driven by ventral striatal activation during reward-related learning, which in turn proved to be inversely associated with ventral striatal dopamine synthesis capacity. PMID:22344813

A Shared Molecular and Genetic Basis for Food and Drug Addiction: Overcoming Hypodopaminergic Trait/State by Incorporating Dopamine Agonistic Therapy in Psychiatry.

PubMed

Gold, Mark S; Badgaiyan, Rajendra D; Blum, Kenneth

2015-09-01

This article focuses on the shared molecular and neurogenetics of food and drug addiction tied to the understanding of reward deficiency syndrome. Reward deficiency syndrome describes a hypodopaminergic trait/state that provides a rationale for commonality in approaches for treating long-term reduced dopamine function across the reward brain regions. The identification of the role of DNA polymorphic associations with reward circuitry has resulted in new understanding of all addictive behaviors. Copyright © 2015 Elsevier Inc. All rights reserved.

Rewarding and aversive effects of nicotine are segregated within the nucleus accumbens.

PubMed

Sellings, Laurie H L; Baharnouri, Golriz; McQuade, Lindsey E; Clarke, Paul B S

2008-07-01

Forebrain dopamine plays a critical role in motivated behavior. According to the classic view, mesolimbic dopamine selectively guides behavior motivated by positive reinforcers. However, this has been challenged in favor of a wider role encompassing aversively motivated behavior. This controversy is particularly striking in the case of nicotine, with opposing claims that either the rewarding or the aversive effect of nicotine is critically dependent on mesolimbic dopamine transmission. In the present study, the effects of 6-hydroxydopamine lesions of nucleus accumbens core vs. medial shell on intravenous nicotine conditioned place preference and conditioned taste aversion were examined in male adult rats. Dopaminergic denervation in accumbens medial shell was associated with decreased nicotine conditioned place preference. Conversely, denervation in accumbens core was associated with an increase in conditioned place preference. In addition, dopaminergic denervation of accumbens core but not medial shell abolished conditioned taste aversion for nicotine. We conclude that nucleus accumbens core and medial shell dopaminergic innervation exert segregated effects on rewarding and aversive effects of nicotine. More generally, our findings indicate that dopaminergic transmission may mediate or enable opposing motivational processes within functionally distinct domains of the accumbens.

AMPA/Kainate, NMDA, and Dopamine D1 Receptor Function in the Nucleus Accumbens Core: A Context-Limited Role in the Encoding and Consolidation of Instrumental Memory

ERIC Educational Resources Information Center

Hernandez, Pepe J.; Andrzejewski, Matthew E.; Sadeghian, Kenneth; Panksepp, Jules B.; Kelley, Ann E.

2005-01-01

Neural integration of glutamate- and dopamine-coded signals within the nucleus accumbens (NAc) is a fundamental process governing cellular plasticity underlying reward-related learning. Intra-NAc core blockade of NMDA or D1 receptors in rats impairs instrumental learning (lever-pressing for sugar pellets), but it is not known during which phase of…

Knockout crickets for the study of learning and memory: Dopamine receptor Dop1 mediates aversive but not appetitive reinforcement in crickets.

PubMed

Awata, Hiroko; Watanabe, Takahito; Hamanaka, Yoshitaka; Mito, Taro; Noji, Sumihare; Mizunami, Makoto

2015-11-02

Elucidation of reinforcement mechanisms in associative learning is an important subject in neuroscience. In mammals, dopamine neurons are thought to play critical roles in mediating both appetitive and aversive reinforcement. Our pharmacological studies suggested that octopamine and dopamine neurons mediate reward and punishment, respectively, in crickets, but recent studies in fruit-flies concluded that dopamine neurons mediates both reward and punishment, via the type 1 dopamine receptor Dop1. To resolve the discrepancy between studies in different insect species, we produced Dop1 knockout crickets using the CRISPR/Cas9 system and found that they are defective in aversive learning with sodium chloride punishment but not appetitive learning with water or sucrose reward. The results suggest that dopamine and octopamine neurons mediate aversive and appetitive reinforcement, respectively, in crickets. We suggest unexpected diversity in neurotransmitters mediating appetitive reinforcement between crickets and fruit-flies, although the neurotransmitter mediating aversive reinforcement is conserved. This study demonstrates usefulness of the CRISPR/Cas9 system for producing knockout animals for the study of learning and memory.

FNDC5/irisin, a molecular target for boosting reward-related learning and motivation.

PubMed

Zsuga, Judit; Tajti, Gabor; Papp, Csaba; Juhasz, Bela; Gesztelyi, Rudolf

2016-05-01

Interventions focusing on the prevention and treatment of chronic non-communicable diseases are on rise. In the current article, we propose that dysfunction of the mesocortico-limbic reward system contributes to the emergence of the WHO-identified risk behaviors (tobacco use, unhealthy diet, physical inactivity and harmful use of alcohol), behaviors that underlie the evolution of major non-communicable diseases (e.g. cardiovascular diseases, cancer, diabetes and chronic respiratory diseases). Given that dopaminergic neurons of the mesocortico-limbic system are tightly associated with reward-related processes and motivation, their dysfunction may fundamentally influence behavior. While nicotine and alcohol alter dopamine neuron function by influencing some receptors, mesocortico-limbic system dysfunction was associated with elevation of metabolic set-point leading to hedonic over-eating. Although there is some empirical evidence, precise molecular mechanism for linking physical inactivity and mesocortico-limbic dysfunction per se seems to be missing; identification of which may contribute to higher success rates for interventions targeting lifestyle changes pertaining to physical activity. In the current article, we compile evidence in support of a link between exercise and the mesocortico-limbic system by elucidating interactions on the axis of muscle - irisin - brain derived neurotrophic factor (BDNF) - and dopaminergic function of the midbrain. Irisin is a contraction-regulated myokine formed primarily in skeletal muscle but also in the brain. Irisin stirred considerable interest, when its ability to induce browning of white adipose tissue parallel to increasing thermogenesis was discovered. Furthermore, it may also play a role in the regulation of behavior given it readily enters the central nervous system, where it induces BDNF expression in several brain areas linked to reward processing, e.g. the ventral tegmental area and the hippocampus. BDNF is a neurotropic factor that increases neuronal dopamine content, modulates dopamine release relevant for neuronal plasticity and increased neuronal survival as well as learning and memory. Further linking BDNF to dopaminergic function is BDNF's ability to activate tropomyosin-related kinase B receptor that shares signalization with presynaptic dopamine-3 receptors in the ventral tegmental area. Summarizing, we propose that the skeletal muscle derived irisin may be the link between physical activity and reward-related processes and motivation. Moreover alteration of this axis may contribute to sedentary lifestyle and subsequent non-communicable diseases. Preclinical and clinical experimental models to test this hypothesis are also proposed. Copyright © 2016 Elsevier Ltd. All rights reserved.

Individual differences in the propensity to approach signals vs goals promote different adaptations in the dopamine system of rats.

PubMed

Flagel, Shelly B; Watson, Stanley J; Robinson, Terry E; Akil, Huda

2007-04-01

The way an individual responds to cues associated with rewards may be a key determinant of vulnerability to compulsive behavioral disorders. We studied individual differences in Pavlovian conditioned approach behavior and examined the expression of neurobiological markers associated with the dopaminergic system, the same neural system implicated in incentive motivational processes. Pavlovian autoshaping procedures consisted of the brief presentation of an illuminated retractable lever (conditioned stimulus) followed by the response-independent delivery of a food pellet (unconditioned stimulus), which lead to a Pavlovian conditioned response. In situ hybridization was performed on brains obtained either following the first or last (fifth) day of training. Two phenotypes emerged. Sign-trackers (ST) exhibited behavior that seemed to be largely controlled by the cue that signaled impending reward delivery; whereas goal-trackers (GT) preferentially approached the location where the reward was delivered. Following a single training session, ST showed greater expression of dopamine D1 receptor mRNA relative to GT. After 5 days of training, GT exhibited greater expression levels of tyrosine hydroxylase, dopamine transporter, and dopamine D2 receptor mRNA relative to ST. These findings suggest that the development of approach behavior towards signals vs goal leads to distinct adaptations in the dopamine system. The sign-tracker vs goal-tracker phenotype may prove to be a valuable animal model to investigate individual differences in the way incentive salience is attributed to environmental stimuli, which may contribute to the development of addiction and other compulsive behavioral disorders.

Cocaine Drives Aversive Conditioning via Delayed Activation of Dopamine-Responsive Habenular and Midbrain Pathways

PubMed Central

Good, Cameron H.; Rowley, Courtney S.; Xu, Sheng-ping; Wang, Huikun; Burnham, Nathan W.; Hoffman, Alexander F.; Lupica, Carl R.; Ikemoto, Satoshi

2013-01-01

Many strong rewards, including abused drugs, also produce aversive effects that are poorly understood. For example, cocaine can produce aversive conditioning after its rewarding effects have dissipated, consistent with opponent process theory, but the neural mechanisms involved are not well known. Using electrophysiological recordings in awake rats, we found that some neurons in the lateral habenula (LHb), where activation produces aversive conditioning, exhibited biphasic responses to single doses of intravenous cocaine, with an initial inhibition followed by delayed excitation paralleling cocaine's shift from rewarding to aversive. Recordings in LHb slice preparations revealed similar cocaine-induced biphasic responses and further demonstrated that biphasic responses were mimicked by dopamine, that the inhibitory phase depended on dopamine D2-like receptors, and that the delayed excitation persisted after drug washout for prolonged durations consistent with findings in vivo. c-Fos experiments further showed that cocaine-activated LHb neurons preferentially projected to and activated neurons in the rostromedial tegmental nucleus (RMTg), a recently identified target of LHb axons that is activated by negative motivational stimuli and inhibits dopamine neurons. Finally, pharmacological excitation of the RMTg produced conditioned place aversion, whereas cocaine-induced avoidance behaviors in a runway operant paradigm were abolished by lesions of LHb efferents, lesions of the RMTg, or by optogenetic inactivation of the RMTg selectively during the period when LHb neurons are activated by cocaine. Together, these results indicate that LHb/RMTg pathways contribute critically to cocaine-induced avoidance behaviors, while also participating in reciprocally inhibitory interactions with dopamine neurons. PMID:23616555

DOE Office of Scientific and Technical Information (OSTI.GOV)

Volkow N. D.; Wang G.; Volkow, N.D.

The ability to resist the urge to eat requires the proper functioning of neuronal circuits involved in top-down control to oppose the conditioned responses that predict reward from eating the food and the desire to eat the food. Imaging studies show that obese subjects might have impairments in dopaminergic pathways that regulate neuronal systems associated with reward sensitivity, conditioning and control. It is known that the neuropeptides that regulate energy balance (homeostatic processes) through the hypothalamus also modulate the activity of dopamine cells and their projections into regions involved in the rewarding processes underlying food intake. It is postulated thatmore » this could also be a mechanism by which overeating and the resultant resistance to homoeostatic signals impairs the function of circuits involved in reward sensitivity, conditioning and cognitive control.« less

Dopaminergic inputs in the dentate gyrus direct the choice of memory encoding

DOE PAGES

Du, Huiyun; Deng, Wei; Aimone, James B.; ...

2016-09-13

Rewarding experiences are often well remembered, and such memory formation is known to be dependent on dopamine modulation of the neural substrates engaged in learning and memory; however, it is unknown how and where in the brain dopamine signals bias episodic memory toward preceding rather than subsequent events. Here we found that photostimulation of channelrhodopsin-2–expressing dopaminergic fibers in the dentate gyrus induced a long-term depression of cortical inputs, diminished theta oscillations, and impaired subsequent contextual learning. Computational modeling based on this dopamine modulation indicated an asymmetric association of events occurring before and after reward in memory tasks. In subsequent behavioralmore » experiments, preexposure to a natural reward suppressed hippocampus-dependent memory formation, with an effective time window consistent with the duration of dopamine-induced changes of dentate activity. Altogether, our results suggest a mechanism by which dopamine enables the hippocampus to encode memory with reduced interference from subsequent experience.« less

Dopaminergic inputs in the dentate gyrus direct the choice of memory encoding

DOE Office of Scientific and Technical Information (OSTI.GOV)

Du, Huiyun; Deng, Wei; Aimone, James B.

Rewarding experiences are often well remembered, and such memory formation is known to be dependent on dopamine modulation of the neural substrates engaged in learning and memory; however, it is unknown how and where in the brain dopamine signals bias episodic memory toward preceding rather than subsequent events. Here we found that photostimulation of channelrhodopsin-2–expressing dopaminergic fibers in the dentate gyrus induced a long-term depression of cortical inputs, diminished theta oscillations, and impaired subsequent contextual learning. Computational modeling based on this dopamine modulation indicated an asymmetric association of events occurring before and after reward in memory tasks. In subsequent behavioralmore » experiments, preexposure to a natural reward suppressed hippocampus-dependent memory formation, with an effective time window consistent with the duration of dopamine-induced changes of dentate activity. Altogether, our results suggest a mechanism by which dopamine enables the hippocampus to encode memory with reduced interference from subsequent experience.« less

Differential Dopamine Release Dynamics in the Nucleus Accumbens Core and Shell Reveal Complementary Signals for Error Prediction and Incentive Motivation

PubMed Central

Cacciapaglia, Fabio; Wightman, R. Mark; Carelli, Regina M.

2015-01-01

Mesolimbic dopamine (DA) is phasically released during appetitive behaviors, though there is substantive disagreement about the specific purpose of these DA signals. For example, prediction error (PE) models suggest a role of learning, while incentive salience (IS) models argue that the DA signal imbues stimuli with value and thereby stimulates motivated behavior. However, within the nucleus accumbens (NAc) patterns of DA release can strikingly differ between subregions, and as such, it is possible that these patterns differentially contribute to aspects of PE and IS. To assess this, we measured DA release in subregions of the NAc during a behavioral task that spatiotemporally separated sequential goal-directed stimuli. Electrochemical methods were used to measure subsecond NAc dopamine release in the core and shell during a well learned instrumental chain schedule in which rats were trained to press one lever (seeking; SL) to gain access to a second lever (taking; TL) linked with food delivery, and again during extinction. In the core, phasic DA release was greatest following initial SL presentation, but minimal for the subsequent TL and reward events. In contrast, phasic shell DA showed robust release at all task events. Signaling decreased between the beginning and end of sessions in the shell, but not core. During extinction, peak DA release in the core showed a graded decrease for the SL and pauses in release during omitted expected rewards, whereas shell DA release decreased predominantly during the TL. These release dynamics suggest parallel DA signals capable of supporting distinct theories of appetitive behavior. SIGNIFICANCE STATEMENT Dopamine signaling in the brain is important for a variety of cognitive functions, such as learning and motivation. Typically, it is assumed that a single dopamine signal is sufficient to support these cognitive functions, though competing theories disagree on how dopamine contributes to reward-based behaviors. Here, we have found that real-time dopamine release within the nucleus accumbens (a primary target of midbrain dopamine neurons) strikingly varies between core and shell subregions. In the core, dopamine dynamics are consistent with learning-based theories (such as reward prediction error) whereas in the shell, dopamine is consistent with motivation-based theories (e.g., incentive salience). These findings demonstrate that dopamine plays multiple and complementary roles based on discrete circuits that help animals optimize rewarding behaviors. PMID:26290234

Prior Haloperidol, but not Olanzapine, Exposure Augments the Pursuit of Reward Cues: Implications for Substance Abuse in Schizophrenia

PubMed Central

Samaha, Anne-Noël

2013-01-01

Drug abuse and addiction are excessively common in schizophrenia. Chronic antipsychotic treatment might contribute to this comorbidity by inducing supersensitivity within the brain’s dopamine system. Dopamine supersensitivity can enhance the incentive motivational properties of reward cues, and reward cues contribute to the maintenance and severity of drug addiction. We have shown previously that rats withdrawn from continuous haloperidol (HAL) treatment (via subcutaneous minipump) develop dopamine supersensitivity and pursue reward cues more vigorously than HAL-naive rats following an amphetamine (AMPH) challenge. Atypical antipsychotic drugs are thought to be less likely than typicals to produce dopamine supersensitivity. Thus, we compared the effects of HAL and the atypical antipsychotic olanzapine (OLZ) on the pursuit of reward cues. Rats were trained to associate a light-tone cue with water then treated with HAL or OLZ. Following antipsychotic withdrawal, we assessed AMPH-induced enhancement of lever pressing for the cue. Withdrawal from HAL, but not from OLZ, enhanced this effect. HAL, but not OLZ, also enhanced AMPH-induced psychomotor activation and c-fos mRNA expression in the caudate-putamen. Thus, prior HAL, but not OLZ, enhanced conditioned reward following an AMPH challenge, and this was potentially linked to enhanced behavioral sensitivity to AMPH and AMPH-induced engagement of the caudate-putamen. These findings suggest that HAL, but not an atypical like OLZ, modifies reward circuitry in ways that increase responsiveness to reward cues. Because enhanced responsiveness to reward cues can promote drug-seeking behavior, it should be investigated whether atypical antipsychotics might be a preferential option in schizophrenic patients at risk for drug abuse or addiction. PMID:22927669

Spontaneous Eye-Blink Rate as an Index of Reward Responsivity: Validation and Links to Bipolar Disorder

PubMed Central

Peckham, Andrew D.; Johnson, Sheri L.

2015-01-01

Extensive research supports the role of striatal dopamine in pursuing and responding to reward, and that eye-blink rate is a valid indicator of striatal dopamine. This study tested whether phasic changes in blink rate could provide an index of reward pursuit. This hypothesis was tested in people with bipolar I disorder (BD; a population with aberrations in reward responsivity), and in those without BD. Thirty-one adults with BD and 28 control participants completed a laboratory task involving effort towards monetary reward. Blink rate was recorded using eye-tracking at baseline, reward anticipation, and post-reward. Those in the BD group completed self-report measures relating to reward and ambition. Results showed that across all participants, blink rates increased from reward anticipation to post-reward. In the BD group, reward-relevant measures were strongly correlated with variation in blink rate. These findings provide validation for phasic changes in blink rate as an index of reward response. PMID:27274949

Dopamine and reward: comment on Hernandez et al. (2006).

PubMed

Gallistel, C R

2006-08-01

Many lines of evidence suggest that the dopaminergic projection from the midbrain tegmentum to the forebrain must play a critical role in mediating the behavioral effects of natural and artificial rewards, with brain stimulation reward and addictive drugs included in the latter category. However, a closer look reveals many incongruities. The work of G. Hernandez et al. (2006) resolves several puzzles. It implies that the dopaminergic projection does not carry the signal that encodes the magnitude of a brain stimulation reward. It suggests that the elevation in the tonic levels of dopamine consequent on brain stimulation reward modulates the registration of the magnitude of the reward. This reconciles the psychophysical evidence with the pharmacological, electrophysiological, and anatomical evidence. However, some serious puzzles do remain.

Dopamine homeostasis: brain functional connectivity in reward deficiency syndrome.

PubMed

Febo, Marcelo; Blum, Kenneth; Badgaiyan, Rajendra D; Baron, David; Thanos, Panayotis K; Colon-Perez, Luis M; Demortrovics, Zsolt; Gold, Mark S

2017-01-01

Reward deficiency syndrome (RDS) was first proposed by Kenneth Blum in 1995 to provide a clinically relevant and predictive term for conditions involving deficits in mesocorticolimbic dopamine function. Genetic, molecular, and neuronal alterations in key components of this circuitry contribute to a reward deficit state that can drive drug-seeking, consumption, and relapse. Among the dysfunctions observed in RDS are dysregulated resting state networks, which recently have been assessed in detail in chronic drug users by, positron emission tomography, functional magnetic resonance imaging, and functional connectivity analysis. A growing number of studies are helping to determine the putative roles of dopamine and glutamatergic neurotransmission in the regulation of activity in resting state networks, particularly in brain reward circuitry affected in drug use disorders. Indeed, we hypothesize in the present review that loss of homeostasis of these systems may lead to 'unbalanced' functional networks that might be both cause and outcome of disrupted synaptic communication between cortical and subcortical systems essential for controlling reward, emotional control, sensation seeking, and chronic drug use.

D1- and D2-like dopamine receptors in the CA1 region of the hippocampus are involved in the acquisition and reinstatement of morphine-induced conditioned place preference.

PubMed

Assar, Nasim; Mahmoudi, Dorna; Farhoudian, Ali; Farhadi, Mohammad Hasan; Fatahi, Zahra; Haghparast, Abbas

2016-10-01

The hippocampus plays a vital role in processing contextual memories and reward related learning tasks, such as conditioned place preference (CPP). Among the neurotransmitters in the hippocampus, dopamine is deeply involved in reward-related processes. This study assessed the role of D1- and D2-like dopamine receptors within the CA1 region of the hippocampus in the acquisition and reinstatement of morphine-CPP. To investigate the role of D1 and D2 receptors in morphine acquisition, the animals received different doses of D1- and/or D2-like dopamine receptor antagonists (SCH23390 and sulpiride, respectively) into the CA1, 5min before the administration of morphine (5mg/kg, subcutaneously) during a 3-days conditioning phase. To evaluate the involvement of these receptors in morphine reinstatement, the animals received different doses of SCH23390 or sulpiride (after extinction period) 5min before the administration of a low dose of morphine (1mg/kg) in order to reinstate the extinguished morphine-CPP. Conditioning scores were recorded by Ethovision software. The results of this study showed that the administration of SCH23390 or sulpiride, significantly decreased the acquisition of morphine-CPP. Besides, the injection of these antagonists before the administration of a priming dose of morphine, following the extinction period, decreased the reinstatement of morphine-CPP in sacrificed rats. However, the effect of sulpiride on the acquisition and reinstatement of morphine-CPP was more significant than that of SCH23390. These findings suggested that D1- and D2-like dopamine receptors in the CA1 are involved in the acquisition and reinstatement of morphine-CPP, and antagonism of these receptors can reduce the rewarding properties of morphine. Copyright © 2016 Elsevier B.V. All rights reserved.

The Behavioral Pharmacology of Effort-Related Choice Behavior: Dopamine, Adenosine and beyond

ERIC Educational Resources Information Center

Salamone, John D.; Correa, Merce; Nunes, Eric J.; Randall, Patrick A.; Pardo, Marta

2012-01-01

For many years, it has been suggested that drugs that interfere with dopamine (DA) transmission alter the "rewarding" impact of primary reinforcers such as food. Research and theory related to the functions of mesolimbic DA are undergoing a substantial conceptual restructuring, with the traditional emphasis on hedonia and primary reward yielding…

Striatal dopaminergic reward response relates to age of first drunkenness and feedback response in at-risk youth.

PubMed

Weiland, Barbara J; Zucker, Robert A; Zubieta, Jon-Kar; Heitzeg, Mary M

2017-03-01

Dopamine receptor concentrations, primarily in the striatum, are hypothesized to contribute to a developmental imbalance between subcortical and prefrontal control systems in emerging adulthood potentially biasing motivation and increasing risky behaviors. Positron emission tomography studies have found significant reductions in striatal dopamine D2 receptors, and blunted amphetamine-induced dopamine release, in substance users compared with healthy controls. Extant literature is limited and inconsistent concerning vulnerability associated with having a family history of substance abuse (FH+). Some studies have reported familial liability associated with higher dopamine receptor levels, reduced dopamine response to stimulant challenges and decreased response to oral alcohol. However, other reports have failed to find group differences based on family history. We explored the interaction of familial liability and behavioral risk with multi-modal molecular and neural imaging of the dopaminergic system. Forty-four young adult male subjects performed monetary incentive delay tasks during both [ 11 C]raclopride positron emission tomography and functional magnetic resonance imaging scans. FH+ subjects were identified as low (n = 24) or high risk (n = 9) based on early initiation of drunkenness. FH+ high-risk subjects exhibited heightened striatal dopamine response to monetary reward but did not differ in neural activations compared with FH+ low risk subjects and controls with no familial loading (n = 11). Across all subjects, a negative relationship was found between dopamine release and age of first drunkenness and a positive relationship with neural response to reward receipt. These results suggest that in at-risk individuals, higher dopamine transmission associated with monetary reward may represent a particularly useful neurobiological phenotype. © 2016 Society for the Study of Addiction.

Identification of a dopamine receptor-mediated opiate reward memory switch in the basolateral amygdala-nucleus accumbens circuit.

PubMed

Lintas, Alessandra; Chi, Ning; Lauzon, Nicole M; Bishop, Stephanie F; Gholizadeh, Shervin; Sun, Ninglei; Tan, Huibing; Laviolette, Steven R

2011-08-03

The basolateral amygdala (BLA), ventral tegmental area (VTA), and nucleus accumbens (NAc) play central roles in the processing of opiate-related associative reward learning and memory. The BLA receives innervation from dopaminergic fibers originating in the VTA, and both dopamine (DA) D1 and D2 receptors are expressed in this region. Using a combination of in vivo single-unit extracellular recording in the NAc combined with behavioral pharmacology studies, we have identified a double dissociation in the functional roles of DA D1 versus D2 receptor transmission in the BLA, which depends on opiate exposure state; thus, in previously opiate-naive rats, blockade of intra-BLA D1, but not D2, receptor transmission blocked the acquisition of associative opiate reward memory, measured in an unbiased conditioned place preference procedure. In direct contrast, in rats made opiate dependent and conditioned in a state of withdrawal, intra-BLA D2, but not D1, receptor blockade blocked opiate reward encoding. This functional switch was dependent on cAMP signaling as comodulation of intra-BLA cAMP levels reversed or replicated the functional effects of intra-BLA D1 or D2 transmission during opiate reward processing. Single-unit in vivo extracellular recordings performed in neurons of the NAc confirmed an opiate-state-dependent role for BLA D1/D2 transmission in NAc neuronal response patterns to morphine. Our results characterize and identify a novel opiate addiction switching mechanism directly in the BLA that can control the processing of opiate reward information as a direct function of opiate exposure state via D1 or D2 receptor signaling substrates.

Nicotine, alcohol and cocaine coupling to reward processes via endogenous morphine signaling: the dopamine-morphine hypothesis.

PubMed

Stefano, George B; Bianchi, Enrica; Guarna, Massimo; Fricchione, Gregory L; Zhu, Wei; Cadet, Patrick; Mantione, Kirk J; Casares, Federico M; Kream, Richard M; Esch, Tobias

2007-06-01

Pleasure is described as a state or feeling of happiness and satisfaction resulting from an experience that one enjoys. We examine the neurobiological factors underlying reward processes and pleasure phenomena. With regard to possible negative effects of pleasure, we focus on addiction and motivational toxicity. Pleasure can serve cognition, productivity and health, but simultaneously promotes addiction and other negative behaviors. It is a complex neurobiological phenomenon, relying on reward circuitry or limbic activity. These processes involve dopaminergic signaling. Moreover, nicotine, cocaine and alcohol appear to exert their pleasure providing action via endogenous morphinergic mechanisms. Natural rewarding activities are necessary for survival and appetitive motivation, usually governing beneficial biological behaviors like eating, sex and reproduction. Social contacts can further facilitate the positive effects exerted by pleasurable experiences. However, artificial stimulants can be detrimental, since flexibility and normal control of behavior are deteriorated. Additionally, addictive drugs are capable of directly acting on reward pathways, now, in part, via endogenous morphine processes.

Dopamine and reward: the anhedonia hypothesis 30 years on.

PubMed

Wise, Roy A

2008-10-01

The anhedonia hypothesis--that brain dopamine plays a critical role in the subjective pleasure associated with positive rewards--was intended to draw the attention of psychiatrists to the growing evidence that dopamine plays a critical role in the objective reinforcement and incentive motivation associated with food and water, brain stimulation reward, and psychomotor stimulant and opiate reward. The hypothesis called to attention the apparent paradox that neuroleptics, drugs used to treat a condition involving anhedonia (schizophrenia), attenuated in laboratory animals the positive reinforcement that we normally associate with pleasure. The hypothesis held only brief interest for psychiatrists, who pointed out that the animal studies reflected acute actions of neuroleptics whereas the treatment of schizophrenia appears to result from neuroadaptations to chronic neuroleptic administration, and that it is the positive symptoms of schizophrenia that neuroleptics alleviate, rather than the negative symptoms that include anhedonia. Perhaps for these reasons, the hypothesis has had minimal impact in the psychiatric literature. Despite its limited heuristic value for the understanding of schizophrenia, however, the anhedonia hypothesis has had major impact on biological theories of reinforcement, motivation, and addiction. Brain dopamine plays a very important role in reinforcement of response habits, conditioned preferences, and synaptic plasticity in cellular models of learning and memory. The notion that dopamine plays a dominant role in reinforcement is fundamental to the psychomotor stimulant theory of addiction, to most neuroadaptation theories of addiction, and to current theories of conditioned reinforcement and reward prediction. Properly understood, it is also fundamental to recent theories of incentive motivation.

Glucocorticoid receptor gene inactivation in dopamine-innervated areas selectively decreases behavioral responses to amphetamine

PubMed Central

Parnaudeau, Sébastien; Dongelmans, Marie-louise; Turiault, Marc; Ambroggi, Frédéric; Delbes, Anne-Sophie; Cansell, Céline; Luquet, Serge; Piazza, Pier-Vincenzo; Tronche, François; Barik, Jacques

2014-01-01

The meso-cortico-limbic system, via dopamine release, encodes the rewarding and reinforcing properties of natural rewards. It is also activated in response to abused substances and is believed to support drug-related behaviors. Dysfunctions of this system lead to several psychiatric conditions including feeding disorders and drug addiction. These disorders are also largely influenced by environmental factors and in particular stress exposure. Stressors activate the corticotrope axis ultimately leading to glucocorticoid hormone (GCs) release. GCs bind the glucocorticoid receptor (GR) a transcription factor ubiquitously expressed including within the meso-cortico-limbic tract. While GR within dopamine-innervated areas drives cocaine's behavioral responses, its implication in responses to other psychostimulants such as amphetamine has never been clearly established. Moreover, while extensive work has been made to uncover the role of this receptor in addicted behaviors, its contribution to the rewarding and reinforcing properties of food has yet to be investigated. Using mouse models carrying GR gene inactivation in either dopamine neurons or in dopamine-innervated areas, we found that GR in dopamine responsive neurons is essential to properly build amphetamine-induced conditioned place preference and locomotor sensitization. c-Fos quantification in the nucleus accumbens further confirmed defective neuronal activation following amphetamine injection. These diminished neuronal and behavioral responses to amphetamine may involve alterations in glutamate transmission as suggested by the decreased MK801-elicited hyperlocomotion and by the hyporeactivity to glutamate of a subpopulation of medium spiny neurons. In contrast, GR inactivation did not affect rewarding and reinforcing properties of food suggesting that responding for natural reward under basal conditions is preserved in these mice. PMID:24574986

Adolescent Maturational Transitions in the Prefrontal Cortex and Dopamine Signaling as a Risk Factor for the Development of Obesity and High Fat/High Sugar Diet Induced Cognitive Deficits

PubMed Central

Reichelt, Amy C.

2016-01-01

Adolescence poses as both a transitional period in neurodevelopment and lifestyle practices. In particular, the developmental trajectory of the prefrontal cortex (PFC), a critical region for behavioral control and self-regulation, is enduring, not reaching functional maturity until the early 20 s in humans. Furthermore, the neurotransmitter dopamine is particularly abundant during adolescence, tuning the brain to rapidly learn about rewards and regulating aspects of neuroplasticity. Thus, adolescence is proposed to represent a period of vulnerability towards reward-driven behaviors such as the consumption of palatable high fat and high sugar diets. This is reflected in the increasing prevalence of obesity in children and adolescents as they are the greatest consumers of “junk foods”. Excessive consumption of diets laden in saturated fat and refined sugars not only leads to weight gain and the development of obesity, but experimental studies with rodents indicate they evoke cognitive deficits in learning and memory process by disrupting neuroplasticity and altering reward processing neurocircuitry. Consumption of these high fat and high sugar diets have been reported to have a particularly pronounced impact on cognition when consumed during adolescence, demonstrating a susceptibility of the adolescent brain to enduring cognitive deficits. The adolescent brain, with heightened reward sensitivity and diminished behavioral control compared to the mature adult brain, appears to be a risk for aberrant eating behaviors that may underpin the development of obesity. This review explores the neurodevelopmental changes in the PFC and mesocortical dopamine signaling that occur during adolescence, and how these potentially underpin the overconsumption of palatable food and development of obesogenic diet-induced cognitive deficits. PMID:27790098

A Tribute to Charlie Chaplin: Induced Positive Affect Improves Reward-Based Decision-Learning in Parkinson’s Disease

PubMed Central

Ridderinkhof, K. Richard; van Wouwe, Nelleke C.; Band, Guido P. H.; Wylie, Scott A.; Van der Stigchel, Stefan; van Hees, Pieter; Buitenweg, Jessika; van de Vijver, Irene; van den Wildenberg, Wery P. M.

2012-01-01

Reward-based decision-learning refers to the process of learning to select those actions that lead to rewards while avoiding actions that lead to punishments. This process, known to rely on dopaminergic activity in striatal brain regions, is compromised in Parkinson’s disease (PD). We hypothesized that such decision-learning deficits are alleviated by induced positive affect, which is thought to incur transient boosts in midbrain and striatal dopaminergic activity. Computational measures of probabilistic reward-based decision-learning were determined for 51 patients diagnosed with PD. Previous work has shown these measures to rely on the nucleus caudatus (outcome evaluation during the early phases of learning) and the putamen (reward prediction during later phases of learning). We observed that induced positive affect facilitated learning, through its effects on reward prediction rather than outcome evaluation. Viewing a few minutes of comedy clips served to remedy dopamine-related problems associated with frontostriatal circuitry and, consequently, learning to predict which actions will yield reward. PMID:22707944

A Role for the Lateral Dorsal Tegmentum in Memory and Decision Neural Circuitry

PubMed Central

Redila, Van; Kinzel, Chantelle; Jo, Yong Sang; Puryear, Corey B.; Mizumori, Sheri J.Y.

2017-01-01

A role for the hippocampus in memory is clear, although the mechanism for its contribution remains a matter of debate. Converging evidence suggests that hippocampus evaluates the extent to which context-defining features of events occur as expected. The consequence of mismatches, or prediction error, signals from hippocampus is discussed in terms of its impact on neural circuitry that evaluates the significance of prediction errors: Ventral tegmental area (VTA) dopamine cells burst fire to rewards or cues that predict rewards (Schultz et al., 1997). Although the lateral dorsal tegmentum (LDTg) importantly controls dopamine cell burst firing (Lodge & Grace, 2006) the behavioral significance of the LDTg control is not known. Therefore, we evaluated LDTg functional activity as rats performed a spatial memory task that generates task-dependent reward codes in VTA (Jo et al., 2013; Puryear et al., 2010) and another VTA afferent, the pedunculopontine nucleus (PPTg, Norton et al., 2011). Reversible inactivation of the LDTg significantly impaired choice accuracy. LDTg neurons coded primarily egocentric information in the form of movement velocity, turning behaviors, and behaviors leading up to expected reward locations. A subset of the velocity-tuned LDTg cells also showed high frequency bursts shortly before or after reward encounters, after which they showed tonic elevated firing during consumption of small, but not large, rewards. Cells that fired before reward encounters showed stronger correlations with velocity as rats moved toward, rather than away from, rewarded sites. LDTg neural activity was more strongly regulated by egocentric behaviors than that observed for PPTg or VTA cells that were recorded by Puryear et al. and Norton et al. While PPTg activity was uniquely sensitive to ongoing sensory input, all three regions encoded reward magnitude (although in different ways), reward expectation, and reward encounters. Only VTA encoded reward prediction errors. LDTg may inform VTA about learned goal-directed movement that reflects the current motivational state, and this in turn may guide VTA determination of expected subjective goal values. When combined it is clear the LDTg and PPTg provide only a portion of the information that dopamine cells need to assess the value of prediction errors, a process that is essential to future adaptive decisions and switches of cognitive (i.e. memorial) strategies and behavioral responses. PMID:24910282

Regulation of monoamine oxidase A by circadian-clock components implies clock influence on mood.

PubMed

Hampp, Gabriele; Ripperger, Jürgen A; Houben, Thijs; Schmutz, Isabelle; Blex, Christian; Perreau-Lenz, Stéphanie; Brunk, Irene; Spanagel, Rainer; Ahnert-Hilger, Gudrun; Meijer, Johanna H; Albrecht, Urs

2008-05-06

The circadian clock has been implicated in addiction and several forms of depression [1, 2], indicating interactions between the circadian and the reward systems in the brain [3-5]. Rewards such as food, sex, and drugs influence this system in part by modulating dopamine neurotransmission in the mesolimbic dopamine reward circuit, including the ventral tegmental area (VTA) and the ventral striatum (NAc). Hence, changes in dopamine levels in these brain areas are proposed to influence mood in humans and mice [6-10]. To establish a molecular link between the circadian-clock mechanism and dopamine metabolism, we analyzed the murine promoters of genes encoding key enzymes important in dopamine metabolism. We find that transcription of the monoamine oxidase A (Maoa) promoter is regulated by the clock components BMAL1, NPAS2, and PER2. A mutation in the clock gene Per2 in mice leads to reduced expression and activity of MAOA in the mesolimbic dopaminergic system. Furthermore, we observe increased levels of dopamine and altered neuronal activity in the striatum, and these results probably lead to behavioral alterations observed in Per2 mutant mice in despair-based tests. These findings suggest a role of circadian-clock components in dopamine metabolism highlighting a role of the clock in regulating mood-related behaviors.

Expectancy-related changes in firing of dopamine neurons depend on orbitofrontal cortex.

PubMed

Takahashi, Yuji K; Roesch, Matthew R; Wilson, Robert C; Toreson, Kathy; O'Donnell, Patricio; Niv, Yael; Schoenbaum, Geoffrey

2011-10-30

The orbitofrontal cortex has been hypothesized to carry information regarding the value of expected rewards. Such information is essential for associative learning, which relies on comparisons between expected and obtained reward for generating instructive error signals. These error signals are thought to be conveyed by dopamine neurons. To test whether orbitofrontal cortex contributes to these error signals, we recorded from dopamine neurons in orbitofrontal-lesioned rats performing a reward learning task. Lesions caused marked changes in dopaminergic error signaling. However, the effect of lesions was not consistent with a simple loss of information regarding expected value. Instead, without orbitofrontal input, dopaminergic error signals failed to reflect internal information about the impending response that distinguished externally similar states leading to differently valued future rewards. These results are consistent with current conceptualizations of orbitofrontal cortex as supporting model-based behavior and suggest an unexpected role for this information in dopaminergic error signaling.

Fear Memory Recall Potentiates Opiate Reward Sensitivity through Dissociable Dopamine D1 versus D4 Receptor-Dependent Memory Mechanisms in the Prefrontal Cortex.

PubMed

Jing Li, Jing; Szkudlarek, Hanna; Renard, Justine; Hudson, Roger; Rushlow, Walter; Laviolette, Steven R

2018-05-09

Disturbances in prefrontal cortical (PFC) dopamine (DA) transmission are well established features of psychiatric disorders involving pathological memory processing, such as post-traumatic stress disorder and opioid addiction. Transmission through PFC DA D4 receptors (D4Rs) has been shown to potentiate the emotional salience of normally nonsalient emotional memories, whereas transmission through PFC DA D1 receptors (D1Rs) has been demonstrated to selectively block recall of reward- or aversion-related associative memories. In the present study, using a combination of fear conditioning and opiate reward conditioning in male rats, we examined the role of PFC D4/D1R signaling during the processing of fear-related memory acquisition and recall and subsequent sensitivity to opiate reward memory formation. We report that PFC D4R activation potentiates the salience of normally subthreshold fear conditioning memory cues and simultaneously potentiates the rewarding effects of systemic or intra-ventral tegmental area (VTA) morphine conditioning cues. In contrast, blocking the recall of salient fear memories with intra-PFC D1R activation, blocks the ability of fear memory recall to potentiate systemic or intra-VTA morphine place preference. These effects were dependent upon dissociable PFC phosphorylation states involving calcium-calmodulin-kinase II or extracellular signal-related kinase 1-2, following intra-PFC D4 or D1R activation, respectively. Together, these findings reveal new insights into how aberrant PFC DAergic transmission and associated downstream molecular signaling pathways may modulate fear-related emotional memory processing and concomitantly increase opioid addiction vulnerability. SIGNIFICANCE STATEMENT Post-traumatic stress disorder is highly comorbid with addiction. In this study, we use a translational model of fear memory conditioning to examine how transmission through dopamine D1 or D4 receptors, in the prefrontal cortex (PFC), may differentially control acquisition or recall of fear memories and how these mechanisms might regulate sensitivity to the rewarding effects of opioids. We demonstrate that PFC D4 activation not only controls the salience of fear memory acquisition, but potentiates the rewarding effects of opioids. In contrast, PFC D1 receptor activation blocks recall of fear memories and prevents potentiation of opioid reward effects. Together, these findings demonstrate novel PFC mechanisms that may account for how emotional memory disturbances might increase the addictive liability of opioid-class drugs. Copyright © 2018 the authors 0270-6474/18/384543-13$15.00/0.

An Anatomical Basis for Opponent Process Mechanisms of Opiate Withdrawal

PubMed Central

Radke, Anna K.; Rothwell, Patrick E.; Gewirtz, Jonathan C.

2011-01-01

Opponent process theory predicts that the first step in the induction of drug withdrawal is the activation of reward-related circuitry. Using the acoustic startle reflex as a model of anxiety-like behavior in rats, we show the emergence of a negative affective state during withdrawal after direct infusion of morphine into the ventral tegmental area (VTA), the origin of the mesolimbic dopamine system. Potentiation of startle during withdrawal from systemic morphine exposure requires a decrease in opiate receptor stimulation in the VTA and can be relieved by administration of the dopamine receptor agonist apomorphine. Together, our results suggest that the emergence of anxiety during withdrawal from acute opiate exposure begins with activation of VTA mesolimbic dopamine circuitry, providing a mechanism for the opponent process view of withdrawal. PMID:21593338

Missing motoric manipulations: rethinking the imaging of the ventral striatum and dopamine in human reward.

PubMed

Kareken, David A

2018-01-26

Human neuroimaging studies of natural rewards and drugs of abuse frequently assay the brain's response to stimuli that, through Pavlovian learning, have come to be associated with a drug's rewarding properties. This might be characterized as a 'sensorial' view of the brain's reward system, insofar as the paradigms are designed to elicit responses to a reward's (drug's) sight, aroma, or flavor. A different field of research nevertheless suggests that the mesolimbic dopamine system may also be critically involved in the motor behaviors provoked by such stimuli. This brief review and commentary surveys some of the preclinical data supporting this more "efferent" (motoric) view of the brain's reward system, and discusses what such findings might mean for how human brain imaging studies of natural rewards and drugs of abuse are designed.

Hedonic and incentive signals for body weight control.

PubMed

Egecioglu, Emil; Skibicka, Karolina P; Hansson, Caroline; Alvarez-Crespo, Mayte; Friberg, P Anders; Jerlhag, Elisabet; Engel, Jörgen A; Dickson, Suzanne L

2011-09-01

Here we review the emerging neurobiological understanding of the role of the brain's reward system in the regulation of body weight in health and in disease. Common obesity is characterized by the over-consumption of palatable/rewarding foods, reflecting an imbalance in the relative importance of hedonic versus homeostatic signals. The popular 'incentive salience theory' of food reward recognises not only a hedonic/pleasure component ('liking') but also an incentive motivation component ('wanting' or 'reward-seeking'). Central to the neurobiology of the reward mechanism is the mesoaccumbal dopamine system that confers incentive motivation not only for natural rewards such as food but also by artificial rewards (eg. addictive drugs). Indeed, this mesoaccumbal dopamine system receives and integrates information about the incentive (rewarding) value of foods with information about metabolic status. Problematic over-eating likely reflects a changing balance in the control exerted by hypothalamic versus reward circuits and/or it could reflect an allostatic shift in the hedonic set point for food reward. Certainly, for obesity to prevail, metabolic satiety signals such as leptin and insulin fail to regain control of appetitive brain networks, including those involved in food reward. On the other hand, metabolic control could reflect increased signalling by the stomach-derived orexigenic hormone, ghrelin. We have shown that ghrelin activates the mesoaccumbal dopamine system and that central ghrelin signalling is required for reward from both chemical drugs (eg alcohol) and also from palatable food. Future therapies for problematic over-eating and obesity may include drugs that interfere with incentive motivation, such as ghrelin antagonists.

Dopamine mediates testosterone-induced social reward in male Syrian hamsters.

PubMed

Bell, Margaret R; Sisk, Cheryl L

2013-03-01

Adolescent maturation of responses to social stimuli is essential for adult-typical sociosexual behavior. Naturally occurring developmental changes in male Syrian hamster responses to a salient social cue, female hamster vaginal secretions (VS), provide a good model system for investigating neuroendocrine mechanisms of adolescent change in social reward. Sexually naïve adult, but not juvenile, males show a conditioned place preference (CPP) to VS, indicating that VS is not rewarding before puberty. In this series of experiments, the authors examined the roles of testosterone and dopamine receptor activation in mediating the adolescent gain in positive valence of VS. Experiment 1 showed that testosterone replacement is necessary for gonadectomized adult hamsters to form a CPP to VS. Experiment 2 showed that testosterone treatment is sufficient for juvenile hamsters to form a CPP to VS, and that the dopamine receptor antagonist haloperidol blocks formation of a CPP to VS in these animals. Experiments 3 and 4 demonstrated that the disruption of VS CPP with low doses of haloperidol is the result of a reduction in the attractive properties of VS and not attributable to aversive properties of haloperidol. Together, these studies demonstrate that the unconditioned rewarding properties of a social cue necessary for successful adult sociosexual interactions come about as the result of the pubertal increase in circulating testosterone in male hamsters. Furthermore, this social reward can be prevented by dopamine receptor antagonism, indicating that hypothalamic and/or mesocorticolimbic dopaminergic circuits are targets for hormonal activation of social reward.

Reconsidering Food Reward, Brain Stimulation, and Dopamine: Incentives Act Forward.

PubMed

Newquist, Gunnar; Gardner, R Allen

2015-01-01

In operant conditioning, rats pressing levers and pigeons pecking keys depend on contingent food reinforcement. Food reward agrees with Skinner's behaviorism, undergraduate textbooks, and folk psychology. However, nearly a century of experimental evidence shows, instead, that food in an operant conditioning chamber acts forward to evoke species-specific feeding behavior rather than backward to reinforce experimenter-defined responses. Furthermore, recent findings in neuroscience show consistently that intracranial stimulation to reward centers and dopamine release, the proposed reward molecule, also act forward to evoke inborn species-specific behavior. These results challenge longstanding views of hedonic learning and must be incorporated into contemporary learning theory.

Associations between Electrophysiological Evidence of Reward and Punishment-Based Learning and Psychotic Experiences and Social Anhedonia in At-Risk Groups

PubMed Central

Karcher, Nicole R; Bartholow, Bruce D; Martin, Elizabeth A; Kerns, John G

2017-01-01

Both positive psychotic symptoms and anhedonia are associated with striatal functioning, but few studies have linked risk for psychotic disorders to a neural measure evoked during a striatal dopamine-related reward and punishment-based learning task, such as a reversal learning task (RLT; Cools et al, 2009). The feedback-related negativity (FRN) is a neural response that in part reflects striatal dopamine functioning. We recorded EEG during the RLT in three groups: (a) people with psychotic experiences (PE; n=20) at increased risk for psychotic disorders; (b) people with extremely elevated social anhedonia (SocAnh; n=22); and (c) controls (n=20). Behaviorally, consistent with increased striatal dopamine, the PE group exhibited better behavioral learning (ie, faster responses) after unexpected reward than after unexpected punishment. Moreover, although the control and SocAnh groups showed a larger FRN to punishment than reward, the PE group showed similar FRNs to punishment and reward, with a numerically larger FRN to reward than punishment (with similar results on these trials also found for a P3a component). These results are among the first to link a neural response evoked by a reward and punishment-based learning task specifically with elevated psychosis risk. PMID:27629367

Associations between Electrophysiological Evidence of Reward and Punishment-Based Learning and Psychotic Experiences and Social Anhedonia in At-Risk Groups.

PubMed

Karcher, Nicole R; Bartholow, Bruce D; Martin, Elizabeth A; Kerns, John G

2017-03-01

Both positive psychotic symptoms and anhedonia are associated with striatal functioning, but few studies have linked risk for psychotic disorders to a neural measure evoked during a striatal dopamine-related reward and punishment-based learning task, such as a reversal learning task (RLT; Cools et al, 2009). The feedback-related negativity (FRN) is a neural response that in part reflects striatal dopamine functioning. We recorded EEG during the RLT in three groups: (a) people with psychotic experiences (PE; n=20) at increased risk for psychotic disorders; (b) people with extremely elevated social anhedonia (SocAnh; n=22); and (c) controls (n=20). Behaviorally, consistent with increased striatal dopamine, the PE group exhibited better behavioral learning (ie, faster responses) after unexpected reward than after unexpected punishment. Moreover, although the control and SocAnh groups showed a larger FRN to punishment than reward, the PE group showed similar FRNs to punishment and reward, with a numerically larger FRN to reward than punishment (with similar results on these trials also found for a P3a component). These results are among the first to link a neural response evoked by a reward and punishment-based learning task specifically with elevated psychosis risk.

Differential Dopamine Release Dynamics in the Nucleus Accumbens Core and Shell Reveal Complementary Signals for Error Prediction and Incentive Motivation.

PubMed

Saddoris, Michael P; Cacciapaglia, Fabio; Wightman, R Mark; Carelli, Regina M

2015-08-19

Mesolimbic dopamine (DA) is phasically released during appetitive behaviors, though there is substantive disagreement about the specific purpose of these DA signals. For example, prediction error (PE) models suggest a role of learning, while incentive salience (IS) models argue that the DA signal imbues stimuli with value and thereby stimulates motivated behavior. However, within the nucleus accumbens (NAc) patterns of DA release can strikingly differ between subregions, and as such, it is possible that these patterns differentially contribute to aspects of PE and IS. To assess this, we measured DA release in subregions of the NAc during a behavioral task that spatiotemporally separated sequential goal-directed stimuli. Electrochemical methods were used to measure subsecond NAc dopamine release in the core and shell during a well learned instrumental chain schedule in which rats were trained to press one lever (seeking; SL) to gain access to a second lever (taking; TL) linked with food delivery, and again during extinction. In the core, phasic DA release was greatest following initial SL presentation, but minimal for the subsequent TL and reward events. In contrast, phasic shell DA showed robust release at all task events. Signaling decreased between the beginning and end of sessions in the shell, but not core. During extinction, peak DA release in the core showed a graded decrease for the SL and pauses in release during omitted expected rewards, whereas shell DA release decreased predominantly during the TL. These release dynamics suggest parallel DA signals capable of supporting distinct theories of appetitive behavior. Dopamine signaling in the brain is important for a variety of cognitive functions, such as learning and motivation. Typically, it is assumed that a single dopamine signal is sufficient to support these cognitive functions, though competing theories disagree on how dopamine contributes to reward-based behaviors. Here, we have found that real-time dopamine release within the nucleus accumbens (a primary target of midbrain dopamine neurons) strikingly varies between core and shell subregions. In the core, dopamine dynamics are consistent with learning-based theories (such as reward prediction error) whereas in the shell, dopamine is consistent with motivation-based theories (e.g., incentive salience). These findings demonstrate that dopamine plays multiple and complementary roles based on discrete circuits that help animals optimize rewarding behaviors. Copyright © 2015 the authors 0270-6474/15/3511572-11$15.00/0.

Motivation deficit in ADHD is associated with dysfunction of the dopamine reward pathway

DOE Office of Scientific and Technical Information (OSTI.GOV)

Volkow, N.D.; Wang, G.; Volkow, N.D.

Attention-deficit hyperactivity disorder (ADHD) is typically characterized as a disorder of inattention and hyperactivity/impulsivity but there is increasing evidence of deficits in motivation. Using positron emission tomography (PET), we showed decreased function in the brain dopamine reward pathway in adults with ADHD, which, we hypothesized, could underlie the motivation deficits in this disorder. To evaluate this hypothesis, we performed secondary analyses to assess the correlation between the PET measures of dopamine D2/D3 receptor and dopamine transporter availability (obtained with [{sup 11}C]raclopride and [{sup 11}C]cocaine, respectively) in the dopamine reward pathway (midbrain and nucleus accumbens) and a surrogate measure of traitmore » motivation (assessed using the Achievement scale on the Multidimensional Personality Questionnaire or MPQ) in 45 ADHD participants and 41 controls. The Achievement scale was lower in ADHD participants than in controls (11 {+-} 5 vs 14 {+-} 3, P < 0.001) and was significantly correlated with D2/D3 receptors (accumbens: r = 0.39, P < 0.008; midbrain: r = 0.41, P < 0.005) and transporters (accumbens: r = 0.35, P < 0.02) in ADHD participants, but not in controls. ADHD participants also had lower values in the Constraint factor and higher values in the Negative Emotionality factor of the MPQ but did not differ in the Positive Emotionality factor - and none of these were correlated with the dopamine measures. In ADHD participants, scores in the Achievement scale were also negatively correlated with symptoms of inattention (CAARS A, E and SWAN I). These findings provide evidence that disruption of the dopamine reward pathway is associated with motivation deficits in ADHD adults, which may contribute to attention deficits and supports the use of therapeutic interventions to enhance motivation in ADHD.« less

Rapid signalling in distinct dopaminergic axons during locomotion and reward.

PubMed

Howe, M W; Dombeck, D A

2016-07-28

Dopaminergic projection axons from the midbrain to the striatum are crucial for motor control, as their degeneration in Parkinson disease results in profound movement deficits. Paradoxically, most recording methods report rapid phasic dopamine signalling (~100-ms bursts) in response to unpredicted rewards, with little evidence for movement-related signalling. The leading model posits that phasic signalling in striatum-targeting dopamine neurons drives reward-based learning, whereas slow variations in firing (tens of seconds to minutes) in these same neurons bias animals towards or away from movement. However, current methods have provided little evidence to support or refute this model. Here, using new optical recording methods, we report the discovery of rapid phasic signalling in striatum-targeting dopaminergic axons that is associated with, and capable of triggering, locomotion in mice. Axons expressing these signals were largely distinct from those that responded to unexpected rewards. These results suggest that dopaminergic neuromodulation can differentially impact motor control and reward learning with sub-second precision, and indicate that both precise signal timing and neuronal subtype are important parameters to consider in the treatment of dopamine-related disorders.

Rapid signaling in distinct dopaminergic axons during locomotion and reward

PubMed Central

Howe, MW; Dombeck, DA

2016-01-01

Summary Dopaminergic projections from the midbrain to striatum are critical for motor control, as their degeneration in Parkinson’s disease results in profound movement deficits. Paradoxically, most recording methods report rapid phasic dopamine signaling (~100ms bursts) to unpredicted rewards, with little evidence for movement-related signaling. The leading model posits that phasic signaling in striatum targeting dopamine neurons drive reward-based learning, while slow variations in firing (tens of seconds to minutes) in these same neurons bias animals towards or away from movement. However, despite widespread acceptance of this model, current methods have provided little evidence to support or refute it. Here, using new optical recording methods, we report the discovery of rapid phasic signaling in striatum-targeting dopaminergic axons that was associated with, and capable of triggering, locomotion in mice. Axons expressing these signals were largely distinct from those signaling during unexpected rewards. These results suggest that dopaminergic neuromodulation can differentially impact motor control and reward learning with sub-second precision and suggest that both precise signal timing and neuronal subtype are important parameters to consider in the treatment of dopamine-related disorders. PMID:27398617

Dopamine, urges to smoke, and the relative salience of drug versus non-drug reward.

PubMed

Freeman, Tom P; Das, Ravi K; Kamboj, Sunjeev K; Curran, H Valerie

2015-01-01

When addicted individuals are exposed to drug-related stimuli, dopamine release is thought to mediate incentive salience attribution, increasing attentional bias, craving and drug seeking. It is unclear whether dopamine acts specifically on drug cues versus other rewards, and if these effects correspond with craving and other forms of cognitive bias. Here, we administered the dopamine D2/D3 agonist pramipexole (0.5 mg) to 16 tobacco smokers in a double-blind placebo-controlled crossover design. Visual fixations on smoking and money images were recorded alongside smoking urges and fluency tasks. Pramipexole attenuated a marked bias in initial orienting towards smoking relative to money but did not alter a maintained attentional bias towards smoking. Pramipexole decreased urges to smoke retrospectively after the task but not on a state scale. Fewer smoking words were generated after pramipexole but phonological and semantic fluency were preserved. Although these treatment effects did not correlate with each other, changes in initial orienting towards smoking and money were inversely related to baseline scores. In conclusion, pramipexole can reduce the salience of an addictive drug compared with other rewards and elicit corresponding changes in smoking urges and cognitive bias. These reward-specific and baseline-dependent effects support an 'inverted-U' shaped profile of dopamine in addiction. © The Author (2014). Published by Oxford University Press. For Permissions, please email: journals.permissions@oup.com.

Dopamine Manipulation Affects Response Vigor Independently of Opportunity Cost.

PubMed

Zénon, Alexandre; Devesse, Sophie; Olivier, Etienne

2016-09-14

Dopamine is known to be involved in regulating effort investment in relation to reward, and the disruption of this mechanism is thought to be central in some pathological situations such as Parkinson's disease, addiction, and depression. According to an influential model, dopamine plays this role by encoding the opportunity cost, i.e., the average value of forfeited actions, which is an important parameter to take into account when making decisions about which action to undertake and how fast to execute it. We tested this hypothesis by asking healthy human participants to perform two effort-based decision-making tasks, following either placebo or levodopa intake in a double blind within-subject protocol. In the effort-constrained task, there was a trade-off between the amount of force exerted and the time spent in executing the task, such that investing more effort decreased the opportunity cost. In the time-constrained task, the effort duration was constant, but exerting more force allowed the subject to earn more substantial reward instead of saving time. Contrary to the model predictions, we found that levodopa caused an increase in the force exerted only in the time-constrained task, in which there was no trade-off between effort and opportunity cost. In addition, a computational model showed that dopamine manipulation left the opportunity cost factor unaffected but altered the ratio between the effort cost and reinforcement value. These findings suggest that dopamine does not represent the opportunity cost but rather modulates how much effort a given reward is worth. Dopamine has been proposed in a prevalent theory to signal the average reward rate, used to estimate the cost of investing time in an action, also referred to as opportunity cost. We contrasted the effect of dopamine manipulation in healthy participants in two tasks, in which increasing response vigor (i.e., the amount of effort invested in an action) allowed either to save time or to earn more reward. We found that levodopa-a synthetic precursor of dopamine-increases response vigor only in the latter situation, demonstrating that, rather than the opportunity cost, dopamine is involved in computing the expected value of effort. Copyright © 2016 the authors 0270-6474/16/369516-10$15.00/0.

The effect of the anabolic steroid, nandrolone, in conditioned place preference and D1 dopamine receptor expression in adolescent and adult mice.

PubMed

Martínez-Rivera, Freddyson J; Natal-Albelo, Eduardo J; Martínez, Namyr A; Orozco-Vega, Roberto A; Muñiz-Seda, Oscar A; Barreto-Estrada, Jennifer L

2015-04-01

Adolescents and adults engage in anabolic-androgenic steroid (AAS) misuse seeking their anabolic effects, even though later on, many could develop neuropsychological dependence. Previously, we have shown that nandrolone induces conditioned place preference (CPP) in adult male mice. However, whether nandrolone induces CPP during adolescence remains unknown. In this study, the CPP test was used to determine the rewarding properties of nandrolone (7.5 mg/kg) in adolescent mice. In addition, since D1 dopamine receptors (D1DR) are critical for reward-related processes, the effect of nandrolone on the expression of D1DR in the nucleus accumbens (NAc) was investigated by Western blot analysis. Similar to our previous results, nandrolone induced CPP in adults. However, in adolescents, nandrolone failed to produce place preference. At the molecular level, nandrolone decreased D1DR expression in the NAc only in adult mice. Our data suggest that nandrolone may not be rewarding in adolescents at least during short-term use. The lack of nandrolone rewarding effects in adolescents may be due, in part to differences in D1DR expression during development. Copyright © 2015 Elsevier B.V. All rights reserved.

The effect of the anabolic steroid, nandrolone, in conditioned place preference and D1 dopamine receptor expression in adolescent and adult mice

PubMed Central

Martínez-Rivera, Freddyson J.; Natal-Albelo, Eduardo J.; Martínez, Namyr A.; Orozco-Vega, Roberto A.; Muñiz-Seda, Oscar A.; Barreto-Estrada, Jennifer L.

2015-01-01

Adolescents and adults engage in anabolic-androgenic steroid (AAS) misuse seeking their anabolic effects, even though later on, many could develop neuropsychological dependence. Previously, we have shown that nandrolone induces conditioned place preference (CPP) in adult male mice. However, whether nandrolone induces CPP during adolescence remains unknown. In this study, the CPP test was used to determine the rewarding properties of nandrolone (7.5 mg/kg) in adolescent mice. In addition, since D1 dopamine receptors (D1DR) are critical for reward-related processes, the effect of nandrolone on the expression of D1DR in the nucleus accumbens (NAc) was investigated by Western blot analysis. Similar to our previous results, nandrolone induced CPP in adults. However, in adolescents, nandrolone failed to produce place preference. At the molecular level, nandrolone decreased D1DR expression in the NAc only in adult mice. Our data suggest that nandrolone may not be rewarding in adolescents at least during short-term use. The lack of nandrolone rewarding effects in adolescents may be due, in part to differences in D1DR expression during development. PMID:25612844

Acute D3 Antagonist GSK598809 Selectively Enhances Neural Response During Monetary Reward Anticipation in Drug and Alcohol Dependence

PubMed Central

Murphy, Anna; Nestor, Liam J; McGonigle, John; Paterson, Louise; Boyapati, Venkataramana; Ersche, Karen D; Flechais, Remy; Kuchibatla, Shankar; Metastasio, Antonio; Orban, Csaba; Passetti, Filippo; Reed, Laurence; Smith, Dana; Suckling, John; Taylor, Eleanor; Robbins, Trevor W; Lingford-Hughes, Anne; Nutt, David J; Deakin, John FW; Elliott, Rebecca

2017-01-01

Evidence suggests that disturbances in neurobiological mechanisms of reward and inhibitory control maintain addiction and provoke relapse during abstinence. Abnormalities within the dopamine system may contribute to these disturbances and pharmacologically targeting the D3 dopamine receptor (DRD3) is therefore of significant clinical interest. We used functional magnetic resonance imaging to investigate the acute effects of the DRD3 antagonist GSK598809 on anticipatory reward processing, using the monetary incentive delay task (MIDT), and response inhibition using the Go/No-Go task (GNGT). A double-blind, placebo-controlled, crossover design approach was used in abstinent alcohol dependent, abstinent poly-drug dependent and healthy control volunteers. For the MIDT, there was evidence of blunted ventral striatal response to reward in the poly-drug-dependent group under placebo. GSK598809 normalized ventral striatal reward response and enhanced response in the DRD3-rich regions of the ventral pallidum and substantia nigra. Exploratory investigations suggested that the effects of GSK598809 were mainly driven by those with primary dependence on alcohol but not on opiates. Taken together, these findings suggest that GSK598809 may remediate reward deficits in substance dependence. For the GNGT, enhanced response in the inferior frontal cortex of the poly-drug group was found. However, there were no effects of GSK598809 on the neural network underlying response inhibition nor were there any behavioral drug effects on response inhibition. GSK598809 modulated the neural network underlying reward anticipation but not response inhibition, suggesting that DRD3 antagonists may restore reward deficits in addiction. PMID:28042871

New developments in brain research of internet and gaming disorder.

PubMed

Weinstein, Aviv; Livny, Abigail; Weizman, Abraham

2017-04-01

There is evidence that the neural mechanisms underlying Internet Gaming Disorder (IGD) resemble those of drug addiction. Functional Magnetic Resonance Imaging (fMRI) studies of the resting state and measures of gray matter volume have shown that Internet game playing was associated with changes to brain regions responsible for attention and control, impulse control, motor function, emotional regulation, sensory-motor coordination. Furthermore, Internet game playing was associated with lower white matter density in brain regions that are involved in decision-making, behavioral inhibition and emotional regulation. Videogame playing involved changes in reward inhibitory mechanisms and loss of control. Structural brain imaging studies showed alterations in the volume of the ventral striatum that is an important part of the brain's reward mechanisms. Finally, videogame playing was associated with dopamine release similar in magnitude to those of drugs of abuse and lower dopamine transporter and dopamine receptor D 2 occupancy indicating sub-sensitivity of dopamine reward mechanisms. Copyright © 2017 Elsevier Ltd. All rights reserved.

The effects of expected reward on creative problem solving.

PubMed

Cristofori, Irene; Salvi, Carola; Beeman, Mark; Grafman, Jordan

2018-06-12

Creative problem solving involves search processes, and it is known to be hard to motivate. Reward cues have been found to enhance performance across a range of tasks, even when cues are presented subliminally, without being consciously detected. It is uncertain whether motivational processes, such as reward, can influence problem solving. We tested the effect of supraliminal and subliminal reward on participant performance on problem solving that can be solved by deliberate analysis or by insight. Forty-one participants attempted to solve 100 compound remote associate problems. At the beginning of each problem, a potential reward cue (1 or 25 cents) was displayed, either subliminally (17 ms) or supraliminally (100 ms). Participants earned the displayed reward if they solved the problem correctly. Results showed that the higher subliminal reward increased the percentage of problems solved correctly overall. Second, we explored if subliminal rewards preferentially influenced solutions that were achieved via a sudden insight (mostly processed below awareness) or via a deliberate analysis. Participants solved more problems via insight following high subliminal reward when compared with low subliminal reward, and compared with high supraliminal reward, with no corresponding effect on analytic solving. Striatal dopamine (DA) is thought to influence motivation, reinforce behavior, and facilitate cognition. We speculate that subliminal rewards activate the striatal DA system, enhancing the kinds of automatic integrative processes that lead to more creative strategies for problem solving, without increasing the selectivity of attention, which could impede insight.

The Effects of Acute Dopamine Precursor Depletion on the Reinforcing Value of Exercise in Anorexia Nervosa.

PubMed

O'Hara, Caitlin B; Keyes, Alexandra; Renwick, Bethany; Leyton, Marco; Campbell, Iain C; Schmidt, Ulrike

2016-01-01

This study investigated whether dopaminergic systems are involved in the motivation to engage in behaviours associated with anorexia nervosa (AN), specifically, the drive to exercise. Women recovered from AN (AN REC, n = 17) and healthy controls (HC, n = 15) were recruited. The acute phenylalanine/tyrosine depletion (APTD) method was used to transiently decrease dopamine synthesis and transmission. The effect of dopamine precursor depletion on drive to exercise was measured using a progressive ratio (PR) exercise breakpoint task. Both groups worked for the opportunity to exercise, and, at baseline, PR breakpoint scores were higher in AN REC than HC. Compared to values on the experimental control session, APTD did not decrease PR breakpoint scores in AN REC, but significantly decreased scores in HC. These data show that women recovered from AN are more motivated to exercise than HC, although in both groups, activity is more reinforcing than inactivity. Importantly, decreasing dopamine does not reduce the motivation to exercise in people recovered from AN, but in contrast, does so in HC. It is proposed that in AN, drive to exercise develops into a behaviour that is largely independent of dopamine mediated reward processes and becomes dependent on cortico-striatal neurocircuitry that regulates automated, habit- or compulsive-like behaviours. These data strengthen the case for the involvement of reward, learning, habit, and dopaminergic systems in the aetiology of AN.

The Effects of Acute Dopamine Precursor Depletion on the Reinforcing Value of Exercise in Anorexia Nervosa

PubMed Central

O’Hara, Caitlin B.; Keyes, Alexandra; Renwick, Bethany; Leyton, Marco; Campbell, Iain C.; Schmidt, Ulrike

2016-01-01

This study investigated whether dopaminergic systems are involved in the motivation to engage in behaviours associated with anorexia nervosa (AN), specifically, the drive to exercise. Women recovered from AN (AN REC, n = 17) and healthy controls (HC, n = 15) were recruited. The acute phenylalanine/tyrosine depletion (APTD) method was used to transiently decrease dopamine synthesis and transmission. The effect of dopamine precursor depletion on drive to exercise was measured using a progressive ratio (PR) exercise breakpoint task. Both groups worked for the opportunity to exercise, and, at baseline, PR breakpoint scores were higher in AN REC than HC. Compared to values on the experimental control session, APTD did not decrease PR breakpoint scores in AN REC, but significantly decreased scores in HC. These data show that women recovered from AN are more motivated to exercise than HC, although in both groups, activity is more reinforcing than inactivity. Importantly, decreasing dopamine does not reduce the motivation to exercise in people recovered from AN, but in contrast, does so in HC. It is proposed that in AN, drive to exercise develops into a behaviour that is largely independent of dopamine mediated reward processes and becomes dependent on cortico-striatal neurocircuitry that regulates automated, habit- or compulsive-like behaviours. These data strengthen the case for the involvement of reward, learning, habit, and dopaminergic systems in the aetiology of AN. PMID:26808920

Sequential neuromodulation of Hebbian plasticity offers mechanism for effective reward-based navigation

PubMed Central

Brzosko, Zuzanna; Zannone, Sara; Schultz, Wolfram

2017-01-01

Spike timing-dependent plasticity (STDP) is under neuromodulatory control, which is correlated with distinct behavioral states. Previously, we reported that dopamine, a reward signal, broadens the time window for synaptic potentiation and modulates the outcome of hippocampal STDP even when applied after the plasticity induction protocol (Brzosko et al., 2015). Here, we demonstrate that sequential neuromodulation of STDP by acetylcholine and dopamine offers an efficacious model of reward-based navigation. Specifically, our experimental data in mouse hippocampal slices show that acetylcholine biases STDP toward synaptic depression, whilst subsequent application of dopamine converts this depression into potentiation. Incorporating this bidirectional neuromodulation-enabled correlational synaptic learning rule into a computational model yields effective navigation toward changing reward locations, as in natural foraging behavior. Thus, temporally sequenced neuromodulation of STDP enables associations to be made between actions and outcomes and also provides a possible mechanism for aligning the time scales of cellular and behavioral learning. DOI: http://dx.doi.org/10.7554/eLife.27756.001 PMID:28691903

The role of motivation and reward neural systems in vocal communication in songbirds

PubMed Central

Riters, Lauren V.

2012-01-01

Many vertebrates are highly motivated to communicate, suggesting that the consequences of communication may be rewarding. Past studies show that dopamine and opioids in the medial preoptic nucleus (mPOA) and ventral tegmental area (VTA) play distinct roles in motivation and reward. In songbirds, multiple lines of recent evidence indicate that the roles of dopamine and opioid activity in mPOA and VTA in male birdsong differ depending upon whether song is used to attract females (sexually-motivated) or is produced spontaneously (undirected). Evidence is reviewed supporting the hypotheses that 1) mPOA and VTA interact to influence the context in which a male sings, 2) distinct patterns of dopamine activity underlie the motivation to produce sexually-motivated and undirected song, 3) sexually-motivated communication is externally reinforced by opioids released as part of social interactions, and 4) undirected communication is facilitated and rewarded by immediate opioid release linked to the act of singing. PMID:22569510

The role of motivation and reward neural systems in vocal communication in songbirds.

PubMed

Riters, Lauren V

2012-04-01

Many vertebrates are highly motivated to communicate, suggesting that the consequences of communication may be rewarding. Past studies show that dopamine and opioids in the medial preoptic nucleus (mPOA) and ventral tegmental area (VTA) play distinct roles in motivation and reward. In songbirds, multiple lines of recent evidence indicate that the roles of dopamine and opioid activity in mPOA and VTA in male birdsong differ depending upon whether song is used to attract females (sexually-motivated) or is produced spontaneously (undirected). Evidence is reviewed supporting the hypotheses that (1) mPOA and VTA interact to influence the context in which a male sings, (2) distinct patterns of dopamine activity underlie the motivation to produce sexually-motivated and undirected song, (3) sexually-motivated communication is externally reinforced by opioids released as part of social interactions, and (4) undirected communication is facilitated and rewarded by immediate opioid release linked to the act of singing. Copyright © 2012 Elsevier Inc. All rights reserved.

Music-related reward responses predict episodic memory performance.

PubMed

Ferreri, Laura; Rodriguez-Fornells, Antoni

2017-12-01

Music represents a special type of reward involving the recruitment of the mesolimbic dopaminergic system. According to recent theories on episodic memory formation, as dopamine strengthens the synaptic potentiation produced by learning, stimuli triggering dopamine release could result in long-term memory improvements. Here, we behaviourally test whether music-related reward responses could modulate episodic memory performance. Thirty participants rated (in terms of arousal, familiarity, emotional valence, and reward) and encoded unfamiliar classical music excerpts. Twenty-four hours later, their episodic memory was tested (old/new recognition and remember/know paradigm). Results revealed an influence of music-related reward responses on memory: excerpts rated as more rewarding were significantly better recognized and remembered. Furthermore, inter-individual differences in the ability to experience musical reward, measured through the Barcelona Music Reward Questionnaire, positively predicted memory performance. Taken together, these findings shed new light on the relationship between music, reward and memory, showing for the first time that music-driven reward responses are directly implicated in higher cognitive functions and can account for individual differences in memory performance.

Modulation of cue-induced firing of ventral tegmental area dopamine neurons by leptin and ghrelin

PubMed Central

van der Plasse, G; van Zessen, R; Luijendijk, M C M; Erkan, H; Stuber, G D; Ramakers, G M J; Adan, R A H

2015-01-01

Background/objectives: The rewarding value of palatable foods contributes to overconsumption, even in satiated subjects. Midbrain dopaminergic activity in response to reward-predicting environmental stimuli drives reward-seeking and motivated behavior for food rewards. This mesolimbic dopamine (DA) system is sensitive to changes in energy balance, yet it has thus far not been established whether reward signaling of DA neurons in vivo is under control of hormones that signal appetite and energy balance such as ghrelin and leptin. Subjects/methods: We trained rats (n=11) on an operant task in which they could earn two different food rewards. We then implanted recording electrodes in the ventral tegmental area (VTA), and recorded from DA neurons during behavior. Subsequently, we assessed the effects of mild food restriction and pretreatment with the adipose tissue-derived anorexigenic hormone leptin or the orexigenic hormone ghrelin on VTA DA reward signaling. Results: Animals showed an increase in performance following mild food restriction (P=0.002). Importantly, food-cue induced DA firing increased when animals were food restricted (P=0.02), but was significantly attenuated after leptin pretreatment (P=0.00). While ghrelin did affect baseline DA activity (P=0.025), it did not affect cue-induced firing (P⩾0.353). Conclusions: Metabolic signals, such as leptin, affect food seeking, a process that is dependent on the formation of cue-reward outcomes and involves midbrain DA signaling. These data show that food restriction engages the encoding of food cues by VTA DA neurons at a millisecond level and leptin suppresses this activity. This suggests that leptin is a key in linking metabolic information to reward signaling. PMID:26183405

Dopamine signaling in reward-related behaviors.

PubMed

Baik, Ja-Hyun

2013-01-01

Dopamine (DA) regulates emotional and motivational behavior through the mesolimbic dopaminergic pathway. Changes in DA mesolimbic neurotransmission have been found to modify behavioral responses to various environmental stimuli associated with reward behaviors. Psychostimulants, drugs of abuse, and natural reward such as food can cause substantial synaptic modifications to the mesolimbic DA system. Recent studies using optogenetics and DREADDs, together with neuron-specific or circuit-specific genetic manipulations have improved our understanding of DA signaling in the reward circuit, and provided a means to identify the neural substrates of complex behaviors such as drug addiction and eating disorders. This review focuses on the role of the DA system in drug addiction and food motivation, with an overview of the role of D1 and D2 receptors in the control of reward-associated behaviors.

Fronto-striatal Dysfunction During Reward Processing in Unaffected Siblings of Schizophrenia Patients

PubMed Central

de Leeuw, Max; Kahn, René S.; Vink, Matthijs

2015-01-01

Schizophrenia is a psychiatric disorder that is associated with impaired functioning of the fronto-striatal network, in particular during reward processing. However, it is unclear whether this dysfunction is related to the illness itself or whether it reflects a genetic vulnerability to develop schizophrenia. Here, we examined reward processing in unaffected siblings of schizophrenia patients using functional magnetic resonance imaging. Brain activity was measured during reward anticipation and reward outcome in 27 unaffected siblings of schizophrenia patients and 29 healthy volunteers using a modified monetary incentive delay task. Task performance was manipulated online so that all subjects won the same amount of money. Despite equal performance, siblings showed reduced activation in the ventral striatum, insula, and supplementary motor area (SMA) during reward anticipation compared to controls. Decreased ventral striatal activation in siblings was correlated with sub-clinical negative symptoms. During the outcome of reward, siblings showed increased activation in the ventral striatum and orbitofrontal cortex compared to controls. Our finding of decreased activity in the ventral striatum during reward anticipation and increased activity in this region during receiving reward may indicate impaired cue processing in siblings. This is consistent with the notion of dopamine dysfunction typically associated with schizophrenia. Since unaffected siblings share on average 50% of their genes with their ill relatives, these deficits may be related to the genetic vulnerability for schizophrenia. PMID:25368371

Lyme and Dopaminergic Function: Hypothesizing Reduced Reward Deficiency Symptomatology by Regulating Dopamine Transmission

PubMed Central

Blum, Kenneth; Modestino, Edward J; Febo, Marcelo; Steinberg, Bruce; McLaughlin, Thomas; Fried, Lyle; Baron, David; Siwicki, David; Badgaiyan, Rajendra D

2017-01-01

The principal vector of Lyme disease in the United States is Ixodes scapularis: black legged or deer ticks. There is increased evidence that those infected may be plagued by anxiety or depression as well. Researchers have identified transcripts coding for two putative cytosolic sulfotransferases in these ticks, which recognized phenolic monoamines as their substrates. It is hypothesized that protracted Lyme disease sequelae may be due to impairment of dopaminergic function of the brain reward circuitry. The subsequent recombinant proteins exhibited sulfotransferase function against two neurotransmitters: dopamine and octopamine. This, in itself, can reduce dopamine function leading to many Reward Deficiency Syndrome behaviors, including depression and possibly, anxiety. In fact, it was shown that activity of Ixosc Sult 1 and Sult 2 in the Ixodid tick salivary glands might contain inactivation of the salivation signal through sulfonation of either dopamine or octopamine. This infraction results in a number of clinically observed mood changes, such as anxiety and depression. In fact, there are common symptoms observed for both Parkinson and Lyme diseases. The importance of understanding the mechanistic and neurobiological effects of Lyme on the central nervous system (CNS) provides the basis for pro-dopamine regulation as a treatment. WC 195 PMID:28736624

Lyme and Dopaminergic Function: Hypothesizing Reduced Reward Deficiency Symptomatology by Regulating Dopamine Transmission.

PubMed

Blum, Kenneth; Modestino, Edward J; Febo, Marcelo; Steinberg, Bruce; McLaughlin, Thomas; Fried, Lyle; Baron, David; Siwicki, David; Badgaiyan, Rajendra D

2017-05-01

The principal vector of Lyme disease in the United States is Ixodes scapularis: black legged or deer ticks. There is increased evidence that those infected may be plagued by anxiety or depression as well. Researchers have identified transcripts coding for two putative cytosolic sulfotransferases in these ticks, which recognized phenolic monoamines as their substrates. It is hypothesized that protracted Lyme disease sequelae may be due to impairment of dopaminergic function of the brain reward circuitry. The subsequent recombinant proteins exhibited sulfotransferase function against two neurotransmitters: dopamine and octopamine. This, in itself, can reduce dopamine function leading to many Reward Deficiency Syndrome behaviors, including depression and possibly, anxiety. In fact, it was shown that activity of Ixosc Sult 1 and Sult 2 in the Ixodid tick salivary glands might contain inactivation of the salivation signal through sulfonation of either dopamine or octopamine. This infraction results in a number of clinically observed mood changes, such as anxiety and depression. In fact, there are common symptoms observed for both Parkinson and Lyme diseases. The importance of understanding the mechanistic and neurobiological effects of Lyme on the central nervous system (CNS) provides the basis for pro-dopamine regulation as a treatment. WC 195.

Addictive behaviors and addiction-prone personality traits: associations with a dopamine multilocus genetic profile.

PubMed

Davis, Caroline; Loxton, Natalie J

2013-07-01

The purpose of this study was to examine reward-related genetic risk for addictive behaviors in a healthy community sample (n=217) of men and women. We tested a mediation model predicting that a quantitative multilocus genetic profile score - reflecting the additive effects of alleles known to confer relatively increased dopamine signaling in the ventral striatum - would relate positively to a composite measure of addictive behaviors, and that this association would be mediated by personality traits consistently associated with addiction disorders. Our model was strongly supported by the data, and accounted for 24% of the variance in addictive behaviors. These data suggest that brain reward processes tend to exert their influence on addiction risk by their role in the development of relatively stable personality traits associated with addictive behaviors. Copyright © 2013 Elsevier Ltd. All rights reserved.

What a relief! A role for dopamine in positive (but not negative) valence.

PubMed

Sharpe, Melissa J

2018-02-27

We have long known that dopamine encodes the predictive relationship between cues and rewards. But what about relief learning? In this issue of Neuropsychopharmacology, Meyer et al. show that the same circuits encoding rewarding events also encode relief from aversive events. And this appears to be in a manner distinct from encoding of the aversive event itself. So does dopamine only contribute to learning about positive events? And are these events encoded in the same way regardless of how that positive experience came about? Not quite. Turns out, the devil is in the details.

Dopamine or opioid stimulation of nucleus accumbens similarly amplify cue-triggered 'wanting' for reward: entire core and medial shell mapped as substrates for PIT enhancement.

PubMed

Peciña, Susana; Berridge, Kent C

2013-05-01

Pavlovian cues [conditioned stimulus (CS+)] often trigger intense motivation to pursue and consume related reward [unconditioned stimulus (UCS)]. But cues do not always trigger the same intensity of motivation. Encountering a reward cue can be more tempting on some occasions than on others. What makes the same cue trigger more intense motivation to pursue reward on a particular encounter? The answer may be the level of incentive salience ('wanting') that is dynamically generated by mesocorticolimbic brain systems, influenced especially by dopamine and opioid neurotransmission in the nucleus accumbens (NAc) at that moment. We tested the ability of dopamine stimulation (by amphetamine microinjection) vs. mu opioid stimulation [by d-Ala, nMe-Phe, Glyol-enkephalin (DAMGO) microinjection] of either the core or shell of the NAc to amplify cue-triggered levels of motivation to pursue sucrose reward, measured with a Pavlovian-Instrumental Transfer (PIT) procedure, a relatively pure assay of incentive salience. Cue-triggered 'wanting' in PIT was enhanced by amphetamine or DAMGO microinjections equally, and also equally at nearly all sites throughout the entire core and medial shell (except for a small far-rostral strip of shell). NAc dopamine/opioid stimulations specifically enhanced CS+ ability to trigger phasic peaks of 'wanting' to obtain UCS, without altering baseline efforts when CS+ was absent. We conclude that dopamine/opioid stimulation throughout nearly the entire NAc can causally amplify the reactivity of mesocorticolimbic circuits, and so magnify incentive salience or phasic UCS 'wanting' peaks triggered by a CS+. Mesolimbic amplification of incentive salience may explain why a particular cue encounter can become irresistibly tempting, even when previous encounters were successfully resisted before. © 2013 Federation of European Neuroscience Societies and John Wiley & Sons Ltd.

Genetic moderation of the association between regulatory focus and reward responsiveness: a proof-of-concept study.

PubMed

Goetz, Elena L; Hariri, Ahmad R; Pizzagalli, Diego A; Strauman, Timothy J

2013-02-01

Recent studies implicate individual differences in regulatory focus as contributing to self-regulatory dysfunction, particularly not responding to positive outcomes. How such individual differences emerge, however, is unclear. We conducted a proof-of-concept study to examine the moderating effects of genetically driven variation in dopamine signaling, a key modulator of neural reward circuits, on the association between regulatory focus and reward cue responsiveness. Healthy Caucasians (N=59) completed a measure of chronic regulatory focus and a probabilistic reward task. A common functional genetic polymorphism impacting prefrontal dopamine signaling (COMT rs4680) was evaluated. Response bias, the participants' propensity to modulate behavior as a function of reward, was predicted by an interaction of regulatory focus and COMT genotype. Specifically, self-perceived success at achieving promotion goals predicted total response bias, but only for individuals with the COMT genotype (Val/Val) associated with relatively increased phasic dopamine signaling and cognitive flexibility. The combination of success in promotion goal pursuit and Val/Val genotype appears to facilitate responding to reward opportunities in the environment. This study is among the first to integrate an assessment of self-regulatory style with an examination of genetic variability that underlies responsiveness to positive outcomes in goal pursuit.

Punishment induced behavioural and neurophysiological variability reveals dopamine-dependent selection of kinematic movement parameters

PubMed Central

Galea, Joseph M.; Ruge, Diane; Buijink, Arthur; Bestmann, Sven; Rothwell, John C.

2013-01-01

Action selection describes the high-level process which selects between competing movements. In animals, behavioural variability is critical for the motor exploration required to select the action which optimizes reward and minimizes cost/punishment, and is guided by dopamine (DA). The aim of this study was to test in humans whether low-level movement parameters are affected by punishment and reward in ways similar to high-level action selection. Moreover, we addressed the proposed dependence of behavioural and neurophysiological variability on DA, and whether this may underpin the exploration of kinematic parameters. Participants performed an out-and-back index finger movement and were instructed that monetary reward and punishment were based on its maximal acceleration (MA). In fact, the feedback was not contingent on the participant’s behaviour but pre-determined. Blocks highly-biased towards punishment were associated with increased MA variability relative to blocks with either reward or without feedback. This increase in behavioural variability was positively correlated with neurophysiological variability, as measured by changes in cortico-spinal excitability with transcranial magnetic stimulation over the primary motor cortex. Following the administration of a DA-antagonist, the variability associated with punishment diminished and the correlation between behavioural and neurophysiological variability no longer existed. Similar changes in variability were not observed when participants executed a pre-determined MA, nor did DA influence resting neurophysiological variability. Thus, under conditions of punishment, DA-dependent processes influence the selection of low-level movement parameters. We propose that the enhanced behavioural variability reflects the exploration of kinematic parameters for less punishing, or conversely more rewarding, outcomes. PMID:23447607

Developmental origins of brain disorders: roles for dopamine

PubMed Central

Money, Kelli M.; Stanwood, Gregg D.

2013-01-01

Neurotransmitters and neuromodulators, such as dopamine, participate in a wide range of behavioral and cognitive functions in the adult brain, including movement, cognition, and reward. Dopamine-mediated signaling plays a fundamental neurodevelopmental role in forebrain differentiation and circuit formation. These developmental effects, such as modulation of neuronal migration and dendritic growth, occur before synaptogenesis and demonstrate novel roles for dopaminergic signaling beyond neuromodulation at the synapse. Pharmacologic and genetic disruptions demonstrate that these effects are brain region- and receptor subtype-specific. For example, the striatum and frontal cortex exhibit abnormal neuronal structure and function following prenatal disruption of dopamine receptor signaling. Alterations in these processes are implicated in the pathophysiology of neuropsychiatric disorders, and emerging studies of neurodevelopmental disruptions may shed light on the pathophysiology of abnormal neuronal circuitry in neuropsychiatric disorders. PMID:24391541

An Integrative Perspective on the Role of Dopamine in Schizophrenia

PubMed Central

Maia, Tiago V.; Frank, Michael J.

2017-01-01

We propose that schizophrenia involves a combination of decreased phasic dopamine responses for relevant stimuli and increased spontaneous phasic dopamine release. Using insights from computational reinforcement-learning models and basic-science studies of the dopamine system, we show that each of these two disturbances contributes to a specific symptom domain and explains a large set of experimental findings associated with that domain. Reduced phasic responses for relevant stimuli help to explain negative symptoms and provide a unified explanation for the following experimental findings in schizophrenia, most of which have been shown to correlate with negative symptoms: reduced learning from rewards; blunted activation of the ventral striatum, midbrain, and other limbic regions for rewards and positive prediction errors; blunted activation of the ventral striatum during reward anticipation; blunted autonomic responding for relevant stimuli; blunted neural activation for aversive outcomes and aversive prediction errors; reduced willingness to expend effort for rewards; and psychomotor slowing. Increased spontaneous phasic dopamine release helps to explain positive symptoms and provides a unified explanation for the following experimental findings in schizophrenia, most of which have been shown to correlate with positive symptoms: aberrant learning for neutral cues (assessed with behavioral and autonomic responses), and aberrant, increased activation of the ventral striatum, midbrain, and other limbic regions for neutral cues, neutral outcomes, and neutral prediction errors. Taken together, then, these two disturbances explain many findings in schizophrenia. We review evidence supporting their co-occurrence and consider their differential implications for the treatment of positive and negative symptoms. PMID:27452791

Striatal dopamine transmission in healthy humans during a passive monetary reward task.

PubMed

Hakyemez, Hélène S; Dagher, Alain; Smith, Stephen D; Zald, David H

2008-02-15

Research on dopamine (DA) transmission has emphasized the importance of increased phasic DA cell firing in the presence of unpredictable rewards. Using [(11)C]raclopride PET, we previously reported that DA transmission was both suppressed and enhanced in different regions of the striatum during an unpredictable reward task [Zald, D.H., Boileau, I., El Dearedy, W., Gunn, R., McGlone, F., Dichter, G.S. et al. (2004). Dopamine transmission in the human striatum during monetary reward tasks. J. Neurosci. 24, 4105-4112]. However, it was unclear if reductions in DA release during this task reflected a response to the high proportion of nonrewarding trials, and whether the behavioral demands of the task influenced the observed response. To test these issues, we presented 10 healthy subjects with an automated (passive) roulette wheel game in which the amount of reward and its timing were unpredictable and the rewarding trials greatly outnumbered the nonrewarding ones. As in the previous study, DA transmission in the putamen was significantly suppressed relative to a predictable control condition. A similar suppression occurred when subjects were presented with temporally unpredictable novel pictures and sounds. At present, models of DA functioning during reward do not account for this suppression, but given that it has been observed in two different studies using different reward paradigms, this phenomenon warrants attention. Neither the unpredictable reward nor the novelty conditions produced consistent increases in striatal DA transmission. These data suggest that active behavioral engagement may be necessary to observe robust statewise increases in DA release in the striatum.

Hypothesizing dopaminergic genetic antecedents in schizophrenia and substance seeking behavior.

PubMed

Blum, Kenneth; Oscar-Berman, Marlene; Badgaiyan, Rajendra D; Palomo, Tomas; Gold, Mark S

2014-05-01

The dopamine system has been implicated in both substance use disorder (SUD) and schizophrenia. A recent meta-analysis suggests that A1 allele of the DRD2 gene imposes genetic risk for SUD, especially alcoholism and has been implicated in Reward Deficiency Syndrome (RDS). We hypothesize that dopamine D2 receptor (DRD2) gene Taq1 A2 allele is associated with a subtype of non-SUD schizophrenics and as such may act as a putative protective agent against the development of addiction to alcohol or other drugs of abuse. Schizophrenics with SUD may be carriers of the DRD2 Taq1 A1 allele, and/or other RDS reward polymorphisms and have hypodopaminergic reward function. One plausible mechanism for alcohol seeking in schizophrenics with SUD, based on previous research, may be a deficiency of gamma type endorphins that has been linked to schizophrenic type psychosis. We also propose that alcohol seeking behavior in schizophrenics, may serve as a physiological self-healing process linked to the increased function of the gamma endorphins, thereby reducing abnormal dopaminergic activity at the nucleus accumbens (NAc). These hypotheses warrant further investigation and cautious interpretation. We, therefore, encourage research involving neuroimaging, genome wide association studies (GWAS), and epigenetic investigation into the relationship between neurogenetics and systems biology to unravel the role of dopamine in psychiatric illness and SUD. Copyright © 2014 Elsevier Ltd. All rights reserved.

Deficient reinforcement learning in medial frontal cortex as a model of dopamine-related motivational deficits in ADHD.

PubMed

Silvetti, Massimo; Wiersema, Jan R; Sonuga-Barke, Edmund; Verguts, Tom

2013-10-01

Attention Deficit/Hyperactivity Disorder (ADHD) is a pathophysiologically complex and heterogeneous condition with both cognitive and motivational components. We propose a novel computational hypothesis of motivational deficits in ADHD, drawing together recent evidence on the role of anterior cingulate cortex (ACC) and associated mesolimbic dopamine circuits in both reinforcement learning and ADHD. Based on findings of dopamine dysregulation and ACC involvement in ADHD we simulated a lesion in a previously validated computational model of ACC (Reward Value and Prediction Model, RVPM). We explored the effects of the lesion on the processing of reinforcement signals. We tested specific behavioral predictions about the profile of reinforcement-related deficits in ADHD in three experimental contexts; probability tracking task, partial and continuous reward schedules, and immediate versus delayed rewards. In addition, predictions were made at the neurophysiological level. Behavioral and neurophysiological predictions from the RVPM-based lesion-model of motivational dysfunction in ADHD were confirmed by data from previously published studies. RVPM represents a promising model of ADHD reinforcement learning suggesting that ACC dysregulation might play a role in the pathogenesis of motivational deficits in ADHD. However, more behavioral and neurophysiological studies are required to test core predictions of the model. In addition, the interaction with different brain networks underpinning other aspects of ADHD neuropathology (i.e., executive function) needs to be better understood. Copyright © 2013 Elsevier Ltd. All rights reserved.

Hypothesizing Dopaminergic Genetic Antecedents in Schizophrenia and Substance Seeking Behavior

PubMed Central

Blum, Kenneth; Oscar-Berman, Marlene; Badgaiyan, Rajendra; Palomo, Tomas; Gold, Mark S.

2014-01-01

The dopamine system has been implicated in both substance use disorder (SUD) and schizophrenia. A recent meta- analysis suggests that A1 allele of the DRD2 gene imposes genetic risk for SUD, especially alcoholism and has been implicated in Reward Deficiency Syndrome (RDS). We hypothesize that dopamine D2 receptor (DRD2) gene Taq1 A2 allele is associated with a subtype of non- SUD schizophrenics and as such may act as a putative protective agent against the development of addiction to alcohol or other drugs of abuse. Schizophrenics with SUD may be carriers of the DRD2 Taq1 A1 allele, and/or other RDS reward polymorphisms and have hypodopaminergic reward function. One plausible mechanism for alcohol seeking in schizophrenics with SUD, based on previous research, may be a deficiency of gamma type endorphins that has been linked to schizophrenic type psychosis.. We also propose that alcohol seeking behavior in schizophrenics, may serve as a physiological self-healing process linked to the increased function of the gamma endorphins, thereby reducing abnormal dopaminergic activity at the nucleus accumbens (NAc). These hypotheses warrant further investigation and cautious interpretation. We, therefore, encourage research involving neuroimaging, genome wide association studies (GWAS), and epigenetic investigation into the relationship between neurogenetics and systems biology to unravel the role of dopamine in psychiatric illness and SUD. PMID:24636783

Dopamine modulates striatal response to reward and punishment in patients with Parkinson's disease: a pharmacological challenge fMRI study.

PubMed

Argyelan, Miklos; Herzallah, Mohammad; Sako, Wataru; DeLucia, Ivana; Sarpal, Deepak; Vo, An; Fitzpatrick, Toni; Moustafa, Ahmed A; Eidelberg, David; Gluck, Mark

2018-05-02

It is well established that Parkinson's disease leads to impaired learning from reward and enhanced learning from punishment. The administration of dopaminergic medications reverses this learning pattern. However, few studies have investigated the neural underpinnings of these cognitive processes. In this study, using fMRI, we tested a group of Parkinson's disease patients on and off dopaminergic medications and matched healthy individuals. All individuals completed an fMRI cognitive task that dissociates feedback learning from reward versus punishment. The administration of dopaminergic medications attenuated blood oxygen level dependent (BOLD) responses to punishment in the bilateral putamen, in bilateral dorsolateral prefrontal cortex and the left premotor cortex. Further, the administration of dopaminergic medications resulted in a higher ratio of BOLD activity between reward and punishment trials in these brain areas. BOLD activity in these brain areas was significantly correlated with learning from punishment, but not from reward trials. Furthermore, the administration of dopaminergic medications altered BOLD activity in the right insula and ventromedial prefrontal cortex when Parkinson's disease patients were anticipating feedback. These findings are in agreement with a large body of literature indicating that Parkinson's disease is associated with enhanced learning from punishment. However, it was surprising that dopaminergic medications modulated punishment learning as opposed to reward learning, although reward learning has been directly linked to dopaminergic function. We argue that these results might be attributed to both a change in the balance between direct and indirect pathway activation in the basal ganglia as well as the differential activity of D1 versus D2 dopamine receptors.

A Neurocomputational model of tonic and phasic dopamine in action selection: A comparison with cognitive deficits in Parkinson’s disease

PubMed Central

Guthrie, M.; Myers, C.E.; Gluck, M.A.

2015-01-01

The striatal dopamine signal has multiple facets; tonic level, phasic rise and fall, and variation of the phasic rise/fall depending on the expectation of reward/punishment. We have developed a network model of the striatal direct pathway using an ionic current level model of the medium spiny neuron that incorporates currents sensitive to changes in the tonic level of dopamine. The model neurons in the network learn action selection based on a novel set of mathematical rules that incorporate the phasic change in the dopamine signal. This network model is capable of learning to perform a sequence learning task that in humans is thought to be dependent on the basal ganglia. When both tonic and phasic levels of dopamine are decreased, as would be expected in unmedicated Parkinson’s disease (PD), the model reproduces the deficits seen in a human PD group off medication. When the tonic level is increased to normal, but with reduced phasic increases and decreases in response to reward and punishment respectively, as would be expected in PD medicated with L-Dopa, the model again reproduces the human data. These findings support the view that the cognitive dysfunctions seen in Parkinson’s disease are not solely due to either the decreased tonic level of dopamine or to the decreased responsiveness of the phasic dopamine signal to reward and punishment, but to a combination of the two factors that varies dependent on disease stage and medication status. PMID:19162084

Modafinil augments brain activation associated with reward anticipation in the nucleus accumbens.

PubMed

Funayama, Takuya; Ikeda, Yumiko; Tateno, Amane; Takahashi, Hidehiko; Okubo, Yoshiro; Fukayama, Haruhisa; Suzuki, Hidenori

2014-08-01

The nucleus accumbens (NAc) works as a key brain structure of the reward system, in which reward-related neural activity is well correlated with dopamine release from mesolimbic dopaminergic neurons. Since modafinil can modulate dopaminergic transmission through re-uptake inhibition of dopamine, we investigated whether modafinil affects the reward-related brain activity in the NAc in healthy subjects. Twenty healthy participants underwent two series of functional magnetic resonance imaging while performing monetary incentive delay task in which they were cued to anticipate and respond to a rapidly presented target to gain or avoid losing varying amounts of money, under modafinil or placebo condition. Blood oxygenation-level dependent (BOLD) activation signals during gain and loss anticipations were analyzed in the NAc as an a priori region of interest as well as the whole brain. Modafinil significantly changed subjective feelings toward positive ones. The activation of BOLD signals was observed during gain anticipation under the placebo and modafinil conditions in the left and bilateral NAc, respectively. The modafinil condition showed significantly higher BOLD signal change at the highest gain (+¥500) cue compared to the placebo condition. The present study showed that modafinil affects reward processing in the NAc in healthy subjects through enhancing more positive anticipation, and it may provide a basis for the use of this drug for treating anhedonia observed in psychiatric disorders.

Fifty Years in the Development of a Glutaminergic-Dopaminergic Optimization Complex (KB220) to Balance Brain Reward Circuitry in Reward Deficiency Syndrome: A Pictorial

PubMed Central

Blum, K; Febo, M; Badgaiyan, RD

2016-01-01

Dopamine along with other chemical messengers like serotonin, cannabinoids, endorphins and glutamine, play significant roles in brain reward processing. There is a devastating opiate/opioid epidemicin the United States. According to the Centers for Disease Control and Prevention (CDC), at least 127 people, young and old, are dying every day due to narcotic overdose and alarmingly heroin overdose is on the rise. The Food and Drug Administration (FDA) has approved some Medication-Assisted Treatments (MATs) for alcoholism, opiate and nicotine dependence, but nothing for psychostimulant and cannabis abuse. While these pharmaceuticals are essential for the short-term induction of “psychological extinction,” in the long-term caution is necessary because their use favors blocking dopaminergic function indispensable for achieving normal satisfaction in life. The two institutions devoted to alcoholism and drug dependence (NIAAA & NIDA) realize that MATs are not optimal and continue to seek better treatment options. We review, herein, the history of the development of a glutaminergic-dopaminergic optimization complex called KB220 to provide for the possible eventual balancing of the brain reward system and the induction of “dopamine homeostasis.” This complex may provide substantial clinical benefit to the victims of Reward Deficiency Syndrome (RDS) and assist in recovery from iatrogenically induced addiction to unwanted opiates/opioids and other addictive behaviors. PMID:27840857

Within-session decrement of the emission of licking bursts following reward devaluation in rats licking for sucrose

PubMed Central

Galistu, Adriana

2017-01-01

We previously observed that dopamine D2-like receptor blockade in rats licking for sucrose produced a within-session decrement of the emission of licking bursts similar to the effect of either reward devaluation, or neuroleptics, on operant responding for different rewards, which, accordingly, we interpreted as an extinction-like effect. This implies that exposing animals to reward devaluation would result in a drop of burst number taking place only after the contact with the devalued reward. To test this prediction, we compared the difference in the within-session time course of burst number in response to high (10%) versus low (2%) concentration sucrose solutions, either in a condition of reward devaluation (exposure to 2% after daily 10%), or in a condition which does not involve changes in the reward value (two groups of subjects each repeatedly exposed to only one of the two concentrations). Reward devaluation resulted in a within-session decrement of the burst number, with the response rate dropping only after the contact with the devalued reward, as predicted. This response pattern was reliably observed only in subjects at their first devaluation experience. In contrast, exposure of separate groups of animals to the two different concentrations yielded lower levels of burst number in the low concentration group apparent since the beginning of the session, as previously observed with dopamine D1-like receptor blockade. These results show that the analysis of burst number, but not of burst size, reveals a specific activation pattern in response to reward devaluation, which differs from the pattern observed comparing the response to two different sucrose concentrations in separate groups of subjects, i.e. in a condition not involving reward devaluation. Finally, the characterisation of the experimental measures of the analysis of licking microstructure in behaviourally (and psychologically) meaningful functional terms, might be relevant for the investigation of the mechanisms underlying behavioural activation and the related evaluation processes. PMID:28493981

Exposure to bright light biases effort-based decisions.

PubMed

Bijleveld, Erik; Knufinke, Melanie

2018-06-01

Secreted in the evening and the night, melatonin suppresses activity of the mesolimbic dopamine pathway, a brain pathway involved in reward processing. However, exposure to bright light diminishes-or even prevents-melatonin secretion. Thus, we hypothesized that reward processing, in the evening, is more pronounced in bright light (vs. dim light). Healthy human participants carried out three tasks that tapped into various aspects of reward processing (effort expenditure for rewards task [EEfRT]; two-armed bandit task [2ABT]; balloon analogue risk task [BART). Brightness was manipulated within-subjects (bright vs. dim light), in separate evening sessions. During the EEfRT, participants used reward-value information more strongly when they were exposed to bright light (vs. dim light). This finding supported our hypothesis. However, exposure to bright light did not significantly affect task behavior on the 2ABT and the BART. While future research is necessary (e.g., to zoom in on working mechanisms), these findings have potential implications for the design of physical work environments. (PsycINFO Database Record (c) 2018 APA, all rights reserved).

Psychostimulants affect dopamine transmission through both dopamine transporter-dependent and independent mechanisms

PubMed Central

dela Peña, Ike; Gevorkiana, Ruzanna; Shi, Wei-Xing

2015-01-01

The precise mechanisms by which cocaine and amphetamine-like psychostimulants exert their reinforcing effects are not yet fully defined. It is widely believed, however, that these drugs produce their effects by enhancing dopamine neurotransmission in the brain, especially in limbic areas such as the nucleus accumbens, by inducing dopamine transporter-mediated reverse transport and/or blocking dopamine reuptake though the dopamine transporter. Here, we present the evidence that aside from dopamine transporter, non-dopamine transporter-mediated mechanisms also participate in psychostimulant-induced dopamine release and contribute to the behavioral effects of these drugs, such as locomotor activation and reward. Accordingly, psychostimulants could increase norepinephrine release in the prefrontal cortex, the latter then alters the firing pattern of dopamine neurons resulting in changes in action potential-dependent dopamine release. These alterations would further affect the temporal pattern of dopamine release in the nucleus accumbens, thereby modifying information processing in that area. Hence, a synaptic input to a nucleus accumbens neuron may be enhanced or inhibited by dopamine depending on its temporal relationship to dopamine release. Specific temporal patterns of dopamine release may also be required for certain forms of synaptic plasticity in the nucleus accumbens. Together, these effects induced by psychostimulants, mediated through a non-dopamine transporter-mediated mechanism involving norepinephrine and the prefrontal cortex, may also contribute importantly to the reinforcing properties of these drugs. PMID:26209364

Emotional modulation of control dilemmas: the role of positive affect, reward, and dopamine in cognitive stability and flexibility.

PubMed

Goschke, Thomas; Bolte, Annette

2014-09-01

Goal-directed action in changing environments requires a dynamic balance between complementary control modes, which serve antagonistic adaptive functions (e.g., to shield goals from competing responses and distracting information vs. to flexibly switch between goals and behavioral dispositions in response to significant changes). Too rigid goal shielding promotes stability but incurs a cost in terms of perseveration and reduced flexibility, whereas too weak goal shielding promotes flexibility but incurs a cost in terms of increased distractibility. While research on cognitive control has long been conducted relatively independently from the study of emotion and motivation, it is becoming increasingly clear that positive affect and reward play a central role in modulating cognitive control. In particular, evidence from the past decade suggests that positive affect not only influences the contents of cognitive processes, but also modulates the balance between complementary modes of cognitive control. In this article we review studies from the past decade that examined effects of induced positive affect on the balance between cognitive stability and flexibility with a focus on set switching and working memory maintenance and updating. Moreover, we review recent evidence indicating that task-irrelevant positive affect and performance-contingent rewards exert different and sometimes opposite effects on cognitive control modes, suggesting dissociations between emotional and motivational effects of positive affect. Finally, we critically review evidence for the popular hypothesis that effects of positive affect may be mediated by dopaminergic modulations of neural processing in prefrontal and striatal brain circuits, and we refine this "dopamine hypothesis of positive affect" by specifying distinct mechanisms by which dopamine may mediate effects of positive affect and reward on cognitive control. We conclude with a discussion of limitations of current research, point to central unresolved questions and outline perspective for future research on affective and motivational modulations of cognitive control modes. Copyright © 2014. Published by Elsevier Ltd.

The roles of the anterior cingulate cortex and its dopamine receptors in self-paced cost-benefit decision making in rats.

PubMed

Wang, Shuai; Hu, Shan-Hu; Shi, Yi; Li, Bao-Ming

2017-03-01

It has been shown that the anterior cingulate cortex (ACC) and its dopamine system are crucial for decision making that requires physical/emotional effort, but not for all forms of cost-benefit decision making. Previous studies had mostly employed behavioral tasks with two competing cost-reward options that were preset by the experimenters. However, few studies have been conducted using scenarios in which the subjects have full control over the energy/time expenditure required to obtain a proportional reward. Here, we assessed the roles of the ACC and its dopamine system in cost-benefit decision making by utilizing a "do more get more" (DMGM) task and a time-reward trade-off (TRTO) task, wherein the animals were able to self-determine how much effort or time to expend at a nosepoke operandum for a proportional reward. Our results showed that (1) ACC inactivation severely impaired DMGM task performance, with a reduction in the rate of correct responses and a decrease in the effort expended, but did not affect the TRTO task; and (2) blocking ACC D2 receptors had no impact on DMGM task performance in the baseline cost-benefit scenario, but it significantly reduced the attempts to invest increased effort for a large reward when the benefit-cost ratio was reduced by half. In contrast, blocking ACC D1 receptors had no effect on DMGM task performance. These findings suggest that the ACC is required for self-paced effort-based but not for time-reward trade-off decision making. Furthermore, ACC dopamine D2 but not D1 receptors are involved in DMGM decision making.

Neuropsychotoxicity of abused drugs: involvement of matrix metalloproteinase-2 and -9 and tissue inhibitor of matrix metalloproteinase-2 in methamphetamine-induced behavioral sensitization and reward in rodents.

PubMed

Mizoguchi, Hiroyuki; Yamada, Kiyofumi; Nabeshima, Toshitaka

2008-01-01

Matrix metalloproteinases (MMPs) and their inhibitors (TIMPs) function to remodel the pericellular environment. We have investigated the role of the MMP/TIMP system in methamphetamine (METH) dependence in rodents, in which the remodeling of neural circuits may be crucial. Repeated METH treatment induced behavioral sensitization, which was accompanied by an increase in MMP-2/-9/TIMP-2 activity in the brain. An antisense TIMP-2 oligonucleotide enhanced the sensitization, which was associated with a potentiation of the METH-induced release of dopamine in the nucleus accumbens (NAc). MMP-2/-9 inhibitors blocked the METH-induced behavioral sensitization and conditioned place preference (CPP), a measure of the rewarding effect of a drug, and reduced the METH-increased dopamine release in the NAc. In MMP-2- and MMP-9-deficient mice, METH-induced behavioral sensitization and CPP as well as dopamine release were attenuated. The MMP/TIMP system may be involved in METH-induced sensitization and reward by regulating extracellular dopamine levels.

Fuel not fun: Reinterpreting attenuated brain responses to reward in obesity.

PubMed

Kroemer, Nils B; Small, Dana M

2016-08-01

There is a well-established literature linking obesity to altered dopamine signaling and brain response to food-related stimuli. Neuroimaging studies frequently report enhanced responses in dopaminergic regions during food anticipation and decreased responses during reward receipt. This has been interpreted as reflecting anticipatory "reward surfeit", and consummatory "reward deficiency". In particular, attenuated response in the dorsal striatum to primary food rewards is proposed to reflect anhedonia, which leads to overeating in an attempt to compensate for the reward deficit. In this paper, we propose an alternative view. We consider brain response to food-related stimuli in a reinforcement-learning framework, which can be employed to separate the contributions of reward sensitivity and reward-related learning that are typically entangled in the brain response to reward. Consequently, we posit that decreased striatal responses to milkshake receipt reflect reduced reward-related learning rather than reward deficiency or anhedonia because reduced reward sensitivity would translate uniformly into reduced anticipatory and consummatory responses to reward. By re-conceptualizing reward deficiency as a shift in learning about subjective value of rewards, we attempt to reconcile neuroimaging findings with the putative role of dopamine in effort, energy expenditure and exploration and suggest that attenuated brain responses to energy dense foods reflect the "fuel", not the fun entailed by the reward. Copyright © 2016 Elsevier Inc. All rights reserved.

Principles of motivation revealed by the diverse functions of neuropharmacological and neuroanatomical substrates underlying feeding behavior

PubMed Central

Baldo, Brian A.; Pratt, Wayne E.; Will, Matthew J.; Hanlon, Erin C.; Bakshi, Vaishali P.; Cador, Martine

2013-01-01

Circuits that participate in specific subcomponents of feeding (e.g., gustatory perception, peripheral feedback relevant to satiety and energy balance, reward coding, etc.) are found at all levels of the neural axis. Further complexity is conferred by the wide variety of feeding-modulatory neurotransmitters and neuropeptides that act within these circuits. An ongoing challenge has been to refine the understanding of the functional specificity of these neurotransmitters and circuits, and there have been exciting advances in recent years. We focus here on foundational work of Dr. Ann Kelley that identified distinguishable actions of striatal opioid peptide modulation and dopamine transmission in subcomponents of reward processing. We also discuss her work in overlaying these neuropharmacological effects upon anatomical pathways that link the telencephalon (cortex and basal ganglia) with feeding-control circuits in the hypothalamus. Using these seminal contributions as a starting point, we will discuss new findings that expand our understanding of (1) the specific, differentiable motivational processes that are governed by central dopamine and opioid transmission, (2) the manner in which other striatal neuromodulators, specifically acetylcholine, endocannabinoids and adenosine, modulate these motivational processes (including via interactions with opioid systems), and (3) the organization of the cortical-subcortical network that subserves opioid-driven feeding. The findings discussed here strengthen the view that incentive-motivational properties of food are coded by substrates and neural circuits that are distinguishable from those that mediate the acute hedonic experience of food reward. Striatal opioid transmission modulates reward processing by engaging frontotemporal circuits, possibly via a hypothalamic-thalamic axis, that ultimately impinges upon hypothalamic modules dedicated to autonomic function and motor pattern control. We will conclude by discussing implications for understanding disorders of “non-homeostatic” feeding. PMID:23466532

Principles of motivation revealed by the diverse functions of neuropharmacological and neuroanatomical substrates underlying feeding behavior.

PubMed

Baldo, Brian A; Pratt, Wayne E; Will, Matthew J; Hanlon, Erin C; Bakshi, Vaishali P; Cador, Martine

2013-11-01

Circuits that participate in specific subcomponents of feeding (e.g., gustatory perception, peripheral feedback relevant to satiety and energy balance, reward coding, etc.) are found at all levels of the neural axis. Further complexity is conferred by the wide variety of feeding-modulatory neurotransmitters and neuropeptides that act within these circuits. An ongoing challenge has been to refine the understanding of the functional specificity of these neurotransmitters and circuits, and there have been exciting advances in recent years. We focus here on foundational work of Dr. Ann Kelley that identified distinguishable actions of striatal opioid peptide modulation and dopamine transmission in subcomponents of reward processing. We also discuss her work in overlaying these neuropharmacological effects upon anatomical pathways that link the telencephalon (cortex and basal ganglia) with feeding-control circuits in the hypothalamus. Using these seminal contributions as a starting point, we will discuss new findings that expand our understanding of (1) the specific, differentiable motivational processes that are governed by central dopamine and opioid transmission, (2) the manner in which other striatal neuromodulators, specifically acetylcholine, endocannabinoids and adenosine, modulate these motivational processes (including via interactions with opioid systems), and (3) the organization of the cortical-subcortical network that subserves opioid-driven feeding. The findings discussed here strengthen the view that incentive-motivational properties of food are coded by substrates and neural circuits that are distinguishable from those that mediate the acute hedonic experience of food reward. Striatal opioid transmission modulates reward processing by engaging frontotemporal circuits, possibly via a hypothalamic-thalamic axis, that ultimately impinges upon hypothalamic modules dedicated to autonomic function and motor pattern control. We will conclude by discussing implications for understanding disorders of "non-homeostatic" feeding. Copyright © 2013 Elsevier Ltd. All rights reserved.

Is social attachment an addictive disorder?

PubMed

Insel, Thomas R

2003-08-01

There is a considerable literature on the neurobiology of reward, based largely on studies of addiction or substance abuse. This review considers the possibility that the neural circuits that mediate reward evolved for ethologically relevant cues, such as social attachment. Specifically, mesocorticolimbic dopamine appears important for maternal behavior in rats and pair bonding in monogamous voles. It is not yet clear that dopamine in this pathway mediates the hedonic properties of social bond formation or whether dopamine's role is more relevant to developing associative networks or assigning salience to social stimuli. The neuropeptides oxytocin (OT) and vasopressin (AVP) appear to be critical for linking social signals to the mesocorticolimbic circuit.

The Role of Dopamine in Inflammation-Associated Depression: Mechanisms and Therapeutic Implications.

PubMed

Felger, Jennifer C

Studies investigating the impact of a variety of inflammatory stimuli on the brain and behavior have consistently reported evidence that inflammatory cytokines affect the basal ganglia and dopamine to mediate depressive symptoms related to motivation and motor activity. Findings have included inflammation-associated reductions in ventral striatal responses to hedonic reward, decreased dopamine and dopamine metabolites in cerebrospinal fluid, and decreased availability of striatal dopamine, all of which correlate with symptoms of anhedonia, fatigue, and psychomotor retardation. Similar relationships between alterations in dopamine-relevant corticostriatal reward circuitry and symptoms of anhedonia and psychomotor slowing have also been observed in patients with major depression who exhibit increased peripheral cytokines and other inflammatory markers, such as C-reactive protein. Of note, these inflammation-associated depressive symptoms are often difficult to treat in patients with medical illnesses or major depression. Furthermore, a wealth of literature suggests that inflammation can decrease dopamine synthesis, packaging, and release, thus sabotaging or circumventing the efficacy of standard antidepressant treatments. Herein, the mechanisms by which inflammation and cytokines affect dopamine neurotransmission are discussed, which may provide novel insights into treatment of inflammation-related behavioral symptoms that contribute to an inflammatory malaise.

Acute fasting increases somatodendritic dopamine release in the ventral tegmental area

PubMed Central

2015-01-01

Fasting and food restriction alter the activity of the mesolimbic dopamine system to affect multiple reward-related behaviors. Food restriction decreases baseline dopamine levels in efferent target sites and enhances dopamine release in response to rewards such as food and drugs. In addition to releasing dopamine from axon terminals, dopamine neurons in the ventral tegmental area (VTA) also release dopamine from their soma and dendrites, and this somatodendritic dopamine release acts as an autoinhibitory signal to inhibit neighboring VTA dopamine neurons. It is unknown whether acute fasting also affects dopamine release, including the local inhibitory somatodendritic dopamine release in the VTA. In these studies, I have tested whether fasting affects the inhibitory somatodendritic dopamine release within the VTA by examining whether an acute 24-h fast affects the inhibitory postsynaptic current mediated by evoked somatodendritic dopamine release (D2R IPSC). Fasting increased the contribution of the first action potential to the overall D2R IPSC and increased the ratio of repeated D2R IPSCs evoked at short intervals. Fasting also reduced the effect of forskolin on the D2R IPSC and led to a significantly bigger decrease in the D2R IPSC in low extracellular calcium. Finally, fasting resulted in an increase in the D2R IPSCs when a more physiologically relevant train of D2R IPSCs was used. Taken together, these results indicate that fasting caused a change in the properties of somatodendritic dopamine release, possibly by increasing dopamine release, and that this increased release can be sustained under conditions where dopamine neurons are highly active. PMID:26084913

Neuroimaging of the Dopamine/Reward System in Adolescent Drug Use

PubMed Central

Ernst, Monique; Luciana, Monica

2015-01-01

Adolescence is characterized by heightened risk-taking, including substance misuse. These behavioral patterns are influenced by ontogenic changes in neurotransmitter systems, particularly the dopamine system, which is fundamentally involved in the neural coding of reward and motivated approach behavior. During adolescence, this system evidences a peak in activity. At the same time, the dopamine system is neuroplastically altered by substance abuse, impacting subsequent function. Here, we describe properties of the dopamine system that change with typical adolescent development and that are altered with substance abuse. Much of this work has been gleaned from animal models due to limitations in measuring dopamine in pediatric samples. Structural and functional neuroimaging techniques have been used to examine structures that are heavily DA-innervated; they measure morphological and functional changes with age and with drug exposure. Presenting marijuana abuse as an exemplar, we consider recent findings that support an adolescent peak in DA-driven reward-seeking behavior and related deviations in motivational systems that are associated with marijuana abuse/dependence. Clinicians are advised that (1) chronic adolescent marijuana use may lead to deficiencies in incentive motivation, (2) that this state is due to marijuana’s interactions with the developing DA system, and (3) that treatment strategies should be directed to remediating resultant deficiencies in goal-directed activity. PMID:26095977

Impulsive actions and choices in laboratory animals and humans: effects of high vs. low dopamine states produced by systemic treatments given to neurologically intact subjects

PubMed Central

D’Amour-Horvat, Valérie; Leyton, Marco

2014-01-01

Increases and decreases in dopamine (DA) transmission have both been suggested to influence reward-related impulse-control. The present literature review suggests that, in laboratory animals, the systemic administration of DA augmenters preferentially increases susceptibility to premature responding; with continued DA transmission, reward approach behaviors are sustained. Decreases in DA transmission, in comparison, diminish the appeal of distal and difficult to obtain rewards, thereby increasing susceptibility to temporal discounting and other forms of impulsive choice. The evidence available in humans is not incompatible with this model but is less extensive. PMID:25566001

An Integrative Perspective on the Role of Dopamine in Schizophrenia.

PubMed

Maia, Tiago V; Frank, Michael J

2017-01-01

We propose that schizophrenia involves a combination of decreased phasic dopamine responses for relevant stimuli and increased spontaneous phasic dopamine release. Using insights from computational reinforcement-learning models and basic-science studies of the dopamine system, we show that each of these two disturbances contributes to a specific symptom domain and explains a large set of experimental findings associated with that domain. Reduced phasic responses for relevant stimuli help to explain negative symptoms and provide a unified explanation for the following experimental findings in schizophrenia, most of which have been shown to correlate with negative symptoms: reduced learning from rewards; blunted activation of the ventral striatum, midbrain, and other limbic regions for rewards and positive prediction errors; blunted activation of the ventral striatum during reward anticipation; blunted autonomic responding for relevant stimuli; blunted neural activation for aversive outcomes and aversive prediction errors; reduced willingness to expend effort for rewards; and psychomotor slowing. Increased spontaneous phasic dopamine release helps to explain positive symptoms and provides a unified explanation for the following experimental findings in schizophrenia, most of which have been shown to correlate with positive symptoms: aberrant learning for neutral cues (assessed with behavioral and autonomic responses), and aberrant, increased activation of the ventral striatum, midbrain, and other limbic regions for neutral cues, neutral outcomes, and neutral prediction errors. Taken together, then, these two disturbances explain many findings in schizophrenia. We review evidence supporting their co-occurrence and consider their differential implications for the treatment of positive and negative symptoms. Copyright © 2016 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.

Dopamine D2-receptor blockade enhances decoding of prefrontal signals in humans.

PubMed

Kahnt, Thorsten; Weber, Susanna C; Haker, Helene; Robbins, Trevor W; Tobler, Philippe N

2015-03-04

The prefrontal cortex houses representations critical for ongoing and future behavior expressed in the form of patterns of neural activity. Dopamine has long been suggested to play a key role in the integrity of such representations, with D2-receptor activation rendering them flexible but weak. However, it is currently unknown whether and how D2-receptor activation affects prefrontal representations in humans. In the current study, we use dopamine receptor-specific pharmacology and multivoxel pattern-based functional magnetic resonance imaging to test the hypothesis that blocking D2-receptor activation enhances prefrontal representations. Human subjects performed a simple reward prediction task after double-blind and placebo controlled administration of the D2-receptor antagonist amisulpride. Using a whole-brain searchlight decoding approach we show that D2-receptor blockade enhances decoding of reward signals in the medial orbitofrontal cortex. Examination of activity patterns suggests that amisulpride increases the separation of activity patterns related to reward versus no reward. Moreover, consistent with the cortical distribution of D2 receptors, post hoc analyses showed enhanced decoding of motor signals in motor cortex, but not of visual signals in visual cortex. These results suggest that D2-receptor blockade enhances content-specific representations in frontal cortex, presumably by a dopamine-mediated increase in pattern separation. These findings are in line with a dual-state model of prefrontal dopamine, and provide new insights into the potential mechanism of action of dopaminergic drugs. Copyright © 2015 the authors 0270-6474/15/354104-08$15.00/0.

NMDA and dopamine D1 receptors within NAc-shell regulate IEG proteins expression in reward circuit during cocaine memory reconsolidation.

PubMed

Li, Y; Ge, S; Li, N; Chen, L; Zhang, S; Wang, J; Wu, H; Wang, X; Wang, X

2016-02-19

Reactivation of consolidated memory initiates a memory reconsolidation process, during which the reactivated memory is susceptible to strengthening, weakening or updating. Therefore, effective interference with the memory reconsolidation process is expected to be an important treatment for drug addiction. The nucleus accumbens (NAc) has been well recognized as a pathway component that can prevent drug relapse, although the mechanism underlying this function is poorly understood. We aimed to clarify the regulatory role of the NAc in the cocaine memory reconsolidation process, by examining the effect of applying different pharmacological interventions to the NAc on Zif 268 and Fos B expression in the entire reward circuit after cocaine memory reactivation. Through the cocaine-induced conditioned place preference (CPP) model, immunohistochemical and immunofluorescence staining for Zif 268 and Fos B were used to explore the functional activated brain nuclei after cocaine memory reactivation. Our results showed that the expression of Zif 268 and Fos B was commonly increased in the medial prefrontal cortex (mPFC), the infralimbic cortex (IL), the NAc-core, the NAc-shell, the hippocampus (CA1, CA2, and CA3 subregions), the amygdala, the ventral tegmental area (VTA), and the supramammillary nucleus (SuM) following memory reconsolidation, and Zif 268/Fos B co-expression was commonly observed (for Zif 268: 51-68%; for Fos B: 52-66%). Further, bilateral NAc-shell infusion of MK 801 and SCH 23390, but not raclopride or propranolol, prior to addictive memory reconsolidation, decreased Zif 268 and Fos B expression in the entire reward circuit, except for the amygdala, and effectively disturbed subsequent CPP-related behavior. In summary, N-methyl-d-aspartate (NMDA) and dopamine D1 receptors, but not dopamine D2 or β adrenergic receptors, within the NAc-shell, may regulate Zif 268 and Fos B expression in most brain nuclei of the reward circuit after cocaine memory reactivation. These findings indicated that the NAc played a key role in regulating addictive memory reconsolidation by influencing the function of the entire addictive memory network. Copyright © 2016. Published by Elsevier Ltd.

Pharmacological stimuli decreasing nucleus accumbens dopamine can act as positive reinforcers but have a low addictive potential.

PubMed

Marinelli, M; Barrot, M; Simon, H; Oberlander, C; Dekeyne, A; Le Moal, M; Piazza, P V

1998-10-01

Opioid peptides, through mu and delta receptors, play an important part in reward. In contrast, the role of kappa receptors is more controversial. We examined the possible positive reinforcing effects of a selective kappa agonist, RU 51599, by studying intravenous self-administration in the rat. The effect of RU 51599 on dopamine release in the nucleus accumbens was also studied, as opioids and dopamine seem to interact in the mediation of reward. The behavioural and dopaminergic effects of RU 51599 were compared with those of the mu agonist heroin. Rats self-administered both RU 51599 (6.5, 20 and 60 microg/inj) and heroin (30 microg/inj) at low ratio requirement. When the ratio requirement, i.e. the number of responses necessary to receive one drug infusion, was increased, self-administration of RU 51599 rapidly extinguished, whereas self-administration of heroin was maintained. Intravenous infusion of RU 51599 (100, 200 and 400 microg) dose-dependently decreased (25, 30 and 40%, respectively) extracellular concentrations of dopamine, as measured by means of microdialysis in freely moving rats. In contrast, heroin increased accumbens dopamine (130% over baseline). These results indicate that kappa receptors, similarly to mu ones, can mediate positive reinforcing effects of opioid peptides. However, the strength of the reinforcement is very low for kappa receptors. This suggests that changes in accumbens dopamine do not correlate with the capacity of a stimulus to induce reward or aversion. In contrast, a parallel seems to exist between an increase in accumbens dopamine and the drive to reach or obtain a positive reinforcer.

Risk of punishment influences discrete and coordinated encoding of reward-guided actions by prefrontal cortex and VTA neurons

PubMed Central

Park, Junchol

2017-01-01

Actions motivated by rewards are often associated with risk of punishment. Little is known about the neural representation of punishment risk during reward-seeking behavior. We modeled this circumstance in rats by designing a task where actions were consistently rewarded but probabilistically punished. Spike activity and local field potentials were recorded during task performance simultaneously from VTA and mPFC, two reciprocally connected regions implicated in reward-seeking and aversive behaviors. At the single unit level, we found that ensembles of putative dopamine and non-dopamine VTA neurons and mPFC neurons encode the relationship between action and punishment. At the network level, we found that coherent theta oscillations synchronize VTA and mPFC in a bottom-up direction, effectively phase-modulating the neuronal spike activity in the two regions during punishment-free actions. This synchrony declined as a function of punishment probability, suggesting that during reward-seeking actions, risk of punishment diminishes VTA-driven neural synchrony between the two regions. PMID:29058673

Music and the nucleus accumbens.

PubMed

Mavridis, Ioannis N

2015-03-01

Music is a universal feature of human societies over time, mainly because it allows expression and regulation of strong emotions, thus influencing moods and evoking pleasure. The nucleus accumbens (NA), the most important pleasure center of the human brain (dominates the reward system), is the 'king of neurosciences' and dopamine (DA) can be rightfully considered as its 'crown' due to the fundamental role that this neurotransmitter plays in the brain's reward system. Purpose of this article was to review the existing literature regarding the relation between music and the NA. Studies have shown that reward value for music can be coded by activity levels in the NA, whose functional connectivity with auditory and frontal areas increases as a function of increasing musical reward. Listening to music strongly modulates activity in a network of mesolimbic structures involved in reward processing including the NA. The functional connectivity between brain regions mediating reward, autonomic and cognitive processing provides insight into understanding why listening to music is one of the most rewarding and pleasurable human experiences. Musical stimuli can significantly increase extracellular DA levels in the NA. NA DA and serotonin were found significantly higher in animals exposed to music. Finally, passive listening to unfamiliar although liked music showed activations in the NA.

The sensory features of a food cue influence its ability to act as an incentive stimulus and evoke dopamine release in the nucleus accumbens core

PubMed Central

Bryan, Myranda A.; Popov, Pavlo; Scarff, Raymond; Carter, Cody; Wright, Erin; Aragona, Brandon J.; Robinson, Terry E.

2016-01-01

The sensory properties of a reward-paired cue (a conditioned stimulus; CS) may impact the motivational value attributed to the cue, and in turn influence the form of the conditioned response (CR) that develops. A cue with multiple sensory qualities, such as a moving lever-CS, may activate numerous neural pathways that process auditory and visual information, resulting in CRs that vary both within and between individuals. For example, CRs include approach to the lever-CS itself (rats that “sign-track”; ST), approach to the location of reward delivery (rats that “goal-track”; GT), or an “intermediate” combination of these behaviors. We found that the multimodal sensory features of the lever-CS were important to the development and expression of sign-tracking. When the lever-CS was covered, and thus could only be heard moving, STs not only continued to approach the lever location but also started to approach the food cup during the CS period. While still predictive of reward, the auditory component of the lever-CS was a much weaker conditioned reinforcer than the visible lever-CS. This plasticity in behavioral responding observed in STs closely resembled behaviors normally seen in rats classified as “intermediates.” Furthermore, the ability of both the lever-CS and the reward-delivery to evoke dopamine release in the nucleus accumbens was also altered by covering the lever—dopamine signaling in STs resembled neurotransmission observed in rats that normally only GT. These data suggest that while the visible lever-CS was attractive, wanted, and had incentive value for STs, when presented in isolation, the auditory component of the cue was simply predictive of reward, lacking incentive salience. Therefore, the specific sensory features of cues may differentially contribute to responding and ensure behavioral flexibility. PMID:27918279

Reward from bugs to bipeds: a comparative approach to understanding how reward circuits function

PubMed Central

Scaplen, Kristin M.; Kaun, Karla R.

2016-01-01

Abstract In a complex environment, animals learn from their responses to stimuli and events. Appropriate response to reward and punishment can promote survival, reproduction and increase evolutionary fitness. Interestingly, the neural processes underlying these responses are remarkably similar across phyla. In all species, dopamine is central to encoding reward and directing motivated behaviors, however, a comprehensive understanding of how circuits encode reward and direct motivated behaviors is still lacking. In part, this is a result of the sheer diversity of neurons, the heterogeneity of their responses and the complexity of neural circuits within which they are found. We argue that general features of reward circuitry are common across model organisms, and thus principles learned from invertebrate model organisms can inform research across species. In particular, we discuss circuit motifs that appear to be functionally equivalent from flies to primates. We argue that a comparative approach to studying and understanding reward circuit function provides a more comprehensive understanding of reward circuitry, and informs disorders that affect the brain’s reward circuitry. PMID:27328845

Interaction between COMT Val(158)Met polymorphism and childhood adversity affects reward processing in adulthood.

PubMed

Boecker-Schlier, Regina; Holz, Nathalie E; Buchmann, Arlette F; Blomeyer, Dorothea; Plichta, Michael M; Jennen-Steinmetz, Christine; Wolf, Isabella; Baumeister, Sarah; Treutlein, Jens; Rietschel, Marcella; Meyer-Lindenberg, Andreas; Banaschewski, Tobias; Brandeis, Daniel; Laucht, Manfred

2016-05-15

Accumulating evidence suggests that altered dopamine transmission may increase the risk of mental disorders such as ADHD, schizophrenia or depression, possibly mediated by reward system dysfunction. This study aimed to clarify the impact of the COMT Val(158)Met polymorphism in interaction with environmental variation (G×E) on neuronal activity during reward processing. 168 healthy young adults from a prospective study conducted over 25years participated in a monetary incentive delay task measured with simultaneous EEG-fMRI. DNA was genotyped for COMT, and childhood family adversity (CFA) up to age 11 was assessed by a standardized parent interview. At reward delivery, a G×E revealed that fMRI activation for win vs. no-win trials in reward-related regions increased with the level of CFA in Met homozygotes as compared to Val/Met heterozygotes and Val homozygotes, who showed no significant effect. During the anticipation of monetary vs. verbal rewards, activation decreased with the level of CFA, which was also observed for EEG, in which the CNV declined with the level of CFA. These results identify convergent genetic and environmental effects on reward processing in a prospective study. Moreover, G×E effects during reward delivery suggest that stress during childhood is associated with higher reward sensitivity and reduced efficiency in processing rewarding stimuli in genetically at-risk individuals. Together with previous evidence, these results begin to define a specific system mediating interacting effects of early environmental and genetic risk factors, which may be targeted by early intervention and prevention. Copyright © 2016 Elsevier Inc. All rights reserved.

Insulin, Central Dopamine D2 Receptors, and Monetary Reward Discounting in Obesity

PubMed Central

Eisenstein, Sarah A.; Gredysa, Danuta M.; Antenor–Dorsey, Jo Ann; Green, Leonard; Arbeláez, Ana Maria; Koller, Jonathan M.; Black, Kevin J.; Perlmutter, Joel S.; Moerlein, Stephen M.; Hershey, Tamara

2015-01-01

Animal research finds that insulin regulates dopamine signaling and reward behavior, but similar research in humans is lacking. We investigated whether individual differences in body mass index, percent body fat, pancreatic β-cell function, and dopamine D2 receptor binding were related to reward discounting in obese and non-obese adult men and women. Obese (n = 27; body mass index>30) and non-obese (n = 20; body mass index<30) adults were assessed for percent body fat with dual-energy X-ray absorptiometry and for β-cell function using disposition index. Choice of larger, but delayed or less certain, monetary rewards relative to immediate, certain smaller monetary rewards was measured using delayed and probabilistic reward discounting tasks. Positron emission tomography using a non-displaceable D2-specific radioligand, [11C](N-methyl)benperidol quantified striatal D2 receptor binding. Groups differed in body mass index, percent body fat, and disposition index, but not in striatal D2 receptor specific binding or reward discounting. Higher percent body fat in non-obese women related to preference for a smaller, certain reward over a larger, less likely one (greater probabilistic discounting). Lower β-cell function in the total sample and lower insulin sensitivity in obese related to stronger preference for an immediate and smaller monetary reward over delayed receipt of a larger one (greater delay discounting). In obese adults, higher striatal D2 receptor binding related to greater delay discounting. Interestingly, striatal D2 receptor binding was not significantly related to body mass index, percent body fat, or β-cell function in either group. Our findings indicate that individual differences in percent body fat, β-cell function, and striatal D2 receptor binding may each contribute to altered reward discounting behavior in non-obese and obese individuals. These results raise interesting questions about whether and how striatal D2 receptor binding and metabolic factors, including β-cell function, interact to affect reward discounting in humans. PMID:26192187

Insulin, Central Dopamine D2 Receptors, and Monetary Reward Discounting in Obesity.

PubMed

Eisenstein, Sarah A; Gredysa, Danuta M; Antenor-Dorsey, Jo Ann; Green, Leonard; Arbeláez, Ana Maria; Koller, Jonathan M; Black, Kevin J; Perlmutter, Joel S; Moerlein, Stephen M; Hershey, Tamara

2015-01-01

Animal research finds that insulin regulates dopamine signaling and reward behavior, but similar research in humans is lacking. We investigated whether individual differences in body mass index, percent body fat, pancreatic β-cell function, and dopamine D2 receptor binding were related to reward discounting in obese and non-obese adult men and women. Obese (n = 27; body mass index>30) and non-obese (n = 20; body mass index<30) adults were assessed for percent body fat with dual-energy X-ray absorptiometry and for β-cell function using disposition index. Choice of larger, but delayed or less certain, monetary rewards relative to immediate, certain smaller monetary rewards was measured using delayed and probabilistic reward discounting tasks. Positron emission tomography using a non-displaceable D2-specific radioligand, [11C](N-methyl)benperidol quantified striatal D2 receptor binding. Groups differed in body mass index, percent body fat, and disposition index, but not in striatal D2 receptor specific binding or reward discounting. Higher percent body fat in non-obese women related to preference for a smaller, certain reward over a larger, less likely one (greater probabilistic discounting). Lower β-cell function in the total sample and lower insulin sensitivity in obese related to stronger preference for an immediate and smaller monetary reward over delayed receipt of a larger one (greater delay discounting). In obese adults, higher striatal D2 receptor binding related to greater delay discounting. Interestingly, striatal D2 receptor binding was not significantly related to body mass index, percent body fat, or β-cell function in either group. Our findings indicate that individual differences in percent body fat, β-cell function, and striatal D2 receptor binding may each contribute to altered reward discounting behavior in non-obese and obese individuals. These results raise interesting questions about whether and how striatal D2 receptor binding and metabolic factors, including β-cell function, interact to affect reward discounting in humans.

Dopamine disruption increases negotiation for cooperative interactions in a fish

PubMed Central

Messias, João P. M.; Paula, José R.; Grutter, Alexandra S.; Bshary, Redouan; Soares, Marta C.

2016-01-01

Humans and other animals use previous experiences to make behavioural decisions, balancing the probabilities of receiving rewards or punishments with alternative actions. The dopaminergic system plays a key role in this assessment: for instance, a decrease in dopamine transmission, which is signalled by the failure of an expected reward, may elicit a distinct behavioural response. Here, we tested the effect of exogenously administered dopaminergic compounds on a cooperative vertebrate’s decision-making process, in a natural setting. We show, in the Indo-Pacific bluestreak cleaner wrasse Labroides dimidiatus, that blocking dopamine receptors in the wild induces cleaners to initiate more interactions with and to provide greater amounts of physical contact to their client fish partners. This costly form of tactile stimulation using their fins is typically used to prolong interactions and to reconcile with clients after cheating. Interestingly, client jolt rate, a correlate of cheating by cleaners, remained unaffected. Thus, in low effective dopaminergic transmission conditions cleaners may renegotiate the occurrence and duration of the interaction with a costly offer. Our results provide first evidence for a prominent role of the dopaminergic system in decision-making in the context of cooperation in fish. PMID:26853241

Toward isolating the role of dopamine in the acquisition of incentive salience attribution.

PubMed

Chow, Jonathan J; Nickell, Justin R; Darna, Mahesh; Beckmann, Joshua S

2016-10-01

Stimulus-reward learning has been heavily linked to the reward-prediction error learning hypothesis and dopaminergic function. However, some evidence suggests dopaminergic function may not strictly underlie reward-prediction error learning, but may be specific to incentive salience attribution. Utilizing a Pavlovian conditioned approach procedure consisting of two stimuli that were equally reward-predictive (both undergoing reward-prediction error learning) but functionally distinct in regard to incentive salience (levers that elicited sign-tracking and tones that elicited goal-tracking), we tested the differential role of D1 and D2 dopamine receptors and nucleus accumbens dopamine in the acquisition of sign- and goal-tracking behavior and their associated conditioned reinforcing value within individuals. Overall, the results revealed that both D1 and D2 inhibition disrupted performance of sign- and goal-tracking. However, D1 inhibition specifically prevented the acquisition of sign-tracking to a lever, instead promoting goal-tracking and decreasing its conditioned reinforcing value, while neither D1 nor D2 signaling was required for goal-tracking in response to a tone. Likewise, nucleus accumbens dopaminergic lesions disrupted acquisition of sign-tracking to a lever, while leaving goal-tracking in response to a tone unaffected. Collectively, these results are the first evidence of an intraindividual dissociation of dopaminergic function in incentive salience attribution from reward-prediction error learning, indicating that incentive salience, reward-prediction error, and their associated dopaminergic signaling exist within individuals and are stimulus-specific. Thus, individual differences in incentive salience attribution may be reflective of a differential balance in dopaminergic function that may bias toward the attribution of incentive salience, relative to reward-prediction error learning only. Copyright © 2016 Elsevier Ltd. All rights reserved.

Mesolimbic leptin signaling negatively regulates cocaine-conditioned reward.

PubMed

Shen, M; Jiang, C; Liu, P; Wang, F; Ma, L

2016-12-06

The regulatory mechanisms underlying the response to addictive drugs are complex, and increasing evidence indicates that there is a role for appetite-regulating pathways in substance abuse. Leptin, an important adipose hormone that regulates energy balance and appetite, exerts its physiological functions via leptin receptors. However, the role of leptin signaling in regulating the response to cocaine remains unclear. Here we examined the potential role of leptin signaling in cocaine reward using a conditioned place preference (CPP) procedure. Our results showed that inhibition of leptin signaling by intracerebroventricular infusion of the leptin receptor (LepR) antagonist SMLA during cocaine conditioning increased the cocaine-CPP and upregulated the level of dopamine and its metabolites in the nucleus accumbens (NAc). We then selectively knocked down the LepR in the mesolimbic ventral tegmental area (VTA), NAc core and central amygdala (CeA) by injecting AAV-Cre into Lepr flox/flox mice. LepR deletion in the VTA increased the dopamine levels in the NAc and enhanced the cocaine-conditioned reward. LepR deletion in the NAc core enhanced the cocaine-conditioned reward and impaired the effect of the D2-dopamine receptor on cocaine-CPP, whereas LepR deletion in the CeA had no effect on cocaine-CPP but increased the anxiety level of mice. In addition, prior exposure to saccharin increased LepR mRNA and STAT3 phosphorylation in the NAc and VTA and impaired cocaine-CPP. These results indicate that leptin signaling is critically involved in cocaine-conditioned reward and the regulation of drug reward by a natural reward and that these effects are dependent on mesolimbic LepR.

Antipsychotic dose modulates behavioral and neural responses to feedback during reinforcement learning in schizophrenia.

PubMed

Insel, Catherine; Reinen, Jenna; Weber, Jochen; Wager, Tor D; Jarskog, L Fredrik; Shohamy, Daphna; Smith, Edward E

2014-03-01

Schizophrenia is characterized by an abnormal dopamine system, and dopamine blockade is the primary mechanism of antipsychotic treatment. Consistent with the known role of dopamine in reward processing, prior research has demonstrated that patients with schizophrenia exhibit impairments in reward-based learning. However, it remains unknown how treatment with antipsychotic medication impacts the behavioral and neural signatures of reinforcement learning in schizophrenia. The goal of this study was to examine whether antipsychotic medication modulates behavioral and neural responses to prediction error coding during reinforcement learning. Patients with schizophrenia completed a reinforcement learning task while undergoing functional magnetic resonance imaging. The task consisted of two separate conditions in which participants accumulated monetary gain or avoided monetary loss. Behavioral results indicated that antipsychotic medication dose was associated with altered behavioral approaches to learning, such that patients taking higher doses of medication showed increased sensitivity to negative reinforcement. Higher doses of antipsychotic medication were also associated with higher learning rates (LRs), suggesting that medication enhanced sensitivity to trial-by-trial feedback. Neuroimaging data demonstrated that antipsychotic dose was related to differences in neural signatures of feedback prediction error during the loss condition. Specifically, patients taking higher doses of medication showed attenuated prediction error responses in the striatum and the medial prefrontal cortex. These findings indicate that antipsychotic medication treatment may influence motivational processes in patients with schizophrenia.

Dopamine and anorexia nervosa.

PubMed

Södersten, P; Bergh, C; Leon, M; Zandian, M

2016-01-01

We have suggested that reduced food intake increases the risk for anorexia nervosa by engaging mesolimbic dopamine neurons, thereby initially rewarding dieting. Recent fMRI studies have confirmed that dopamine neurons are activated in anorexia nervosa, but it is not clear whether this response is due to the disorder or to its resulting nutritional deficit. When the body senses the shortage of nutrients, it rapidly shifts behavior toward foraging for food as a normal physiological response and the mesolimbic dopamine neurons may be involved in that process. On the other hand, the altered dopamine status of anorexics has been suggested to result from a brain abnormality that underlies their complex emotional disorder. We suggest that the outcomes of the treatments that emerge from that perspective remain poor because they target the mental symptoms that are actually the consequences of the food deprivation that accompanies anorexia. On the other hand, a method that normalizes the disordered eating behavior of anorexics results in much better physiological, behavioral, and emotional outcomes. Copyright © 2015 Elsevier Ltd. All rights reserved.

Neuronal Reward and Decision Signals: From Theories to Data

PubMed Central

Schultz, Wolfram

2015-01-01

Rewards are crucial objects that induce learning, approach behavior, choices, and emotions. Whereas emotions are difficult to investigate in animals, the learning function is mediated by neuronal reward prediction error signals which implement basic constructs of reinforcement learning theory. These signals are found in dopamine neurons, which emit a global reward signal to striatum and frontal cortex, and in specific neurons in striatum, amygdala, and frontal cortex projecting to select neuronal populations. The approach and choice functions involve subjective value, which is objectively assessed by behavioral choices eliciting internal, subjective reward preferences. Utility is the formal mathematical characterization of subjective value and a prime decision variable in economic choice theory. It is coded as utility prediction error by phasic dopamine responses. Utility can incorporate various influences, including risk, delay, effort, and social interaction. Appropriate for formal decision mechanisms, rewards are coded as object value, action value, difference value, and chosen value by specific neurons. Although all reward, reinforcement, and decision variables are theoretical constructs, their neuronal signals constitute measurable physical implementations and as such confirm the validity of these concepts. The neuronal reward signals provide guidance for behavior while constraining the free will to act. PMID:26109341

People newly in love are more responsive to positive feedback.

PubMed

Brown, Cassandra L; Beninger, Richard J

2012-06-01

Passionate love is associated with increased activity in dopamine-rich regions of the brain. Increased dopamine in these regions is associated with a greater tendency to learn from reward in trial-and-error learning tasks. This study examined the prediction that individuals who were newly in love would be better at responding to reward (positive feedback). In test trials, people who were newly in love selected positive outcomes significantly more often than their single (not in love) counterparts but were no better at the task overall. This suggests that people who are newly in love show a bias toward responding to positive feedback, which may reflect a general bias towards reward-seeking.

Opiate exposure state controls dopamine D3 receptor and cdk5/calcineurin signaling in the basolateral amygdala during reward and withdrawal aversion memory formation.

PubMed

Rosen, Laura G; Rushlow, Walter J; Laviolette, Steven R

2017-10-03

The dopamine (DA) D3 receptor (D3R) is highly expressed in the basolateral nucleus of the amygdala (BLA), a neural region critical for processing opiate-related reward and withdrawal aversion-related memories. Functionally, D3R transmission is linked to downstream Cdk5 and calcineurin signaling, both of which regulate D3R activity states and play critical roles in memory-related synaptic plasticity. Previous evidence links D3R transmission to opiate-related memory processing, however little is known regarding how chronic opiate exposure may alter D3R-dependent memory mechanisms. Using conditioned place preference (CPP) and withdrawal aversion (conditioned place aversion; CPA) procedures in rats, combined with molecular analyses of BLA protein expression, we examined the effects of chronic opiate exposure on the functional role of intra-BLA D3R transmission during the acquisition of opiate reward or withdrawal aversion memories. Remarkably, we report that the state of opiate exposure during behavioural conditioning (opiate-naïve/non-dependent vs. chronically exposed and in withdrawal) controlled the functional role of intra-BLA D3R transmission during the acquisition of both opiate reward memories and withdrawal-aversion associative memories. Thus, whereas intra-BLA D3R blockade had no effect on opiate reward memory formation in the non-dependent state, blockade of intra-BLA D3R transmission prevented the formation of opiate reward and withdrawal aversion memory in the chronically exposed state. This switch in the functional role of D3R transmission corresponded to significant increases in Cdk5 phosphorylation and total expression levels of calcineurin, and a corresponding decrease in intra-BLA D3R expression. Inhibition of either intra-BLA Cdk5 or calcineurin reversed these effects, switching intra-BLA associative memory formation back to a D3R-independent mechanism. Copyright © 2017 Elsevier Inc. All rights reserved.

Model-based predictions for dopamine.

PubMed

Langdon, Angela J; Sharpe, Melissa J; Schoenbaum, Geoffrey; Niv, Yael

2018-04-01

Phasic dopamine responses are thought to encode a prediction-error signal consistent with model-free reinforcement learning theories. However, a number of recent findings highlight the influence of model-based computations on dopamine responses, and suggest that dopamine prediction errors reflect more dimensions of an expected outcome than scalar reward value. Here, we review a selection of these recent results and discuss the implications and complications of model-based predictions for computational theories of dopamine and learning. Copyright © 2017. Published by Elsevier Ltd.

Genetic basis of delay discounting in frequent gamblers: examination of a priori candidates and exploration of a panel of dopamine-related loci

PubMed Central

Gray, Joshua C; MacKillop, James

2014-01-01

Introduction Delay discounting is a behavioral economic index of impulsivity that reflects preferences for small immediate rewards relative to larger delayed rewards. It has been consistently linked to pathological gambling and other forms of addictive behavior, and has been proposed to be a behavioral characteristic that may link genetic variation and risk of developing addictive disorders (i.e., an endophenotype). Studies to date have revealed significant associations with polymorphisms associated with dopamine neurotransmission. The current study examined associations between delay discounting and both previously linked variants and a novel panel of dopamine-related variants in a sample of frequent gamblers. Methods Participants were 175 weekly gamblers of European ancestry who completed the Monetary Choice Questionnaire to assess delay discounting preferences and provided a DNA via saliva. Results In a priori tests, two loci previously associated with delayed reward discounting (rs1800497 and rs4680) were not replicated, however, the long form of DRD4 VNTR was significantly associated with lower discounting of delayed rewards. Exploratory analysis of the dopamine-related panel revealed 11 additional significant associations in genes associated with dopamine synthesis, breakdown, reuptake, and receptor function (DRD3, SLC6A3, DDC, DBH, and SLC18A2). An aggregate genetic risk score from the nominally significant loci accounted for 17% of the variance in discounting. Mediational analyses largely supported the presence of indirect effects between the associated loci, delay discounting, and pathological gambling severity. Conclusions These findings do not replicate previously reported associations but identify several novel candidates and provide preliminary support for a systems biology approach to understand the genetic basis of delay discounting. PMID:25365808

Chronic blockade or constitutive deletion of the serotonin transporter reduces operant responding for food reward.

PubMed

Sanders, Amy Cecilia; Hussain, Ali J; Hen, René; Zhuang, Xiaoxi

2007-11-01

The therapeutic effects of chronic selective serotonin reuptake inhibitors (SSRIs) are well documented, yet the elementary behavioral processes that are affected by such treatment have not been fully investigated. We report here the effects of chronic fluoxetine treatment and genetic deletion of the serotonin transporter (SERT) on food reinforced behavior in three paradigms: the progressive ratio operant task, the concurrent choice operant task, and the Pavlovian-to-Instrumental transfer task. We consistently find that chronic pharmacological blockade or genetic deletion of SERT result in similar behavioral consequences: reduced operant responding for natural reward. This is in line with previous studies reporting declines in operant responding for drugs and intracranial self-stimulation with fluoxetine treatment, suggesting that the effect of SERT blockade can be generalized to different reward types. Detailed analyses of behavioral parameters indicate that this reduction in operant responding affect both goal-directed and non-goal-directed behaviors without affecting the Pavlovian cue-triggered excessive operant responding. In addition, both pharmacological and genetic manipulations reduce locomotor activity in the open field novel environment. Our data contrast with the effect of dopamine in increasing operant responding for natural reward specifically in goal-directed behaviors and in increasing Pavlovian cue-triggered excessive operant responding. Serotonin and dopamine have been proposed to serve opposing functions in motivational processes. Our data suggest that their interactions do not result in simple opponency. The fact that pharmacological blockade and genetic deletion of SERT have similar behavioral consequences reinforces the utility of the SERT null mice for investigation of the mechanisms underlying chronic SSRIs treatment.

Activation of Pedunculopontine Glutamate Neurons Is Reinforcing

PubMed Central

Yoo, Ji Hoon; Zell, Vivien; Wu, Johnathan; Punta, Cindy; Ramajayam, Nivedita; Shen, Xinyi; Faget, Lauren; Lilascharoen, Varoth; Lim, Byung Kook

2017-01-01

Dopamine transmission from midbrain ventral tegmental area (VTA) neurons underlies behavioral processes related to motivation and drug addiction. The pedunculopontine tegmental nucleus (PPTg) is a brainstem nucleus containing glutamate-, acetylcholine-, and GABA-releasing neurons with connections to basal ganglia and limbic brain regions. Here we investigated the role of PPTg glutamate neurons in reinforcement, with an emphasis on their projections to VTA dopamine neurons. We used cell-type-specific anterograde tracing and optogenetic methods to selectively label and manipulate glutamate projections from PPTg neurons in mice. We used anatomical, electrophysiological, and behavioral assays to determine their patterns of connectivity and ascribe functional roles in reinforcement. We found that photoactivation of PPTg glutamate cell bodies could serve as a direct positive reinforcer on intracranial self-photostimulation assays. Further, PPTg glutamate neurons directly innervate VTA; photostimulation of this pathway preferentially excites VTA dopamine neurons and is sufficient to induce behavioral reinforcement. These results demonstrate that ascending PPTg glutamate projections can drive motivated behavior, and PPTg to VTA synapses may represent an important target relevant to drug addiction and other mental health disorders. SIGNIFICANCE STATEMENT Uncovering brain circuits underlying reward-seeking is an important step toward understanding the circuit bases of drug addiction and other psychiatric disorders. The dopaminergic system emanating from the ventral tegmental area (VTA) plays a key role in regulating reward-seeking behaviors. We used optogenetics to demonstrate that the pedunculopontine tegmental nucleus sends glutamatergic projections to VTA dopamine neurons, and that stimulation of this circuit promotes behavioral reinforcement. The findings support a critical role for pedunculopontine tegmental nucleus glutamate neurotransmission in modulating VTA dopamine neuron activity and behavioral reinforcement. PMID:28053028

DAT isn’t all that: cocaine reward and reinforcement requires Toll Like Receptor 4 signaling

PubMed Central

Northcutt, A.L.; Hutchinson, M.R.; Wang, X.; Baratta, M.V.; Hiranita, T.; Cochran, T.A.; Pomrenze, M.B.; Galer, E.L.; Kopajtic, T.A.; Li, C.M.; Amat, J.; Larson, G.; Cooper, D.C.; Huang, Y.; O’Neill, C.E.; Yin, H.; Zahniser, N.R.; Katz, J.L.; Rice, K.C.; Maier, S.F.; Bachtell, R.K.; Watkins, L.R.

2014-01-01

The initial reinforcing properties of drugs of abuse, such as cocaine, are largely attributed to their ability to activate the mesolimbic dopamine system. Resulting increases in extracellular dopamine in the nucleus accumbens (NAc) are traditionally thought to result from cocaine’s ability to block dopamine transporters (DATs). Here we demonstrate that cocaine also interacts with the immunosurveillance receptor complex, Toll-Like Receptor 4 (TLR4), on microglial cells to initiate central innate immune signaling. Disruption of cocaine signaling at TLR4 suppresses cocaine-induced extracellular dopamine in the NAc, as well as cocaine conditioned place preference and cocaine self-administration. These results provide a novel understanding of the neurobiological mechanisms underlying cocaine reward/reinforcement that includes a critical role for central immune signaling, and offer a new target for medication development for cocaine abuse treatment. PMID:25644383

Placebo neural systems: nitric oxide, morphine and the dopamine brain reward and motivation circuitries.

PubMed

Fricchione, Gregory; Stefano, George B

2005-05-01

Evidence suggests that the placebo response is related to the tonic effects of constitutive nitric oxide in neural, vascular and immune tissues. Constitutive nitric oxide levels play a role in the modulation of dopamine outflow in the nigrostriatal movement and the mesolimbic and mesocortical reward and motivation circuitries. Endogenous morphine, which stimulates constitutive nitric oxide, may be an important signal molecule working at mu receptors on gamma aminobutyric acid B interneurons to disinhibit nigral and tegmental dopamine output. We surmise that placebo induced belief will activate the prefrontal cortex with downstream stimulatory effects on these dopamine systems as well as on periaqueductal grey opioid output neurons. Placebo responses in Parkinson's disease, depression and pain disorder may result. In addition, mesolimbic/mesocortical control of the stress response systems may provide a way for the placebo response to benefit other medical conditions.

Can cleanerfish overcome temptation? A selective role for dopamine influence on cooperative-based decision making.

PubMed

Soares, Marta C; Cardoso, Sónia C; Malato, João T; Messias, João P M

2017-02-01

Evidence suggests that animals are selected to make accurate choices and prioritize goals within the constraints of a given social environment to maximize fitness. These decisions are mostly based on complex processes in which value is linked to reward and cues may carry variable incentive salience. However, the level in which the incentive elicited by a cue is able to shift individual choices should differ between individuals and neurophysiological states. Here we used a notorious cooperative cleanerfish species Labroides dimidiatus to probe for differences in the incentive motivational valences given to food cues and then tested for the role of the dopaminergic system in the appraisal of such cues. We found that cleaners differed in Pavlovian conditioned approach behavioural responses to reward-associated stimuli: while the majority were fast to engage physically with the cue plate that indicated future reward delivery (sign trackers), only a few took significantly more time to respond (goal trackers). But amongst those that were considering the sole cue attractive, we discovered that the dopaminergic blockage decreased their initial propensity to approach and touch the cue plate. Our results show that dopamine disruption contributes to shifting the attribution of motivational incentive from the predictive cue towards the actual reward and provides key insight into the physiological framework of cooperative-based decision making. Copyright © 2016 Elsevier Inc. All rights reserved.

Behavioral and Neural Manifestations of Reward Memory in Carriers of Low-Expressing versus High-Expressing Genetic Variants of the Dopamine D2 Receptor

PubMed Central

Richter, Anni; Barman, Adriana; Wüstenberg, Torsten; Soch, Joram; Schanze, Denny; Deibele, Anna; Behnisch, Gusalija; Assmann, Anne; Klein, Marieke; Zenker, Martin; Seidenbecher, Constanze; Schott, Björn H.

2017-01-01

Dopamine is critically important in the neural manifestation of motivated behavior, and alterations in the human dopaminergic system have been implicated in the etiology of motivation-related psychiatric disorders, most prominently addiction. Patients with chronic addiction exhibit reduced dopamine D2 receptor (DRD2) availability in the striatum, and the DRD2 TaqIA (rs1800497) and C957T (rs6277) genetic polymorphisms have previously been linked to individual differences in striatal dopamine metabolism and clinical risk for alcohol and nicotine dependence. Here, we investigated the hypothesis that the variants of these polymorphisms would show increased reward-related memory formation, which has previously been shown to jointly engage the mesolimbic dopaminergic system and the hippocampus, as a potential intermediate phenotype for addiction memory. To this end, we performed functional magnetic resonance imaging (fMRI) in 62 young, healthy individuals genotyped for DRD2 TaqIA and C957T variants. Participants performed an incentive delay task, followed by a recognition memory task 24 h later. We observed effects of both genotypes on the overall recognition performance with carriers of low-expressing variants, namely TaqIA A1 carriers and C957T C homozygotes, showing better performance than the other genotype groups. In addition to the better memory performance, C957T C homozygotes also exhibited a response bias for cues predicting monetary reward. At the neural level, the C957T polymorphism was associated with a genotype-related modulation of right hippocampal and striatal fMRI responses predictive of subsequent recognition confidence for reward-predicting items. Our results indicate that genetic variations associated with DRD2 expression affect explicit memory, specifically for rewarded stimuli. We suggest that the relatively better memory for rewarded stimuli in carriers of low-expressing DRD2 variants may reflect an intermediate phenotype of addiction memory. PMID:28507526

Ventral striatal network connectivity reflects reward learning and behavior in patients with Parkinson's disease.

PubMed

Petersen, Kalen; Van Wouwe, Nelleke; Stark, Adam; Lin, Ya-Chen; Kang, Hakmook; Trujillo-Diaz, Paula; Kessler, Robert; Zald, David; Donahue, Manus J; Claassen, Daniel O

2018-01-01

A subgroup of Parkinson's disease (PD) patients treated with dopaminergic therapy develop compulsive reward-driven behaviors, which can result in life-altering morbidity. The mesocorticolimbic dopamine network guides reward-motivated behavior; however, its role in this treatment-related behavioral phenotype is incompletely understood. Here, mesocorticolimbic network function in PD patients who develop impulsive and compulsive behaviors (ICB) in response to dopamine agonists was assessed using BOLD fMRI. The tested hypothesis was that network connectivity between the ventral striatum and the limbic cortex is elevated in patients with ICB and that reward-learning proficiency reflects the extent of mesocorticolimbic network connectivity. To evaluate this hypothesis, 3.0T BOLD-fMRI was applied to measure baseline functional connectivity on and off dopamine agonist therapy in age and sex-matched PD patients with (n = 19) or without (n = 18) ICB. An incentive-based task was administered to a subset of patients (n = 20) to quantify positively or negatively reinforced learning. Whole-brain voxelwise analyses and region-of-interest-based mixed linear effects modeling were performed. Elevated ventral striatal connectivity to the anterior cingulate gyrus (P = 0.013), orbitofrontal cortex (P = 0.034), insula (P = 0.044), putamen (P = 0.014), globus pallidus (P < 0.01), and thalamus (P < 0.01) was observed in patients with ICB. A strong trend for elevated amygdala-to-midbrain connectivity was found in ICB patients on dopamine agonist. Ventral striatum-to-subgenual cingulate connectivity correlated with reward learning (P < 0.01), but not with punishment-avoidance learning. These data indicate that PD-ICB patients have elevated network connectivity in the mesocorticolimbic network. Behaviorally, proficient reward-based learning is related to this enhanced limbic and ventral striatal connectivity. Hum Brain Mapp 39:509-521, 2018. © 2017 Wiley Periodicals, Inc. © 2017 Wiley Periodicals, Inc.

How we learn to make decisions: rapid propagation of reinforcement learning prediction errors in humans.

PubMed

Krigolson, Olav E; Hassall, Cameron D; Handy, Todd C

2014-03-01

Our ability to make decisions is predicated upon our knowledge of the outcomes of the actions available to us. Reinforcement learning theory posits that actions followed by a reward or punishment acquire value through the computation of prediction errors-discrepancies between the predicted and the actual reward. A multitude of neuroimaging studies have demonstrated that rewards and punishments evoke neural responses that appear to reflect reinforcement learning prediction errors [e.g., Krigolson, O. E., Pierce, L. J., Holroyd, C. B., & Tanaka, J. W. Learning to become an expert: Reinforcement learning and the acquisition of perceptual expertise. Journal of Cognitive Neuroscience, 21, 1833-1840, 2009; Bayer, H. M., & Glimcher, P. W. Midbrain dopamine neurons encode a quantitative reward prediction error signal. Neuron, 47, 129-141, 2005; O'Doherty, J. P. Reward representations and reward-related learning in the human brain: Insights from neuroimaging. Current Opinion in Neurobiology, 14, 769-776, 2004; Holroyd, C. B., & Coles, M. G. H. The neural basis of human error processing: Reinforcement learning, dopamine, and the error-related negativity. Psychological Review, 109, 679-709, 2002]. Here, we used the brain ERP technique to demonstrate that not only do rewards elicit a neural response akin to a prediction error but also that this signal rapidly diminished and propagated to the time of choice presentation with learning. Specifically, in a simple, learnable gambling task, we show that novel rewards elicited a feedback error-related negativity that rapidly decreased in amplitude with learning. Furthermore, we demonstrate the existence of a reward positivity at choice presentation, a previously unreported ERP component that has a similar timing and topography as the feedback error-related negativity that increased in amplitude with learning. The pattern of results we observed mirrored the output of a computational model that we implemented to compute reward prediction errors and the changes in amplitude of these prediction errors at the time of choice presentation and reward delivery. Our results provide further support that the computations that underlie human learning and decision-making follow reinforcement learning principles.

Concomitant Release of Ventral Tegmental Acetylcholine and Accumbal Dopamine by Ghrelin in Rats

PubMed Central

Jerlhag, Elisabet; Janson, Anna Carin; Waters, Susanna; Engel, Jörgen A.

2012-01-01

Ghrelin, an orexigenic peptide, regulates energy balance specifically via hypothalamic circuits. Growing evidence suggest that ghrelin increases the incentive value of motivated behaviours via activation of the cholinergic-dopaminergic reward link. It encompasses the cholinergic afferent projection from the laterodorsal tegmental area (LDTg) to the dopaminergic cells of the ventral tegmental area (VTA) and the mesolimbic dopamine system projecting from the VTA to nucleus accumbens (N.Acc.). Ghrelin receptors (GHS-R1A) are expressed in these reward nodes and ghrelin administration into the LDTg increases accumbal dopamine, an effect involving nicotinic acetylcholine receptors in the VTA. The present series of experiments were undertaken directly to test this hypothesis. Here we show that ghrelin, administered peripherally or locally into the LDTg concomitantly increases ventral tegmental acetylcholine as well as accumbal dopamine release. A GHS-R1A antagonist blocks this synchronous neurotransmitter release induced by peripheral ghrelin. In addition, local perfusion of the unselective nicotinic antagonist mecamylamine into the VTA blocks the ability of ghrelin (administered into the LDTg) to increase N.Acc.-dopamine, but not VTA-acetylcholine. Collectively our data indicate that ghrelin activates the LDTg causing a release of acetylcholine in the VTA, which in turn activates local nicotinic acetylcholine receptors causing a release of accumbal dopamine. Given that a dysfunction in the cholinergic-dopaminergic reward system is involved in addictive behaviours, including compulsive overeating and alcohol use disorder, and that hyperghrelinemia is associated with such addictive behaviours, ghrelin-responsive circuits may serve as a novel pharmacological target for treatment of alcohol use disorder as well as binge eating. PMID:23166710

Pleasurable music affects reinforcement learning according to the listener

PubMed Central

Gold, Benjamin P.; Frank, Michael J.; Bogert, Brigitte; Brattico, Elvira

2013-01-01

Mounting evidence links the enjoyment of music to brain areas implicated in emotion and the dopaminergic reward system. In particular, dopamine release in the ventral striatum seems to play a major role in the rewarding aspect of music listening. Striatal dopamine also influences reinforcement learning, such that subjects with greater dopamine efficacy learn better to approach rewards while those with lesser dopamine efficacy learn better to avoid punishments. In this study, we explored the practical implications of musical pleasure through its ability to facilitate reinforcement learning via non-pharmacological dopamine elicitation. Subjects from a wide variety of musical backgrounds chose a pleasurable and a neutral piece of music from an experimenter-compiled database, and then listened to one or both of these pieces (according to pseudo-random group assignment) as they performed a reinforcement learning task dependent on dopamine transmission. We assessed musical backgrounds as well as typical listening patterns with the new Helsinki Inventory of Music and Affective Behaviors (HIMAB), and separately investigated behavior for the training and test phases of the learning task. Subjects with more musical experience trained better with neutral music and tested better with pleasurable music, while those with less musical experience exhibited the opposite effect. HIMAB results regarding listening behaviors and subjective music ratings indicate that these effects arose from different listening styles: namely, more affective listening in non-musicians and more analytical listening in musicians. In conclusion, musical pleasure was able to influence task performance, and the shape of this effect depended on group and individual factors. These findings have implications in affective neuroscience, neuroaesthetics, learning, and music therapy. PMID:23970875

Dopamine D2 receptors in addiction-like reward dysfunction and compulsive eating in obese rats.

PubMed

Johnson, Paul M; Kenny, Paul J

2010-05-01

We found that development of obesity was coupled with emergence of a progressively worsening deficit in neural reward responses. Similar changes in reward homeostasis induced by cocaine or heroin are considered to be crucial in triggering the transition from casual to compulsive drug-taking. Accordingly, we detected compulsive-like feeding behavior in obese but not lean rats, measured as palatable food consumption that was resistant to disruption by an aversive conditioned stimulus. Striatal dopamine D2 receptors (D2Rs) were downregulated in obese rats, as has been reported in humans addicted to drugs. Moreover, lentivirus-mediated knockdown of striatal D2Rs rapidly accelerated the development of addiction-like reward deficits and the onset of compulsive-like food seeking in rats with extended access to palatable high-fat food. These data demonstrate that overconsumption of palatable food triggers addiction-like neuroadaptive responses in brain reward circuits and drives the development of compulsive eating. Common hedonic mechanisms may therefore underlie obesity and drug addiction.

Hypothalamic melanin concentrating hormone neurons communicate the nutrient value of sugar

PubMed Central

Domingos, Ana I; Sordillo, Aylesse; Dietrich, Marcelo O; Liu, Zhong-Wu; Tellez, Luis A; Vaynshteyn, Jake; Ferreira, Jozelia G; Ekstrand, Mats I; Horvath, Tamas L; de Araujo, Ivan E; Friedman, Jeffrey M

2013-01-01

Sugars that contain glucose, such as sucrose, are generally preferred to artificial sweeteners owing to their post-ingestive rewarding effect, which elevates striatal dopamine (DA) release. While the post-ingestive rewarding effect, which artificial sweeteners do not have, signals the nutrient value of sugar and influences food preference, the neural circuitry that mediates the rewarding effect of glucose is unknown. In this study, we show that optogenetic activation of melanin-concentrating hormone (MCH) neurons during intake of the artificial sweetener sucralose increases striatal dopamine levels and inverts the normal preference for sucrose vs sucralose. Conversely, animals with ablation of MCH neurons no longer prefer sucrose to sucralose and show reduced striatal DA release upon sucrose ingestion. We further show that MCH neurons project to reward areas and are required for the post-ingestive rewarding effect of sucrose in sweet-blind Trpm5−/− mice. These studies identify an essential component of the neural pathways linking nutrient sensing and food reward. DOI: http://dx.doi.org/10.7554/eLife.01462.001 PMID:24381247

Ghrelin receptor antagonism attenuates cocaine- and amphetamine-induced locomotor stimulation, accumbal dopamine release, and conditioned place preference.

PubMed

Jerlhag, Elisabet; Egecioglu, Emil; Dickson, Suzanne L; Engel, Jörgen A

2010-09-01

Recently we demonstrated that genetic or pharmacological suppression of the central ghrelin signaling system, involving the growth hormone secretagogue receptor 1A (GHS-R1A), lead to a reduced reward profile from alcohol. As the target circuits for ghrelin in the brain include a mesolimbic reward pathway that is intimately associated with reward-seeking behaviour, we sought to determine whether the central ghrelin signaling system is required for reward from drugs of abuse other than alcohol, namely cocaine or amphetamine. We found that amphetamine-as well as cocaine-induced locomotor stimulation and accumbal dopamine release were reduced in mice treated with a GHS-R1A antagonist. Moreover, the ability of these drugs to condition a place preference was also attenuated by the GHS-R1A antagonist. Thus GHS-R1A appears to be required not only for alcohol-induced reward, but also for reward induced by psychostimulant drugs. Our data suggest that the central ghrelin signaling system constitutes a novel potential target for treatment of addictive behaviours such as drug dependence.

Impact of Early Life Adversity on Reward Processing in Young Adults: EEG-fMRI Results from a Prospective Study over 25 Years

PubMed Central

Boecker, Regina; Holz, Nathalie E.; Buchmann, Arlette F.; Blomeyer, Dorothea; Plichta, Michael M.; Wolf, Isabella; Baumeister, Sarah; Meyer-Lindenberg, Andreas; Banaschewski, Tobias

2014-01-01

Several lines of evidence have implicated the mesolimbic dopamine reward pathway in altered brain function resulting from exposure to early adversity. The present study examined the impact of early life adversity on different stages of neuronal reward processing later in life and their association with a related behavioral phenotype, i.e. attention deficit/hyperactivity disorder (ADHD). 162 healthy young adults (mean age = 24.4 years; 58% female) from an epidemiological cohort study followed since birth participated in a simultaneous EEG-fMRI study using a monetary incentive delay task. Early life adversity according to an early family adversity index (EFA) and lifetime ADHD symptoms were assessed using standardized parent interviews conducted at the offspring's age of 3 months and between 2 and 15 years, respectively. fMRI region-of-interest analysis revealed a significant effect of EFA during reward anticipation in reward-related areas (i.e. ventral striatum, putamen, thalamus), indicating decreased activation when EFA increased. EEG analysis demonstrated a similar effect for the contingent negative variation (CNV), with the CNV decreasing with the level of EFA. In contrast, during reward delivery, activation of the bilateral insula, right pallidum and bilateral putamen increased with EFA. There was a significant association of lifetime ADHD symptoms with lower activation in the left ventral striatum during reward anticipation and higher activation in the right insula during reward delivery. The present findings indicate a differential long-term impact of early life adversity on reward processing, implicating hyporesponsiveness during reward anticipation and hyperresponsiveness when receiving a reward. Moreover, a similar activation pattern related to lifetime ADHD suggests that the impact of early life stress on ADHD may possibly be mediated by a dysfunctional reward pathway. PMID:25118701

Opiate-induced dopamine release is modulated by severity of alcohol dependence: an [(18)F]fallypride positron emission tomography study.

PubMed

Spreckelmeyer, Katja N; Paulzen, Michael; Raptis, Mardjan; Baltus, Thomas; Schaffrath, Sabrina; Van Waesberghe, Julia; Zalewski, Magdalena M; Rösch, Frank; Vernaleken, Ingo; Schäfer, Wolfgang M; Gründer, Gerhard

2011-10-15

Preclinical data implicate the reinforcing effects of alcohol to be mediated by interaction between the opioid and dopamine systems of the brain. Specifically, alcohol-induced release of β-endorphins stimulates μ-opioid receptors (MORs), which is believed to cause dopamine release in the brain reward system. Individual differences in opioid or dopamine neurotransmission have been suggested to be responsible for enhanced liability to abuse alcohol. In the present study, a single dose of the MOR agonist remifentanil was administered in detoxified alcohol-dependent patients and healthy control subjects to mimic the β-endorphin-releasing properties of ethanol and to assess the effects of direct MOR stimulation on dopamine release in the mesolimbic reward system. Availability of D(2/3) receptors was assessed before and after single-dose administration of the MOR agonist remifentanil in 11 detoxified alcohol-dependent patients and 11 healthy control subjects with positron emission tomography with the radiotracer [(18)F]fallypride. Severity of dependence as assessed with the Alcohol Use Disorders Identification Test was compared with remifentanil-induced percentage change in [(18)F]fallypride binding (Δ%BP(ND)). The [(18)F]fallypride binding potentials (BP(ND)s) were significantly reduced in the ventral striatum, dorsal putamen, and amygdala after remifentanil application in both patients and control subjects. In the patient group, ventral striatum Δ%BP(ND) was correlated with the Alcohol Use Disorders Identification Test score. The data provide evidence for a MOR-mediated interaction between the opioid and the dopamine system, supporting the assumption that one way by which alcohol unfolds its rewarding effects is via a MOR-(γ-aminobutyric acid)-dopamine pathway. No difference in dopamine release was found between patients and control subjects, but evidence for a patient-specific association between sensitivity to MOR stimulation and severity of alcohol dependence was found. Copyright © 2011 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.

Altered brain activation in a reversal learning task unmasks adaptive changes in cognitive control in writer's cramp.

PubMed

Zeuner, Kirsten E; Knutzen, Arne; Granert, Oliver; Sablowsky, Simone; Götz, Julia; Wolff, Stephan; Jansen, Olav; Dressler, Dirk; Schneider, Susanne A; Klein, Christine; Deuschl, Günther; van Eimeren, Thilo; Witt, Karsten

2016-01-01

Previous receptor binding studies suggest dopamine function is altered in the basal ganglia circuitry in task-specific dystonia, a condition characterized by contraction of agonist and antagonist muscles while performing specific tasks. Dopamine plays a role in reward-based learning. Using fMRI, this study compared 31 right-handed writer's cramp patients to 35 controls in reward-based learning of a probabilistic reversal-learning task. All subjects chose between two stimuli and indicated their response with their left or right index finger. One stimulus response was rewarded 80%, the other 20%. After contingencies reversal, the second stimulus response was rewarded in 80%. We further linked the DRD2/ANKK1-TaqIa polymorphism, which is associated with 30% reduction of the striatal dopamine receptor density with reward-based learning and assumed impaired reversal learning in A + subjects. Feedback learning in patients was normal. Blood-oxygen level dependent (BOLD) signal in controls increased with negative feedback in the insula, rostral cingulate cortex, middle frontal gyrus and parietal cortex (pFWE < 0.05). In comparison to controls, patients showed greater increase in BOLD activity following negative feedback in the dorsal anterior cingulate cortex (BA32). The genetic status was not correlated with the BOLD activity. The Brodmann area 32 (BA32) is part of the dorsal anterior cingulate cortex (dACC) that plays an important role in coordinating and integrating information to guide behavior and in reward-based learning. The dACC is connected with the basal ganglia-thalamo-loop modulated by dopaminergic signaling. This finding suggests disturbed integration of reinforcement history in decision making and implicate that the reward system might contribute to the pathogenesis in writer's cramp.

The effect of a dopamine antagonist on conditioning of sexual arousal in women.

PubMed

Brom, Mirte; Laan, Ellen; Everaerd, Walter; Spinhoven, Philip; Trimbos, Baptist; Both, Stephanie

2016-04-01

Dopamine (DA) plays a key role in reward-seeking behaviours. Accumulating evidence from animal and human studies suggests that human sexual reward learning may also depend on DA transmission. However, research on the role of DA in human sexual reward learning is completely lacking. To investigate whether DA antagonism attenuates classical conditioning of sexual response in humans. Healthy women were randomly allocated to one of two treatment conditions: haloperidol (n = 29) or placebo (n = 29). A differential conditioning paradigm was applied with genital vibrostimulation as unconditional stimulus (US) and neutral pictures as conditional stimuli (CSs). Genital arousal was assessed, and ratings of affective value and subjective sexual arousal were obtained. Haloperidol administration affected unconditional genital responding. However, no significant effects of medication were found for conditioned responding. No firm conclusions can be drawn about whether female sexual reward learning implicates DA transmission since the results do not lend themselves to unambiguous interpretation.

Dopamine prediction errors in reward learning and addiction: from theory to neural circuitry

PubMed Central

Keiflin, Ronald; Janak, Patricia H.

2015-01-01

Summary Midbrain dopamine (DA) neurons are proposed to signal reward prediction error (RPE), a fundamental parameter in associative learning models. This RPE hypothesis provides a compelling theoretical framework for understanding DA function in reward learning and addiction. New studies support a causal role for DA-mediated RPE activity in promoting learning about natural reward; however, this question has not been explicitly tested in the context of drug addiction. In this review, we integrate theoretical models with experimental findings on the activity of DA systems, and on the causal role of specific neuronal projections and cell types, to provide a circuit-based framework for probing DA-RPE function in addiction. By examining error-encoding DA neurons in the neural network in which they are embedded, hypotheses regarding circuit-level adaptations that possibly contribute to pathological error-signaling and addiction can be formulated and tested. PMID:26494275

Prefrontal cortex as a meta-reinforcement learning system.

PubMed

Wang, Jane X; Kurth-Nelson, Zeb; Kumaran, Dharshan; Tirumala, Dhruva; Soyer, Hubert; Leibo, Joel Z; Hassabis, Demis; Botvinick, Matthew

2018-06-01

Over the past 20 years, neuroscience research on reward-based learning has converged on a canonical model, under which the neurotransmitter dopamine 'stamps in' associations between situations, actions and rewards by modulating the strength of synaptic connections between neurons. However, a growing number of recent findings have placed this standard model under strain. We now draw on recent advances in artificial intelligence to introduce a new theory of reward-based learning. Here, the dopamine system trains another part of the brain, the prefrontal cortex, to operate as its own free-standing learning system. This new perspective accommodates the findings that motivated the standard model, but also deals gracefully with a wider range of observations, providing a fresh foundation for future research.

What is abnormal about addiction-related attentional biases?

PubMed

Anderson, Brian A

2016-10-01

The phenotype of addiction includes prominent attentional biases for drug cues, which play a role in motivating drug-seeking behavior and contribute to relapse. In a separate line of research, arbitrary stimuli have been shown to automatically capture attention when previously associated with reward in non-clinical samples. Here, I argue that these two attentional biases reflect the same cognitive process. I outline five characteristics that exemplify attentional biases for drug cues: resistant to conflicting goals, robust to extinction, linked to dorsal striatal dopamine and to biases in approach behavior, and can distinguish between individuals with and without a history of drug dependence. I then go on to describe how attentional biases for arbitrary reward-associated stimuli share all of these features, and conclude by arguing that the attentional components of addiction reflect a normal cognitive process that promotes reward-seeking behavior. Copyright © 2016 Elsevier Ireland Ltd. All rights reserved.

A genetic determinant of the striatal dopamine response to alcohol in men

PubMed Central

Ramchandani, Vijay A.; Umhau, John; Pavon, Francisco J.; Ruiz-Velasco, Victor; Margas, Wojciech; Sun, Hui; Damadzic, Ruslan; Eskay, Robert; Schoor, Michael; Thorsell, Annika; Schwandt, Melanie L.; Sommer, Wolfgang H.; George, David T.; Parsons, Loren H.; Herscovitch, Peter; Hommer, Daniel; Heilig, Markus

2010-01-01

Excessive alcohol use, a major cause of morbidity and mortality, is less well understood than other addictive disorders. Dopamine release in ventral striatum is a common element of drug reward, but alcohol has an unusually complex pharmacology, and humans vary greatly in their alcohol responses. This variation is related to genetic susceptibility for alcoholism, which contributes more than half of alcoholism risk. Here, we report that a functional OPRM1 A118G polymorphism is a major determinant of striatal dopamine responses to alcohol. Social drinkers recruited based on OPRM1 genotype were challenged in separate sessions with alcohol and placebo under pharmacokinetically controlled conditions, and examined for striatal dopamine release using positron emission tomography and [11C]-raclopride displacement. A striatal dopamine response to alcohol was restricted to carriers of the minor 118G allele. To directly establish the causal role of OPRM1 A118G variation, we generated two humanized mouse lines, carrying the respective human sequence variant. Brain microdialysis showed a four-fold greater peak dopamine response to an alcohol challenge in h/mOPRM1-118GG than in h/mOPRM1-118AA mice. OPRM1 A118G variation is a genetic determinant of dopamine responses to alcohol, a mechanism by which it likely modulates alcohol reward. PMID:20479755

Impulse Control Disorders and Related Complications of Parkinson’s Disease Therapy

PubMed Central

Lopez, Alexander M.; Weintraub, Daniel; Claassen, Daniel O.

2017-01-01

Impulsive and compulsive behaviors in Parkinson’s disease (PD) patients are most often attributed to dopamine agonist therapy; dysregulation of the mesocorticolimbic system accounts for this behavioral phenotype. The clinical presentation is commonly termed impulse control disorder (ICD): Behaviors include hypersexuality, compulsive eating, shopping, pathological gambling, and compulsive hobby participation. However, not all PD individuals taking dopamine agonists develop these behavioral changes. In this review, the authors focus on the similarities between the phenotypic presentation of ICDs with that of other reward-based behavioral disorders, including binge eating disorder, pathological gambling, and substance use disorders. With this comparison, we emphasize that the transition from an impulsive to compulsive behavior likely follows a ventral to dorsal striatal pattern, where an altered dopaminergic reward system underlies the emergence of these problematic behaviors. The authors discuss the neurobiological similarities between these latter disorders and ICDs, emphasizing similar pathophysiological processes and discussing treatment options that have potential for translation to PD patients. PMID:28511259

Imaging genetics and the neurobiological basis of individual differences in vulnerability to addiction.

PubMed

Sweitzer, Maggie M; Donny, Eric C; Hariri, Ahmad R

2012-06-01

Addictive disorders are heritable, but the search for candidate functional polymorphisms playing an etiological role in addiction is hindered by complexity of the phenotype and the variety of factors interacting to impact behavior. Advances in human genome sequencing and neuroimaging technology provide an unprecedented opportunity to explore the impact of functional genetic variants on variability in behaviorally relevant neural circuitry. Here, we present a model for merging these technologies to trace the links between genes, brain, and addictive behavior. We describe imaging genetics and discuss the utility of its application to addiction. We then review data pertaining to impulsivity and reward circuitry as an example of how genetic variation may lead to variation in behavioral phenotype. Finally, we present preliminary data relating the neural basis of reward processing to individual differences in nicotine dependence. Complex human behaviors such as addiction can be traced to their basic genetic building blocks by identifying intermediate behavioral phenotypes, associated neural circuitry, and underlying molecular signaling pathways. Impulsivity has been linked with variation in reward-related activation in the ventral striatum (VS), altered dopamine signaling, and functional polymorphisms of DRD2 and DAT1 genes. In smokers, changes in reward-related VS activation induced by smoking abstinence may be associated with severity of nicotine dependence. Variation in genes related to dopamine signaling may contribute to heterogeneity in VS sensitivity to reward and, ultimately, to addiction. These findings illustrate the utility of the imaging genetics approach for investigating the neurobiological basis for vulnerability to addiction. Copyright © 2012 Elsevier Ireland Ltd. All rights reserved.

Dopamine cells respond to predicted events during classical conditioning: evidence for eligibility traces in the reward-learning network.

PubMed

Pan, Wei-Xing; Schmidt, Robert; Wickens, Jeffery R; Hyland, Brian I

2005-06-29

Behavioral conditioning of cue-reward pairing results in a shift of midbrain dopamine (DA) cell activity from responding to the reward to responding to the predictive cue. However, the precise time course and mechanism underlying this shift remain unclear. Here, we report a combined single-unit recording and temporal difference (TD) modeling approach to this question. The data from recordings in conscious rats showed that DA cells retain responses to predicted reward after responses to conditioned cues have developed, at least early in training. This contrasts with previous TD models that predict a gradual stepwise shift in latency with responses to rewards lost before responses develop to the conditioned cue. By exploring the TD parameter space, we demonstrate that the persistent reward responses of DA cells during conditioning are only accurately replicated by a TD model with long-lasting eligibility traces (nonzero values for the parameter lambda) and low learning rate (alpha). These physiological constraints for TD parameters suggest that eligibility traces and low per-trial rates of plastic modification may be essential features of neural circuits for reward learning in the brain. Such properties enable rapid but stable initiation of learning when the number of stimulus-reward pairings is limited, conferring significant adaptive advantages in real-world environments.

Cannabinoid transmission in the prelimbic cortex bidirectionally controls opiate reward and aversion signaling through dissociable kappa versus μ-opiate receptor dependent mechanisms.

PubMed

Ahmad, Tasha; Lauzon, Nicole M; de Jaeger, Xavier; Laviolette, Steven R

2013-09-25

Cannabinoid, dopamine (DA), and opiate receptor pathways play integrative roles in emotional learning, associative memory, and sensory perception. Modulation of cannabinoid CB1 receptor transmission within the medial prefrontal cortex (mPFC) regulates the emotional valence of both rewarding and aversive experiences. Furthermore, CB1 receptor substrates functionally interact with opiate-related motivational processing circuits, particularly in the context of reward-related learning and memory. Considerable evidence demonstrates functional interactions between CB1 and DA signaling pathways during the processing of motivationally salient information. However, the role of mPFC CB1 receptor transmission in the modulation of behavioral opiate-reward processing is not currently known. Using an unbiased conditioned place preference paradigm with rats, we examined the role of intra-mPFC CB1 transmission during opiate reward learning. We report that activation or inhibition of CB1 transmission within the prelimbic cortical (PLC) division of the mPFC bidirectionally regulates the motivational valence of opiates; whereas CB1 activation switched morphine reward signaling into an aversive stimulus, blockade of CB1 transmission potentiated the rewarding properties of normally sub-reward threshold conditioning doses of morphine. Both of these effects were dependent upon DA transmission as systemic blockade of DAergic transmission prevented CB1-dependent modulation of morphine reward and aversion behaviors. We further report that CB1-mediated intra-PLC opiate motivational signaling is mediated through a μ-opiate receptor-dependent reward pathway, or a κ-opiate receptor-dependent aversion pathway, directly within the ventral tegmental area. Our results provide evidence for a novel CB1-mediated motivational valence switching mechanism within the PLC, controlling dissociable subcortical reward and aversion pathways.

Pro-Dopamine Regulator – (KB220) to Balance Brain Reward Circuitry in Reward Deficiency Syndrome (RDS)

PubMed Central

Blum, Kenneth; Febo, Marcelo; Fried, Lyle; Baron, David; Braverman, Eric R.; Dushaj, Kristina; Li, Mona; Demetrovics, Zsolt; Badgaiyan, Rajendra D.

2017-01-01

We are faced with a worldwide opiate/opioid epidemic that is devastating. According to the Centers for Disease Control and Prevention (CDC), at least 127 people, young and old, are dying every day in America due to narcotic overdose. The Food and Drug Administration (FDA) has approved Medication-Assisted Treatments (MATs) for opiate/opioids as well as alcohol and nicotine. The mechanism of action of most MATS favors either blocking of dopaminergic function or a form of Opiate Substitution Therapy (OST). These treatment options are adequate for short-term treatment of the symptoms of addiction and harm reduction but fail long-term to deal with the cause or lead to recovery. There is a need to continue to seek better treatment options. This mini-review is the history of the development of one such treatment; a glutaminergic-dopaminergic optimization complex called KB220. Growing evidence indicates that brain reward circuitry controls drug addiction, in conjunction with “anti-reward systems” as the “anti-reward systems” can be affected by both glutaminergic and dopaminergic transmission. KB220 may likely alter the function of these regions and provide for the possible eventual balancing the brain reward system and the induction of “dopamine homeostasis.” Many of these concepts have been reported elsewhere and have become an integral part of the addiction science literature. However, the concise review may encourage readership to reconsider these facts and stimulate further research focused on the impact that the induction of “dopamine homeostasis” may have on recovery and relapse prevention. PMID:28804788

Dorsolateral neostriatum contribution to incentive salience: Opioid or dopamine stimulation makes one reward cue more motivationally attractive than another

PubMed Central

DiFeliceantonio, Alexandra G.; Berridge, Kent C.

2016-01-01

Pavlovian cues for rewards can become attractive incentives: approached and ‘wanted’ as the rewards themselves. The motivational attractiveness of a previously learned cue is not fixed, but can be dynamically amplified during re-encounter by simultaneous activation of brain limbic circuitry. Here we report that opioid or dopamine microinjections in the dorsolateral quadrant of the neostriatum (DLS) of rats selectively amplify attraction toward a previously learned Pavlovian cue in an individualized fashion, at the expense of a competing cue. In an autoshaping (sign-tracking vs goal-tracking) paradigm, microinjection of the mu opioid receptor agonist (DAMGO) or dopamine indirect agonist (amphetamine) in DLS of sign-tracker individuals selectively enhanced their sign-tracking attraction toward the reward-predictive lever cue. By contrast, DAMGO or amphetamine in DLS of goal-trackers selectively enhanced prepotent attraction toward the reward-proximal cue of sucrose dish. Amphetamine also enhanced goal-tracking in some sign-tracker individuals (if they ever defected to the dish even once). That DLS enhancement of cue attraction was due to stronger motivation, not stronger habits was suggested by: 1) sign-trackers flexibly followed their cue to a new location when the lever was suddenly moved after DLS DAMGO microinjection, and 2) DAMGO in DLS also made sign-trackers work harder on a new instrumental nose-poke response required to earn presentations of their Pavlovian lever cue (instrumental conditioned reinforcement). Altogether, our results suggest that DLS circuitry can enhance the incentive salience of a Pavlovian reward cue, selectively making that cue a stronger motivational magnet. PMID:26924040

Dopamine and the Neural "Now": Essay and Review of Addiction: A Disorder of Choice.

PubMed

Lewis, Marc D

2011-03-01

Rather than view addiction as a disease, Heyman sees it as a choice-one that works like other choices, whereby immediate rewards outshine long-term gains. He rejects neuroscientific explanations of addictive behavior, because he believes they cast it as involuntary or disease-like. I argue that the disease-versus-choice debate creates a false dichotomy: Neuroscience does not have to frame addiction as a disease. Rather, it can help explain how addicts make impulsive choices in the moment and distort appraisal and decision-making habits in the long run. Specifically, the salience of drug-related cues is enhanced by dopamine activity in the ventral striatum, orbitofrontal cortex, and amygdala, due to the intense hedonic impact of repeated drug experiences. Moreover, dopamine-based craving peaks when drug (or alcohol or gambling) rewards become available, in the moment, and this rapid increase in attractiveness preempts rational judgment. Finally, repeated dopamine enhancement modifies brain structures to maximize the appeal of addictive activities, minimize the appeal of competing rewards, and undermine the cognitive capacities necessary to choose between them. I conclude that addiction is not a monolithic state but a recurrent series of choices that permit negotiation, and sometimes cooperation, between immediate and long-range goals. © The Author(s) 2011.

Methylphenidate-Elicited Dopamine Increases in Ventral Striatum Are Associated with Long-Term Symptom Improvement in Adults with Attention Deficit Hyperactivity Disorder

PubMed Central

Volkow, Nora D.; Wang, Gene-Jack; Tomasi, Dardo; Kollins, Scott H.; Wigal, Tim L.; Newcorn, Jeffrey H.; Telang, Frank W.; Fowler, Joanna S.; Logan, Jean; Wong, Christopher T.; Swanson, James M.

2012-01-01

Stimulant medications, such as methylphenidate, which are effective treatments for attention deficit hyperactivity disorder (ADHD), enhance brain dopamine signaling. However, the relationship between regional brain dopamine enhancement and treatment response has not been evaluated. Here, we assessed whether the dopamine increases elicited by methylphenidate are associated with long-term clinical response. We used a prospective design to study 20 treatment-naive adults with ADHD who were evaluated before treatment initiation and after 12 months of clinical treatment with a titrated regimen of oral methylphenidate. Methylphenidate-induced dopamine changes were evaluated with positron emission tomography and [11C]raclopride (D2/D3 receptor radioligand sensitive to competition with endogenous dopamine). Clinical responses were assessed using the Conners' Adult ADHD Rating Scale and revealed a significant reduction in symptoms of inattention and hyperactivity with long-term methylphenidate treatment. A challenge dose of 0.5 mg/kg intravenous methylphenidate significantly increased dopamine in striatum (assessed as decreases in D2/D3 receptor availability). In the ventral striatum, these dopamine increases were associated with the reductions in ratings of symptoms of inattention with clinical treatment. Statistical parametric mapping additionally showed dopamine increases in prefrontal and temporal cortices with intravenous methylphenidate that were also associated with decreases in symptoms of inattention. Our findings indicate that dopamine enhancement in ventral striatum (the brain region involved with reward and motivation) was associated with therapeutic response to methylphenidate, further corroborating the relevance of the dopamine reward/motivation circuitry in ADHD. It also provides preliminary evidence that methylphenidate-elicited dopamine increases in prefrontal and temporal cortices may also contribute to the clinical response. PMID:22262882

Methylphenidate-Elicited Dopamine Increases in Ventral Striatum Are Associated with Long-Term Symptom Improvement in Adults with Attention Deficit Hyperactivity Disorder

DOE Office of Scientific and Technical Information (OSTI.GOV)

Volkow N. D.; Wang G.; Volkow, N.D.

Stimulant medications, such as methylphenidate, which are effective treatments for attention deficit hyperactivity disorder (ADHD), enhance brain dopamine signaling. However, the relationship between regional brain dopamine enhancement and treatment response has not been evaluated. Here, we assessed whether the dopamine increases elicited by methylphenidate are associated with long-term clinical response. We used a prospective design to study 20 treatment-naive adults with ADHD who were evaluated before treatment initiation and after 12 months of clinical treatment with a titrated regimen of oral methylphenidate. Methylphenidate-induced dopamine changes were evaluated with positron emission tomography and [{sup 11}C]raclopride (D{sub 2}/D{sub 3} receptor radioligand sensitivemore » to competition with endogenous dopamine). Clinical responses were assessed using the Conners Adult ADHD Rating Scale and revealed a significant reduction in symptoms of inattention and hyperactivity with long-term methylphenidate treatment. A challenge dose of 0.5 mg/kg intravenous methylphenidate significantly increased dopamine in striatum (assessed as decreases in D{sub 2}/D{sub 3} receptor availability). In the ventral striatum, these dopamine increases were associated with the reductions in ratings of symptoms of inattention with clinical treatment. Statistical parametric mapping additionally showed dopamine increases in prefrontal and temporal cortices with intravenous methylphenidate that were also associated with decreases in symptoms of inattention. Our findings indicate that dopamine enhancement in ventral striatum (the brain region involved with reward and motivation) was associated with therapeutic response to methylphenidate, further corroborating the relevance of the dopamine reward/motivation circuitry in ADHD. It also provides preliminary evidence that methylphenidate-elicited dopamine increases in prefrontal and temporal cortices may also contribute to the clinical response.« less

The impact of junk foods on the adolescent brain.

PubMed

Reichelt, Amy C; Rank, Michelle M

2017-12-01

Adolescence is a significant period of physical, social, and emotional development, and is characterized by prominent neurobiological changes in the brain. The maturational processes that occur in brain regions responsible for cognitive control and reward seeking may underpin excessive consumption of palatable high fat and high sugar "junk" foods during adolescence. Recent studies have highlighted the negative impact of these foods on brain function, resulting in cognitive impairments and altered reward processing. The increased neuroplasticity during adolescence may render the brain vulnerable to the negative effects of these foods on cognition and behavior. In this review, we describe the mechanisms by which junk food diets influence neurodevelopment during adolescence. Diet can lead to alterations in dopamine-mediated reward signaling, and inhibitory neurotransmission controlled by γ-aminobutyric acid (GABA), two major neurotransmitter systems that are under construction across adolescence. We propose that poor dietary choices may derail the normal adolescent maturation process and influence neurodevelopmental trajectories, which can predispose individuals to dysregulated eating and impulsive behaviors. © 2017 Wiley Periodicals, Inc.

Reward, interrupted: Inhibitory control and its relevance to addictions.

PubMed

Jentsch, James David; Pennington, Zachary T

2014-01-01

There are broad individual differences in the ability to voluntarily and effortfully suppress motivated, reward-seeking behaviors, and this review presents the hypothesis that these individual differences are relevant to addictive disorders. On one hand, cumulative experience with drug abuse appears to alter the molecular, cellular and circuit mechanisms that mediate inhibitory abilities, leading to increasingly uncontrolled patterns of drug-seeking and -taking. On the other, native inter-individual differences in inhibitory control are apparently a risk factor for aspects of drug-reinforced responding and substance use disorders. In both cases, the behavioral manifestation of poor inhibitory abilities is linked to relatively low striatal dopamine D2-like receptor availability, and evidence is accumulating for a more direct contribution of striatopallidal neurons to cognitive control processes. Mechanistic research is now identifying genes upstream of dopamine transmission that mediate these relationships, as well as the involvement of other neurotransmitter systems, acting alone and in concert with dopamine. The reviewed research stands poised to identify new mechanisms that can be targeted by pharmacotherapies and/or by behavioral interventions that are designed to prevent or treat addictive behaviors and associated behavioral pathology. This article is part of a Special Issue entitled 'NIDA 40th Anniversary Issue'. Copyright © 2013 Elsevier Ltd. All rights reserved.

Dopamine D3 receptor antagonism inhibits cocaine-seeking and cocaine-enhanced brain reward in rats.

PubMed

Vorel, Stanislav R; Ashby, Charles R; Paul, Mousumi; Liu, Xinhe; Hayes, Robert; Hagan, Jim J; Middlemiss, Derek N; Stemp, Geoffrey; Gardner, Eliot L

2002-11-01

dopamine D3 receptor is preferentially localized to the mesocorticolimbic dopaminergic system and has been hypothesized to play a role in cocaine addiction. To study the involvement of the D3 receptor in brain mechanisms and behaviors commonly assumed to be involved in the addicting properties of cocaine, the potent and selective D3 receptor antagonist trans-N-[4-[2-(6-cyano-1,2,3,4-tetrahydroisoquinolin-2-yl)ethyl] cyclohexyl]-4-quinolininecarboxamide (SB-277011-A) was administered to laboratory rats, and the following measures were assessed: (1) cocaine-enhanced electrical brain-stimulation reward, (2) cocaine-induced conditioned place preference, and (3) cocaine-triggered reinstatement of cocaine seeking behavior. Systemic injections of SB-277011-A were found to (1) block enhancement of electrical brain stimulation reward by cocaine, (2) dose-dependently attenuate cocaine-induced conditioned place preference, and (3) dose-dependently attenuate cocaine-triggered reinstatement of cocaine seeking behavior. Thus, D3 receptor blockade attenuates both the rewarding effects of cocaine and cocaine-induced drug-seeking behavior. These data suggest an important role for D3 receptors in mediating the addictive properties of cocaine and suggest that blockade of dopamine D3 receptors may constitute a new and useful target for prospective pharmacotherapies for cocaine addiction.

Epigenetic dysregulation of the dopamine system in diet-induced obesity.

PubMed

Vucetic, Zivjena; Carlin, Jesse Lea; Totoki, Kathy; Reyes, Teresa M

2012-03-01

Chronic intake of high-fat (HF) diet is known to alter brain neurotransmitter systems that participate in the central regulation of food intake. Dopamine (DA) system changes in response to HF diet have been observed in the hypothalamus, important in the homeostatic control of food intake, as well as within the central reward circuitry [ventral tegmental area (VTA), nucleus accumbens (NAc), and pre-frontal cortex (PFC)], critical for coding the rewarding properties of palatable food and important in hedonically driven feeding behavior. Using a mouse model of diet-induced obesity (DIO), significant alterations in the expression of DA-related genes were documented in adult animals, and the general pattern of gene expression changes was opposite within the hypothalamus versus the reward circuitry (increased vs. decreased, respectively). Differential DNA methylation was identified within the promoter regions of tyrosine hydroxylase (TH) and dopamine transporter (DAT), and the pattern of this response was consistent with the pattern of gene expression. Behaviors consistent with increased hypothalamic DA and decreased reward circuitry DA were observed. These data identify differential DNA methylation as an epigenetic mechanism linking the chronic intake of HF diet with altered DA-related gene expression, and this response varies by brain region and DNA sequence. © 2012 The Authors. Journal of Neurochemistry © 2012 International Society for Neurochemistry.

Reward circuitry dysfunction in psychiatric and neurodevelopmental disorders and genetic syndromes: animal models and clinical findings.

PubMed

Dichter, Gabriel S; Damiano, Cara A; Allen, John A

2012-07-06

This review summarizes evidence of dysregulated reward circuitry function in a range of neurodevelopmental and psychiatric disorders and genetic syndromes. First, the contribution of identifying a core mechanistic process across disparate disorders to disease classification is discussed, followed by a review of the neurobiology of reward circuitry. We next consider preclinical animal models and clinical evidence of reward-pathway dysfunction in a range of disorders, including psychiatric disorders (i.e., substance-use disorders, affective disorders, eating disorders, and obsessive compulsive disorders), neurodevelopmental disorders (i.e., schizophrenia, attention-deficit/hyperactivity disorder, autism spectrum disorders, Tourette's syndrome, conduct disorder/oppositional defiant disorder), and genetic syndromes (i.e., Fragile X syndrome, Prader-Willi syndrome, Williams syndrome, Angelman syndrome, and Rett syndrome). We also provide brief overviews of effective psychopharmacologic agents that have an effect on the dopamine system in these disorders. This review concludes with methodological considerations for future research designed to more clearly probe reward-circuitry dysfunction, with the ultimate goal of improved intervention strategies.

Reward circuitry dysfunction in psychiatric and neurodevelopmental disorders and genetic syndromes: animal models and clinical findings

PubMed Central

2012-01-01

This review summarizes evidence of dysregulated reward circuitry function in a range of neurodevelopmental and psychiatric disorders and genetic syndromes. First, the contribution of identifying a core mechanistic process across disparate disorders to disease classification is discussed, followed by a review of the neurobiology of reward circuitry. We next consider preclinical animal models and clinical evidence of reward-pathway dysfunction in a range of disorders, including psychiatric disorders (i.e., substance-use disorders, affective disorders, eating disorders, and obsessive compulsive disorders), neurodevelopmental disorders (i.e., schizophrenia, attention-deficit/hyperactivity disorder, autism spectrum disorders, Tourette’s syndrome, conduct disorder/oppositional defiant disorder), and genetic syndromes (i.e., Fragile X syndrome, Prader–Willi syndrome, Williams syndrome, Angelman syndrome, and Rett syndrome). We also provide brief overviews of effective psychopharmacologic agents that have an effect on the dopamine system in these disorders. This review concludes with methodological considerations for future research designed to more clearly probe reward-circuitry dysfunction, with the ultimate goal of improved intervention strategies. PMID:22958744

Extracellular level of basolateral amygdalar dopamine responding to reversal of appetitive-conditioned discrimination in young and old rats.

PubMed

Nomura, Masahiko; Izaki, Yoshinori; Takita, Masatoshi; Tanaka, Junichi; Hori, Koji

2004-08-27

Young and old rats, aged 3 and 24 months old, respectively, were conditioned to press a lever under lamp-on conditions for reward acquisition and lamp-off for no reward using a variable interval reinforcement schedule that averaged 15 s; i.e., the minimal requirement was 4 responses/min. Over a 30-day period, young and old groups showed increased response to lamp-on from 22 to 35/min and from 10 to 23/min, respectively, and shortened response to lamp-off after initial training. Response to lamp-on as a percentage of total response to lamp-on and -off (the discrimination ratio) was over 80%. For the next 30 days, reversal learning was imposed to reinforce discrimination of the lamp-off state. Young rats showed a steadily increasing discrimination ratio from 40% to 70%, and old rats from 30% to 60%. In comparison with the initial training, young rats showed a total response increase from 50% to 60%, while old rats showed an approximately 5% decrease without loss of reward-obtaining efficiency. In vivo microdialysis during reversal revealed that young rats had higher dopamine transmission in the basolateral amygdala than old rats. The dopamine level was positively correlated with the number of responses to state of reward in young rats and negatively with the numbers of both NRF and RF responses to lamp-on and -off states in old rats. These results suggest that in reversal discrimination, basolateral amygdalar dopamine efflux correlates with the manner of age-related conditioned response rather than the ability to learn.

The role of dopamine in the nucleus accumbens and striatum during sexual behavior in the female rat.

PubMed

Becker, J B; Rudick, C N; Jenkins, W J

2001-05-01

Dopamine in dialysate from the nucleus accumbens (NAcc) increases during sexual and feeding behavior and after administration of drugs of abuse, even those that do not directly activate dopaminergic systems (e.g., morphine or nicotine). These findings and others have led to hypotheses that propose that dopamine is rewarding, predicts that reinforcement will occur, or attributes incentive salience. Examining increases in dopamine in NAcc or striatum during sexual behavior in female rats provides a unique situation to study these relations. This is because, for the female rat, sexual behavior is associated with an increase in NAcc dopamine and conditioned place preference only under certain testing conditions. This experiment was conducted to determine what factors are important for the increase in dopamine in dialysate from NAcc and striatum during sexual behavior in female rats. The factors considered were the number of contacts by the male, the timing of contacts by the male, or the ability of the female to control contacts by the male. The results indicate that increased NAcc dopamine is dependent on the timing of copulatory stimuli, independent of whether the female rat is actively engaged in regulating this timing. For the striatum, the timing of copulatory behavior influences the magnitude of the increase in dopamine in dialysate, but other factors are also involved. We conclude that increased extracellular dopamine in the NAcc and striatum conveys qualitative or interpretive information about the rewarding value of stimuli. Sexual behavior in the female rat is proposed as a model to determine the role of dopamine in motivated behavior.

Striatal dopaminergic modulation of reinforcement learning predicts reward-oriented behavior in daily life.

PubMed

Kasanova, Zuzana; Ceccarini, Jenny; Frank, Michael J; Amelsvoort, Thérèse van; Booij, Jan; Heinzel, Alexander; Mottaghy, Felix; Myin-Germeys, Inez

2017-07-01

Much human behavior is driven by rewards. Preclinical neurophysiological and clinical positron emission tomography (PET) studies have implicated striatal phasic dopamine (DA) release as a primary modulator of reward processing. However, the relationship between experimental reward-induced striatal DA release and responsiveness to naturalistic rewards, and therefore functional relevance of these findings, has been elusive. We therefore combined, for the first time, a DA D 2/3 receptor [ 18 F]fallypride PET during a probabilistic reinforcement learning (RL) task with a six day ecological momentary assessments (EMA) of reward-related behavior in the everyday life of 16 healthy volunteers. We detected significant reward-induced DA release in the bilateral putamen, caudate nucleus and ventral striatum, the extent of which was associated with better behavioral performance on the RL task across all regions. Furthermore, individual variability in the extent of reward-induced DA release in the right caudate nucleus and ventral striatum modulated the tendency to be actively engaged in a behavior if the active engagement was previously deemed enjoyable. This study suggests a link between striatal reward-related DA release and ecologically relevant reward-oriented behavior, suggesting an avenue for the inquiry into the DAergic basis of optimal and impaired motivational drive. Copyright © 2017 Elsevier B.V. All rights reserved.

Examining the role of dopamine D2 and D3 receptors in Pavlovian conditioned approach behaviors.

PubMed

Fraser, Kurt M; Haight, Joshua L; Gardner, Eliot L; Flagel, Shelly B

2016-05-15

Elucidating the neurobiological mechanisms underlying individual differences in the extent to which reward cues acquire the ability to act as incentive stimuli may contribute to the development of successful treatments for addiction and related disorders. We used the sign-tracker/goal-tracker animal model to examine the role of dopamine D2 and D3 receptors in the propensity to attribute incentive salience to reward cues. Following Pavlovian training, wherein a discrete lever-cue was paired with food reward, rats were classified as sign- or goal-trackers based on the resultant conditioned response. We examined the effects of D2/D3 agonists, 7-OH-DPAT (0.01-0.32mg/kg) or pramipexole (0.032-0.32mg/kg), the D2/D3 antagonist raclopride (0.1mg/kg), and the selective D3 antagonist, SB-277011A (6 or 24mg/kg), on the expression of sign- and goal-tracking conditioned responses. The lever-cue acquired predictive value and elicited a conditioned response for sign- and goal-trackers, but only for sign-trackers did it also acquire incentive value. Following administration of either 7-OH-DPAT, pramipexole, or raclopride, the performance of the previously acquired conditioned response was attenuated for both sign- and goal-trackers. For sign-trackers, the D2/D3 agonist, 7-OH-DPAT, also attenuated the conditioned reinforcing properties of the lever-cue. The selective D3 antagonist did not affect either conditioned response. Alterations in D2/D3 receptor signaling, but not D3 signaling alone, transiently attenuate a previously acquired Pavlovian conditioned response, regardless of whether the response is a result of incentive motivational processes. These findings suggest activity at the dopamine D2 receptor is critical for a reward cue to maintain either its incentive or predictive qualities. Copyright © 2016 Elsevier B.V. All rights reserved.

Examining the Role of Dopamine D2 and D3 Receptors in Pavlovian Conditioned Approach Behaviors

PubMed Central

Fraser, Kurt M.; Haight, Joshua L.; Gardner, Eliot L.; Flagel, Shelly B.

2016-01-01

Elucidating the neurobiological mechanisms underlying individual differences in the extent to which reward cues acquire the ability to act as incentive stimuli may contribute to the development of successful treatments for addiction and related disorders. We used the sign-tracker/goal-tracker animal model to examine the role of dopamine D2 and D3 receptors in the propensity to attribute incentive salience to reward cues. Following Pavlovian training, wherein a discrete lever-cue was paired with food reward, rats were classified as sign- or goal-trackers based on the resultant conditioned response. We examined the effects of D2/D3 agonists, 7-OH-DPAT (0.01–0.32 mg/kg) or pramipexole (0.032–0.32 mg/kg), the D2/D3 antagonist raclopride (0.1 mg/kg), and the selective D3 antagonist, SB-277011A (6 or 24 mg/kg), on the expression of sign- and goal-tracking conditioned responses. The lever-cue acquired predictive value and elicited a conditioned response for sign- and goal-trackers, but only for sign-trackers did it also acquire incentive value. Following administration of either 7-OH-DPAT, pramipexole, or raclopride, the performance of the previously acquired conditioned response was attenuated for both sign- and goal-trackers. For sign-trackers, the D2/D3 agonist, 7-OH-DPAT, also attenuated the conditioned reinforcing properties of the lever-cue. The selective D3 antagonist did not affect either conditioned response. Alterations in D2/D3 receptor signaling, but not D3 signaling alone, transiently attenuate a previously acquired Pavlovian conditioned response, regardless of whether the response is a result of incentive motivational processes. These findings suggest activity at the dopamine D2 receptor is critical for a reward cue to maintain either its incentive or predictive qualities. PMID:26909847

Continuous, but not intermittent, antipsychotic drug delivery intensifies the pursuit of reward cues.

PubMed

Bédard, Anne-Marie; Maheux, Jérôme; Lévesque, Daniel; Samaha, Anne-Noël

2011-05-01

Chronic exposure to antipsychotic medications can persistently change brain dopamine systems. Most studies on the functional significance of these neural changes have focused on motor behavior and few have addressed how long-term antipsychotic treatment might influence dopamine-mediated reward function. We asked, therefore, whether a clinically relevant antipsychotic treatment regimen would alter the incentive motivational properties of a reward cue. We assessed the ability of a Pavlovian-conditioned stimulus to function as a conditioned reward, as well as to elicit approach behavior in rats treated with haloperidol, either continuously (achieved via subcutaneous osmotic minipump) or intermittently (achieved via daily subcutaneous injections). Continuous, but not intermittent, treatment enhanced the ability of amphetamine to potentiate the conditioned reinforcing effects of a cue associated with water. This effect was not related to differences in the ability to attribute predictive value to a conditioned stimulus (as measured by conditioned approach behavior), but was potentially linked to the development of behavioral supersensitivity to amphetamine and to augmented amphetamine-induced immediate early-gene expression (c-fos and Nur77) in dorsal striatopallidal and striatonigral cells. By enhancing the ability of reward cues to control behavior and by intensifying dopamine-mediated striatopallidal and striatonigral cell activity, standard (ie, continuous) antipsychotic treatment regimens might exacerbate drug-seeking and drug-taking behavior in schizophrenia. Achieving regular but transiently high antipsychotic levels in the brain (as modeled in the intermittent condition) might be a viable option to prevent these changes. This possibility should be explored in the clinic.

The neuroscience of positive memory deficits in depression

PubMed Central

Dillon, Daniel G.

2015-01-01

Adults with unipolar depression typically show poor episodic memory for positive material, but the neuroscientific mechanisms responsible for this deficit have not been characterized. I suggest a simple hypothesis: weak memory for positive material in depression reflects disrupted communication between the mesolimbic dopamine pathway and medial temporal lobe (MTL) memory systems during encoding. This proposal draws on basic research showing that dopamine release in the hippocampus is critical for the transition from early- to late-phase long-term potentiation (LTP) that marks the conversion of labile, short-term memories into stable, long-term memories. Neuroimaging and pharmacological data from healthy humans paint a similar picture: activation of the mesolimbic reward circuit enhances encoding and boosts retention. Unipolar depression is characterized by anhedonia–loss of pleasure–and reward circuit dysfunction, which is believed to reflect negative effects of stress on the mesolimbic dopamine pathway. Thus, I propose that the MTL is deprived of strengthening reward signals in depressed adults and memory for positive events suffers accordingly. Although other mechanisms are important, this hypothesis holds promise as an explanation for positive memory deficits in depression. PMID:26441703

Pleasure seeking and birdsong.

PubMed

Riters, Lauren V

2011-10-01

Songbirds sing at high rates within multiple contexts, suggesting that they are highly motivated to communicate and that the act of singing itself may be rewarding. Little is known about the neural regulation of the motivation to communicate. Dopamine and opioid neuropeptides play a primary role in reward seeking and sensory pleasure. In songbirds, these neurochemicals are found within brain regions implicated in both motivation and reward, including the medial preoptic nucleus (mPOA) and ventral tegmental area (VTA). Several lines of research indicate that dopamine and opioids in these regions play a role in birdsong that differs depending upon whether song is used to attract females (female-directed song) or is not directed towards other individuals (undirected song). Evidence is reviewed supporting the hypotheses: (1) that distinct patterns of dopamine activity influence the motivation to produce undirected and female-directed song, (2) that undirected communication is intrinsically reinforced by immediate release of opioids induced by the act of singing, and (3) that directed communication is socially reinforced by opioids released as part of social interactions. Copyright © 2011 Elsevier Ltd. All rights reserved.

Event-related brain potentials and the study of reward processing: Methodological considerations.

PubMed

Krigolson, Olave E

2017-11-14

There is growing interest in using electroencephalography and specifically the event-related brain potential (ERP) methodology to study human reward processing. Since the discovery of the feedback related negativity (Miltner et al., 1997) and the development of theories associating the feedback related negativity and more recently the reward positivity with reinforcement learning, midbrain dopamine function, and the anterior cingulate cortex (i.e., Holroyd and Coles, 2002) researchers have used the ERP methodology to probe the neural basis of reward learning in humans. However, examination of the feedback related negativity and the reward positivity cannot be done without an understanding of some key methodological issues that must be taken into account when using ERPs and examining these ERP components. For example, even the component name - the feedback related negativity - is a source of debate within the research community as some now strongly feel that the component should be named the reward positivity (Proudfit, 2015). Here, ten key methodological issues are discussed - confusion in component naming, the reward positivity, component identification, peak quantification and the use of difference waveforms, frequency (the N200) and component contamination (the P300), the impact of feedback timing, action, and task learnability, and how learning results in changes in the amplitude of the feedback-related negativity/reward positivity. The hope here is to not provide a definitive approach for examining the feedback related negativity/reward positivity, but instead to outline the key issues that must be taken into account when examining this component to assist researchers in their study of human reward processing with the ERP methodology. Copyright © 2017 Elsevier B.V. All rights reserved.

Neural mechanisms regulating different forms of risk-related decision-making: Insights from animal models.

PubMed

Orsini, Caitlin A; Moorman, David E; Young, Jared W; Setlow, Barry; Floresco, Stan B

2015-11-01

Over the past 20 years there has been a growing interest in the neural underpinnings of cost/benefit decision-making. Recent studies with animal models have made considerable advances in our understanding of how different prefrontal, striatal, limbic and monoaminergic circuits interact to promote efficient risk/reward decision-making, and how dysfunction in these circuits underlies aberrant decision-making observed in numerous psychiatric disorders. This review will highlight recent findings from studies exploring these questions using a variety of behavioral assays, as well as molecular, pharmacological, neurophysiological, and translational approaches. We begin with a discussion of how neural systems related to decision subcomponents may interact to generate more complex decisions involving risk and uncertainty. This is followed by an overview of interactions between prefrontal-amygdala-dopamine and habenular circuits in regulating choice between certain and uncertain rewards and how different modes of dopamine transmission may contribute to these processes. These data will be compared with results from other studies investigating the contribution of some of these systems to guiding decision-making related to rewards vs. punishment. Lastly, we provide a brief summary of impairments in risk-related decision-making associated with psychiatric disorders, highlighting recent translational studies in laboratory animals. Copyright © 2015 Elsevier Ltd. All rights reserved.

Aldehyde dehydrogenase 1a1 mediates a GABA synthesis pathway in midbrain dopaminergic neurons.

PubMed

Kim, Jae-Ick; Ganesan, Subhashree; Luo, Sarah X; Wu, Yu-Wei; Park, Esther; Huang, Eric J; Chen, Lu; Ding, Jun B

2015-10-02

Midbrain dopamine neurons are an essential component of the basal ganglia circuitry, playing key roles in the control of fine movement and reward. Recently, it has been demonstrated that γ-aminobutyric acid (GABA), the chief inhibitory neurotransmitter, is co-released by dopamine neurons. Here, we show that GABA co-release in dopamine neurons does not use the conventional GABA-synthesizing enzymes, glutamate decarboxylases GAD65 and GAD67. Our experiments reveal an evolutionarily conserved GABA synthesis pathway mediated by aldehyde dehydrogenase 1a1 (ALDH1a1). Moreover, GABA co-release is modulated by ethanol (EtOH) at concentrations seen in blood alcohol after binge drinking, and diminished ALDH1a1 leads to enhanced alcohol consumption and preference. These findings provide insights into the functional role of GABA co-release in midbrain dopamine neurons, which may be essential for reward-based behavior and addiction. Copyright © 2015, American Association for the Advancement of Science.

The effects of extreme nutritional conditions on the neurochemistry of reward and addiction

NASA Astrophysics Data System (ADS)

Pothos, Emmanuel N.

2001-08-01

Weight loss is a frequent problem in space flights. We now claim that it may affect performance and drug-seeking behavior by altering midbrain neurochemistry. In food-deprived rats (20-30% underweight) basal extracellular dopamine levels in the nucleus accumbens decrease to 40-50% of normal and locomotion is depressed. However, amphetamine-induced dopamine release and locomotion are higher than in controls (1825% vs. 595% after a 25 μM d-amphetamine intraaccumbens infusion). The lower basal and the higher stimulated dopamine levels suggest that the neurotransmitter accumulates presynaptically in the accumbens of the underweight rats due to subnormal basal release. Psychostimulants are more rewarding for underweight subjects possibly because they release significantly more dopamine from elevated presynaptic stores into the accumbens. Consequently, weight loss can lead both to depression of performance and propensity to substance abuse. These effects should be considered when providing nutritional resources for space flights so that weight loss is limited.

Contemporary approaches to neural circuit manipulation and mapping: focus on reward and addiction

PubMed Central

Saunders, Benjamin T.; Richard, Jocelyn M.; Janak, Patricia H.

2015-01-01

Tying complex psychological processes to precisely defined neural circuits is a major goal of systems and behavioural neuroscience. This is critical for understanding adaptive behaviour, and also how neural systems are altered in states of psychopathology, such as addiction. Efforts to relate psychological processes relevant to addiction to activity within defined neural circuits have been complicated by neural heterogeneity. Recent advances in technology allow for manipulation and mapping of genetically and anatomically defined neurons, which when used in concert with sophisticated behavioural models, have the potential to provide great insight into neural circuit bases of behaviour. Here we discuss contemporary approaches for understanding reward and addiction, with a focus on midbrain dopamine and cortico-striato-pallidal circuits. PMID:26240425

[Study on effects of Corydalis yanhusuo and L-THP on dopamine of reward circuitry in conditioned place preference rats and comparison].

PubMed

Yu, Shou-Yang; Yang, Pei-Run; Qian, Gang; Wu, Ming-Song; Bai, Wei-Feng; Tu, Ping; Luo, Su-Yuan

2013-11-01

To study and compare the effect of Corydalis yanhusuo and L-THP on dopamine neurotransmitter and D2 receptor of reward circuitry in various cerebral areas of conditioned place preference model rats and the comparison of their effects. The CPP model was established by injecting morphine in rats with increasing doses for 10 days. The initial dose of 10 mg x kg(-1), and the final dose of 100 mg x kg(-1), with 10 mg x kg(-1) increased each day. At 48 h after the final training, CPP was adopted to detect the successful establishment of the model. On the same day (12 d), they were orally administered with 2, 1, 0.5 g x kg(-1) C. yanhusuo (containing 0.153, 0.077 and 0.038 mg L-THP) and L-THP (3.76, 1.88, 0.94 mg x kg(-1)) for six days. On 18 d, CPP test was performed again. Next day, HPLC was adopted to determine the content of dopamine neurotransmitters of reward circuitry in VTA-NAc-PFC; Immunohistochemistry and Western blotting were adopted to detect the expression of D2 receptors. Compared with the physiological saline treatment group, C. yanhusuo (2, 1 g x kg(-1)) and L-THP (3.76, 1.88 mg x kg(-1)) groups showed that rats stayed in a notably shorter period in white boxes (morphine-accompanied boxes) (P < 0.01 or P < 0.05), and revealed a remarkably lower dopamine content in VTA, NAc and PFC and the significant increase in the expression of D2 receptor (P < 0.01 or P < 0.05). The down-regulation of the increased dopamine content in reward nervous circuitry and the up-regulation of the expression of D2 receptor may be one of mechanisms of C. yanhusuo and L-THP in accelerating the recession of morphine's CPP effect Regarding the inhibition of morphine's CPP effect and the effect on dopamine system, the effect of C. yanhusuo traditional Chinese medicine containing one-fold L-THP monomer is equal to that of the independent application of around 24-fold L-THP monomer.

Reciprocal Inhibitory Interactions Between the Reward-Related Effects of Leptin and Cocaine.

PubMed

You, Zhi-Bing; Wang, Bin; Liu, Qing-Rong; Wu, Yan; Otvos, Laszlo; Wise, Roy A

2016-03-01

Cocaine is habit-forming because of its ability to enhance dopaminergic neurotransmission in the forebrain. In addition to neuronal inputs, forebrain dopamine circuits are modulated by hormonal influences; one of these is leptin, an adipose-derived hormone that attenuates the rewarding effects of food- and hunger-associated brain stimulation reward. Here we report reciprocal inhibition between the reward-related effects of leptin and the reward-related effects of cocaine in rats. First, we report that cocaine and the expectancy of cocaine each depresses plasma leptin levels. Second, we report that exogenous leptin, given systemically or directly into the ventral tegmental area, attenuates the ability of cocaine to elevate dopamine levels in the nucleus accumbens, the ability of cocaine to establish a conditioned place preference, and the ability of cocaine-predictive stimuli to prolong responding in extinction of cocaine-seeking. Thus, whereas leptin represents an endogenous antagonist of the habit-forming and habit-sustaining effects of cocaine, this antagonism is attenuated by cocaine and comes to be attenuated by the expectancy of cocaine.

Neurogenetics and Nutrigenomics of Neuro-Nutrient Therapy for Reward Deficiency Syndrome (RDS): Clinical Ramifications as a Function of Molecular Neurobiological Mechanisms

PubMed Central

Blum, Kenneth; Oscar-Berman, Marlene; Stuller, Elizabeth; Miller, David; Giordano, John; Morse, Siobhan; McCormick, Lee; Downs, William B; Waite, Roger L; Barh, Debmalya; Neal, Dennis; Braverman, Eric R; Lohmann, Raquel; Borsten, Joan; Hauser, Mary; Han, David; Liu, Yijun; Helman, Manya; Simpatico, Thomas

2013-01-01

In accord with the new definition of addiction published by American Society of Addiction Medicine (ASAM) it is well-known that individuals who present to a treatment center involved in chemical dependency or other documented reward dependence behaviors have impaired brain reward circuitry. They have hypodopaminergic function due to genetic and/or environmental negative pressures upon the reward neuro-circuitry. This impairment leads to aberrant craving behavior and other behaviors such as Substance Use Disorder (SUD). Neurogenetic research in both animal and humans revealed that there is a well-defined cascade in the reward site of the brain that leads to normal dopamine release. This cascade has been termed the “Brain Reward Cascade” (BRC). Any impairment due to either genetics or environmental influences on this cascade will result in a reduced amount of dopamine release in the brain reward site. Manipulation of the BRC has been successfully achieved with neuro-nutrient therapy utilizing nutrigenomic principles. After over four decades of development, neuro-nutrient therapy has provided important clinical benefits when appropriately utilized. This is a review, with some illustrative case histories from a number of addiction professionals, of certain molecular neurobiological mechanisms which if ignored may lead to clinical complications. PMID:23926462

The role of orgasm in the development and shaping of partner preferences.

PubMed

Coria-Avila, Genaro A; Herrera-Covarrubias, Deissy; Ismail, Nafissa; Pfaus, James G

2016-01-01

The effect of orgasm on the development and shaping of partner preferences may involve a catalysis of the neurochemical mechanisms of bonding. Therefore, understanding such process is relevant for neuroscience and psychology. A systematic review was carried out using the terms Orgasm, Sexual Reward, Partner Preference, Pair Bonding, Brain, Learning, Sex, Copulation. In humans, concentrations of arousing neurotransmitters and potential bonding neurotransmitters increase during orgasm in the cerebrospinal fluid and the bloodstream. Similarly, studies in animals indicate that those neurotransmitters (noradrenaline, oxytocin, prolactin) and others (e.g. dopamine, opioids, serotonin) modulate the appetitive and consummatory phases of sexual behavior and reward. This suggests a link between the experience of orgasm/sexual reward and the neurochemical mechanisms of pair bonding. Orgasm/reward functions as an unconditioned stimulus (UCS). Some areas in the nervous system function as UCS-detection centers, which become activated during orgasm. Partner-related cues function as conditioned stimuli (CS) and are processed in CS-detector centers. Throughout the article, we discuss how UCS- and CS-detection centers must interact to facilitate memory consolidation and produce recognition and motivation during future social encounters.

Contributions of dopaminergic and non-dopaminergic neurons to VTA-stimulation induced neurovascular responses in brain reward circuits.

PubMed

Brocka, Marta; Helbing, Cornelia; Vincenz, Daniel; Scherf, Thomas; Montag, Dirk; Goldschmidt, Jürgen; Angenstein, Frank; Lippert, Michael

2018-04-30

Mapping the activity of the human mesolimbic dopamine system by BOLD-fMRI is a tempting approach to non-invasively study the action of the brain reward system during different experimental conditions. However, the contribution of dopamine release to the BOLD signal is disputed. To assign the actual contribution of dopaminergic and non-dopaminergic VTA neurons to the formation of BOLD responses in target regions of the mesolimbic system, we used two optogenetic approaches in rats. We either activated VTA dopaminergic neurons selectively, or dopaminergic and mainly glutamatergic projecting neurons together. We further used electrical stimulation to non-selectively activate neurons in the VTA. All three stimulation conditions effectively activated the mesolimbic dopaminergic system and triggered dopamine releases into the NAcc as measured by in vivo fast-scan cyclic voltammetry. Furthermore, both optogenetic stimulation paradigms led to indistinguishable self-stimulation behavior. In contrast to these similarities, however, the BOLD response pattern differed greatly between groups. In general, BOLD responses were weaker and sparser with increasing stimulation specificity for dopaminergic neurons. In addition, repetitive stimulation of the VTA caused a progressive decoupling of dopamine release and BOLD signal strength, and dopamine receptor antagonists were unable to block the BOLD signal elicited by VTA stimulation. To exclude that the sedation during fMRI is the cause of minimal mesolimbic BOLD in response to specific dopaminergic stimulation, we repeated our experiments using CBF SPECT in awake animals. Again, we found activations only for less-specific stimulation. Based on these results we conclude that canonical BOLD responses in the reward system represent mainly the activity of non-dopaminergic neurons. Thus, the minor effects of projecting dopaminergic neurons are concealed by non-dopaminergic activity, a finding which highlights the importance of a careful interpretation of reward-related human fMRI data. Copyright © 2018 The Authors. Published by Elsevier Inc. All rights reserved.

Dopaminergic dysregulation in mice selectively bred for excessive exercise or obesity.

PubMed

Mathes, Wendy Foulds; Nehrenberg, Derrick L; Gordon, Ryan; Hua, Kunjie; Garland, Theodore; Pomp, Daniel

2010-07-11

Dysregulation of the dopamine system is linked to various aberrant behaviors, including addiction, compulsive exercise, and hyperphagia leading to obesity. The goal of the present experiments was to determine how dopamine contributes to the expression of opposing phenotypes, excessive exercise and obesity. We hypothesized that similar alterations in dopamine and dopamine-related gene expression may underly obesity and excessive exercise, as competing traits for central reward pathways. Moreover, we hypothesized that selective breeding for high levels of exercise or obesity may have influenced genetic variation controlling these pathways, manifesting as opposing complex traits. Dopamine, dopamine-related peptide concentrations, and gene expression were evaluated in dorsal striatum (DS) and nucleus accumbens (NA) of mice from lines selectively bred for high rates of wheel running (HR) or obesity (M16), and the non-selected ICR strain from which these lines were derived. HPLC analysis showed significantly greater neurotransmitter concentrations in DS and NA of HR mice compared to M16 and ICR. Microarray analysis showed significant gene expression differences between HR and M16 compared to ICR in both brain areas, with changes revealed throughout the dopamine pathway including D1 and D2 receptors, associated G-proteins (e.g., Golf), and adenylate cyclase (e.g., Adcy5). The results suggest that similar modifications within the dopamine system may contribute to the expression of opposite phenotypes in mice, demonstrating that alterations within central reward pathways can contribute to both obesity and excessive exercise. Copyright 2010 Elsevier B.V. All rights reserved.

Dopaminergic Dysregulation in Mice Selectively Bred for Excessive Exercise or Obesity

PubMed Central

Nehrenberg, Derrick L.; Gordon, Ryan; Hua, Kunjie; Garland, Theodore; Pomp, Daniel

2010-01-01

Dysregulation of the dopamine system is linked to various aberrant behaviors, including addiction, compulsive exercise, and hyperphagia leading to obesity. The goal of the present experiments was to determine how dopamine contributes to the expression of opposing phenotypes, excessive exercise and obesity. We hypothesized that similar alterations in dopamine and dopamine-related gene expression may underly obesity and excessive exercise, as competing traits for central reward pathways. Moreover, we hypothesized that selective breeding for high levels of exercise or obesity may have influenced genetic variation controlling these pathways, manifesting as opposing complex traits. Dopamine, dopamine-related peptide concentrations, and gene expression were evaluated in dorsal striatum (DS) and nucleus accumbens (NA) of mice from lines selectively bred for high rates of wheel running (HR) or obesity (M16), and the non-selected ICR strain from which these lines were derived. HPLC analysis showed significantly greater neurotransmitter concentrations in DS and NA of HR mice compared to M16 and ICR. Microarray analysis showed significant gene expression differences between HR and M16 compared to ICR in both brain areas, with changes revealed throughout the dopamine pathway including D1 and D2 receptors, associated G-proteins (eg. Golf), and adenylate cyclase (eg. Adcy5). The results suggest similar modifications within the dopamine system may contribute to the expression of opposite phenotypes in mice, demonstrating that alterations within central reward pathways can contribute to both obesity and excessive exercise. PMID:20156488

Reward-seeking and discrimination deficits displayed by hypodopaminergic mice are prevented in mice lacking dopamine D4 receptors.

PubMed

Nemirovsky, Sergio I; Avale, M Elena; Brunner, Daniela; Rubinstein, Marcelo

2009-11-01

The dopamine D4 receptor (D4R) is predominantly expressed in the prefrontal cortex, a brain area that integrates motor, rewarding, and cognitive information. Because participation of D4Rs in executive learning is largely unknown, we challenged D4R knockout mice (Drd4(-/-)) and their wild-type (WT) littermates, neonatally treated with 6-hydroxydopamine (6-OHDA; icv) or vehicle in two operant learning paradigms. A continuous reinforcement task, in which one food-pellet was delivered after every lever press, showed that 6-OHDA-treated mice (hypodopaminergic) WT mice pressed the reinforcing lever at much lower rates than normodopaminergic WT mice. In contrast, Drd4(-/-) mice displayed increased lever pressing rates, regardless of their dopamine content. In another study, mice were trained to solve an operant two-choice task in which a first showing lever was coupled to the delivery of one food pellet only after a second lever emerged. Interval between presentation of both levers was initially 12 s and progressively shortened to 6, 2, and finally 0.5 s. Normodopaminergic WT mice obtained a pellet reward in more than 75% of the trials at 12, 6, and 2 s, whereas hypodopaminergic WT mice were severely impaired to select the reward-paired lever. Absence of D4Rs was not detrimental in this task. Moreover, hypodopaminergic Drd4(-/-) mice were as efficient as their normodopaminergic Drd4(-/-) siblings in selecting the reward-paired lever. In summary, hypodopaminergic mice exhibit severe impairments to retrieve rewards in two operant positive reinforcement tasks, but these deleterious effects are totally prevented in the absence of functional D4Rs.

Sex differences and the role of dopamine receptors in the reward-enhancing effects of nicotine and bupropion.

PubMed

Barrett, Scott T; Geary, Trevor N; Steiner, Amy N; Bevins, Rick A

2017-01-01

Nicotine and bupropion have been demonstrated to enhance the value of other reinforcers, and this may partially account for nicotine reward and dependence. Evidence suggests that the sexes differ in their sensitivity to the primary and secondary reinforcing effects of nicotine and nicotine-associated stimuli. Whether the sexes also differ in sensitivity to the reward-enhancing effects of nicotine (and bupropion) is yet unclear. The present study evaluated potential sex differences in the enhancement effects of nicotine and bupropion using a reinforcer demand approach. Furthermore, we sought to investigate the role that D1- and D2-type dopamine receptors play in the reward-enhancing effects of nicotine and bupropion. Demand for sensory reinforcement was assessed in male and female rats responding on a progression of fixed ratio schedules. The effects of nicotine and 10 or 20 mg/kg bupropion on reinforcer demand were assessed within subjects. Subsequently, the effects of SCH-23390 and eticlopride were assessed on the enhancing effects of nicotine and bupropion on progressive ratio responding. Nicotine and bupropion enhanced demand metrics of reinforcement value in both sexes. Females were more sensitive to the enhancement effects of bupropion assessed by reinforcer demand and progressive ratio performance. D2-like dopamine receptor antagonism by eticlopride attenuated the enhancement effects of bupropion, but not of nicotine. Nicotine and bupropion both enhance reinforcement value in both sexes, though females may be more sensitive to the reward-enhancing effects of bupropion. D2- and possibly D1-type receptors appear to be involved in the reward-enhancing effects of bupropion, but not necessarily nicotine.

CB1-Dependent Long-Term Depression in Ventral Tegmental Area GABA Neurons: A Novel Target for Marijuana

PubMed Central

Friend, Lindsey; Sandoval, Philip; Nufer, Teresa; Ostlund, Isaac

2017-01-01

The VTA is necessary for reward behavior with dopamine cells critically involved in reward signaling. Dopamine cells in turn are innervated and regulated by neighboring inhibitory GABA cells. Using whole-cell electrophysiology in juvenile-adolescent GAD67-GFP male mice, we examined excitatory plasticity in fluorescent VTA GABA cells. A novel CB1-dependent LTD was induced in GABA cells that was dependent on metabotropic glutamate receptor 5, and cannabinoid receptor 1 (CB1). LTD was absent in CB1 knock-out mice but preserved in heterozygous littermates. Bath applied Δ9-tetrahydrocannabinol depressed GABA cell activity, therefore downstream dopamine cells will be disinhibited; and thus, this could potentially result in increased reward. Chronic injections of Δ9-tetrahydrocannabinol occluded LTD compared with vehicle injections; however, a single exposure was insufficient to do so. As synaptic modifications by drugs of abuse are often tied to addiction, these data suggest a possible mechanism for the addictive effects of Δ9-tetrahydrocannabinol in juvenile-adolescents, by potentially altering reward behavioral outcomes. SIGNIFICANCE STATEMENT The present study identifies a novel form of glutamatergic synaptic plasticity in VTA GABA neurons, a currently understudied cell type that is critical for the brain's reward circuit, and how Δ9-tetrahydrocannabinol occludes this plasticity. This study specifically addresses a potential unifying mechanism whereby marijuana could exert rewarding and addictive/withdrawal effects. Marijuana use and legalization are a pressing issue for many states in the United States. Although marijuana is the most commonly abused illicit drug, the implications of legalized, widespread, or continued usage are speculative. This study in juvenile-adolescent aged mice identifies a novel form of synaptic plasticity in VTA GABA cells, and the synaptic remodeling that can occur after Δ9-tetrahydrocannabinol use. PMID:29038246

The effects of HIV-1 regulatory TAT protein expression on brain reward function, response to psychostimulants and delay-dependent memory in mice.

PubMed

Kesby, James P; Markou, Athina; Semenova, Svetlana

2016-10-01

Depression and psychostimulant abuse are common comorbidities among humans with immunodeficiency virus (HIV) disease. The HIV regulatory protein TAT is one of multiple HIV-related proteins associated with HIV-induced neurotoxicity. TAT-induced dysfunction of dopamine and serotonin systems in corticolimbic brain areas may result in impaired reward function, thus, contributing to depressive symptoms and psychostimulant abuse. Transgenic mice with doxycycline-induced TAT protein expression in the brain (TAT+, TAT- control) show neuropathology resembling brain abnormalities in HIV+ humans. We evaluated brain reward function in response to TAT expression, nicotine and methamphetamine administration in TAT+ and TAT- mice using the intracranial self-stimulation procedure. We evaluated the brain dopamine and serotonin systems with high-performance liquid chromatography. The effects of TAT expression on delay-dependent working memory in TAT+ and TAT- mice using the operant delayed nonmatch-to-position task were also assessed. During doxycycline administration, reward thresholds were elevated by 20% in TAT+ mice compared with TAT- mice. After the termination of doxycycline treatment, thresholds of TAT+ mice remained significantly higher than those of TAT- mice and this was associated with changes in mesolimbic serotonin and dopamine levels. TAT+ mice showed a greater methamphetamine-induced threshold lowering compared with TAT- mice. TAT expression did not alter delay-dependent working memory. These results indicate that TAT expression in mice leads to reward deficits, a core symptom of depression, and a greater sensitivity to methamphetamine-induced reward enhancement. Our findings suggest that the TAT protein may contribute to increased depressive-like symptoms and continued methamphetamine use in HIV-positive individuals. Copyright © 2016 Elsevier Ltd. All rights reserved.

Dorsolateral neostriatum contribution to incentive salience: opioid or dopamine stimulation makes one reward cue more motivationally attractive than another.

PubMed

DiFeliceantonio, Alexandra G; Berridge, Kent C

2016-05-01

Pavlovian cues for rewards can become attractive incentives: approached and 'wanted' as the rewards themselves. The motivational attractiveness of a previously learned cue is not fixed, but can be dynamically amplified during re-encounter by simultaneous activation of brain limbic circuitry. Here it was reported that opioid or dopamine microinjections in the dorsolateral quadrant of the neostriatum (DLS) of rats selectively amplify attraction toward a previously learned Pavlovian cue in an individualized fashion, at the expense of a competing cue. In an autoshaping (sign-tracking vs. goal-tracking) paradigm, microinjection of the mu opioid receptor agonist (DAMGO) or dopamine indirect agonist (amphetamine) in the DLS of sign-tracker individuals selectively enhanced their sign-tracking attraction toward the reward-predictive lever cue. By contrast, DAMGO or amphetamine in the DLS of goal-trackers selectively enhanced prepotent attraction toward the reward-proximal cue of sucrose dish. Amphetamine also enhanced goal-tracking in some sign-tracker individuals (if they ever defected to the dish even once). That DLS enhancement of cue attraction was due to stronger motivation, not stronger habits, was suggested by: (i) sign-trackers flexibly followed their cue to a new location when the lever was suddenly moved after DLS DAMGO microinjection; and (ii) DAMGO in the DLS also made sign-trackers work harder on a new instrumental nose-poke response required to earn presentations of their Pavlovian lever cue (instrumental conditioned reinforcement). Altogether, the current results suggest that DLS circuitry can enhance the incentive salience of a Pavlovian reward cue, selectively making that cue a stronger motivational magnet. © 2016 Federation of European Neuroscience Societies and John Wiley & Sons Ltd.

The role of learning-related dopamine signals in addiction vulnerability.

PubMed

Huys, Quentin J M; Tobler, Philippe N; Hasler, Gregor; Flagel, Shelly B

2014-01-01

Dopaminergic signals play a mathematically precise role in reward-related learning, and variations in dopaminergic signaling have been implicated in vulnerability to addiction. Here, we provide a detailed overview of the relationship between theoretical, mathematical, and experimental accounts of phasic dopamine signaling, with implications for the role of learning-related dopamine signaling in addiction and related disorders. We describe the theoretical and behavioral characteristics of model-free learning based on errors in the prediction of reward, including step-by-step explanations of the underlying equations. We then use recent insights from an animal model that highlights individual variation in learning during a Pavlovian conditioning paradigm to describe overlapping aspects of incentive salience attribution and model-free learning. We argue that this provides a computationally coherent account of some features of addiction. © 2014 Elsevier B.V. All rights reserved.

Reward Pays the Cost of Noise Reduction in Motor and Cognitive Control.

PubMed

Manohar, Sanjay G; Chong, Trevor T-J; Apps, Matthew A J; Batla, Amit; Stamelou, Maria; Jarman, Paul R; Bhatia, Kailash P; Husain, Masud

2015-06-29

Speed-accuracy trade-off is an intensively studied law governing almost all behavioral tasks across species. Here we show that motivation by reward breaks this law, by simultaneously invigorating movement and improving response precision. We devised a model to explain this paradoxical effect of reward by considering a new factor: the cost of control. Exerting control to improve response precision might itself come at a cost--a cost to attenuate a proportion of intrinsic neural noise. Applying a noise-reduction cost to optimal motor control predicted that reward can increase both velocity and accuracy. Similarly, application to decision-making predicted that reward reduces reaction times and errors in cognitive control. We used a novel saccadic distraction task to quantify the speed and accuracy of both movements and decisions under varying reward. Both faster speeds and smaller errors were observed with higher incentives, with the results best fitted by a model including a precision cost. Recent theories consider dopamine to be a key neuromodulator in mediating motivational effects of reward. We therefore examined how Parkinson's disease (PD), a condition associated with dopamine depletion, alters the effects of reward. Individuals with PD showed reduced reward sensitivity in their speed and accuracy, consistent in our model with higher noise-control costs. Including a cost of control over noise explains how reward may allow apparent performance limits to be surpassed. On this view, the pattern of reduced reward sensitivity in PD patients can specifically be accounted for by a higher cost for controlling noise. Copyright © 2015 The Authors. Published by Elsevier Ltd.. All rights reserved.

Mechanisms of the psychostimulant effects of caffeine: Implications for substance use disorders

PubMed Central

Ferré, Sergi

2016-01-01

Background The psychostimulant properties of caffeine are reviewed and compared with those of prototypical psychostimulants, able to cause substance use disorders (SUD). Caffeine produces psychomotor activating, reinforcing and arousing effects, which depend on its ability to disinhibit the brake that endogenous adenosine imposes on the ascending dopamine and arousal systems. Objectives A model that considers the striatal adenosine A2A-dopamine D2 receptor heteromer as a key modulator of dopamine-dependent striatal functions (reward-oriented behavior and learning of stimulus-reward and reward-response associations) is introduced, which should explain most of the psychomotor and reinforcing effects of caffeine. Highlights The model can explain the caffeine-induced rotational behavior in rats with unilateral striatal dopamine denervation and the ability of caffeine to reverse the adipsic-aphagic syndrome in dopamine-deficient rodents. The model can also explain the weaker reinforcing effects and low abuse liability of caffeine, compared with prototypical psychostimulants. Finally the model can explain the actual major societal dangers of caffeine: the ability of caffeine to potentiate the addictive and toxic effects of drugs of abuse, with the particularly alarming associations of caffeine (as adulterant) with cocaine, amphetamine derivatives and synthetic cathinones and energy drinks with alcohol; and the higher sensitivity of children and adolescents to the psychostimulants effects of caffeine and its possible increase in the vulnerability to develop SUD. Conclusions The striatal A2A-D2 receptor heteromer constitutes an unequivocal main pharmacological target of caffeine and provides the main mechanisms by which caffeine potentiates the acute and long-term effects of prototypical psychostimulants. PMID:26786412

Neural Correlates of Impaired Reward-Effort Integration in Remitted Bulimia Nervosa.

PubMed

Mueller, Stefanie Verena; Morishima, Yosuke; Schwab, Simon; Wiest, Roland; Federspiel, Andrea; Hasler, Gregor

2018-03-01

The integration of reward magnitudes and effort costs is required for an effective behavioral guidance. This reward-effort integration was reported to be dependent on dopaminergic neurotransmission. As bulimia nervosa has been associated with a dysregulated dopamine system and catecholamine depletion led to reward-processing deficits in remitted bulimia nervosa, the purpose of this study was to identify the role of catecholamine dysfunction and its relation to behavioral and neural reward-effort integration in bulimia nervosa. To investigate the interaction between catecholamine functioning and behavioral, and neural responses directly, 17 remitted bulimic (rBN) and 21 healthy individuals (HC) received alpha-methyl-paratyrosine (AMPT) over 24 h to achieve catecholamine depletion in a randomized, crossover study design. We used functional magnetic resonance imaging (fMRI) and the monetary incentive delay (MID) task to assess reward-effort integration in relation to catecholaminergic neurotransmission at the behavioral and neural level. AMPT reduced the ability to integrate rewards and efforts effectively in HC participants. In contrast, in rBN participants, the reduced reward-effort integration was associated with illness duration in the sham condition and unrelated to catecholamine depletion. Regarding neural activation, AMPT decreased the reward anticipation-related neural activation in the anteroventral striatum. This decrease was associated with the AMPT-induced reduction of monetary earning in HC in contrast to rBN participants. Our findings contributed to the theory of a desensitized dopaminergic system in bulimia nervosa. A disrupted processing of reward magnitudes and effort costs might increase the probability of maintenance of bulimic symptoms.

Dopamine Modulates Reward Expectancy During Performance of a Slot Machine Task in Rats: Evidence for a ‘Near-miss' Effect

PubMed Central

Winstanley, Catharine A; Cocker, Paul J; Rogers, Robert D

2011-01-01

Cognitive accounts of gambling suggest that the experience of almost winning—so-called ‘near-misses'—encourage continued play and accelerate the development of pathological gambling (PG) in vulnerable individuals. One explanation for this effect is that near-misses signal imminent winning outcomes and heighten reward expectancy, galvanizing further play. Determining the neurochemical processes underlying the drive to gamble could facilitate the development of more effective treatments for PG. With this aim in mind, we evaluated rats' performance on a novel model of slot machine play, a form of gambling in which near-miss events are particularly salient. Subjects responded to a series of three flashing lights, loosely analogous to the wheels of a slot machine, causing the lights to set to ‘on' or ‘off'. A winning outcome was signaled if all three lights were illuminated. At the end of each trial, rats chose between responding on the ‘collect' lever, resulting in reward on win trials, but a time penalty on loss trials, or starting a new trial. Rats showed a marked preference for the collect lever when both two and three lights were illuminated, indicating heightened reward expectancy following near-misses similar to wins. Erroneous collect responses were increased by amphetamine and the D2 receptor agonist quinpirole, but not by the D1 receptor agonist SKF 81297 or receptor subtype selective antagonists. These data suggest that dopamine modulates reward expectancy following the experience of almost winning during slot machine play, via activity at D2 receptors, and this may result in an enhancement of the near-miss effect and facilitate further gambling. PMID:21209612

Dopamine modulates reward expectancy during performance of a slot machine task in rats: evidence for a 'near-miss' effect.

PubMed

Winstanley, Catharine A; Cocker, Paul J; Rogers, Robert D

2011-04-01

Cognitive accounts of gambling suggest that the experience of almost winning-so-called 'near-misses'-encourage continued play and accelerate the development of pathological gambling (PG) in vulnerable individuals. One explanation for this effect is that near-misses signal imminent winning outcomes and heighten reward expectancy, galvanizing further play. Determining the neurochemical processes underlying the drive to gamble could facilitate the development of more effective treatments for PG. With this aim in mind, we evaluated rats' performance on a novel model of slot machine play, a form of gambling in which near-miss events are particularly salient. Subjects responded to a series of three flashing lights, loosely analogous to the wheels of a slot machine, causing the lights to set to 'on' or 'off'. A winning outcome was signaled if all three lights were illuminated. At the end of each trial, rats chose between responding on the 'collect' lever, resulting in reward on win trials, but a time penalty on loss trials, or starting a new trial. Rats showed a marked preference for the collect lever when both two and three lights were illuminated, indicating heightened reward expectancy following near-misses similar to wins. Erroneous collect responses were increased by amphetamine and the D(2) receptor agonist quinpirole, but not by the D(1) receptor agonist SKF 81297 or receptor subtype selective antagonists. These data suggest that dopamine modulates reward expectancy following the experience of almost winning during slot machine play, via activity at D(2) receptors, and this may result in an enhancement of the near-miss effect and facilitate further gambling.

How attentional boost interacts with reward: the effect of dopaminergic medications in Parkinson's disease.

PubMed

Kéri, Szabolcs; Nagy, Helga; Levy-Gigi, Einat; Kelemen, Oguz

2013-12-01

There is widespread evidence that dopamine is implicated in the regulation of reward and salience. However, it is less known how these processes interact with attention and recognition memory. To explore this question, we used the attentional boost test in patients with Parkinson's disease (PD) before and after the administration of dopaminergic medications. Participants performed a visual letter detection task (remembering rewarded target letters and ignoring distractor letters) while also viewing a series of photos of natural and urban scenes in the background of the letters. The aim of the game was to retrieve the target letter after each trial and to win as much virtual money as possible. The recognition of background scenes was not rewarded. We enrolled 26 drug-naïve, newly diagnosed patients with PD and 25 healthy controls who were evaluated at baseline and follow-up. Patients with PD received dopamine agonists (pramipexole, ropinirole, rotigotine) during the 12-week follow-up period. At baseline, we found intact attentional boost in patients with PD: they were able to recognize target-associated scenes similarly to controls. At follow-up, patients with PD outperformed controls for both target- and distractor-associated scenes, but not when scenes were presented without letters. The alerting, orienting and executive components of attention were intact in PD. Enhanced attentional boost was replicated in a smaller group of patients with PD (n = 15) receiving l-3,4-dihydroxyphenylalanine (L-DOPA). These results suggest that dopaminergic medications facilitate attentional boost for background information regardless of whether the central task (letter detection) is rewarded or not. © 2013 Federation of European Neuroscience Societies and John Wiley & Sons Ltd.

On the nature of extraversion: variation in conditioned contextual activation of dopamine-facilitated affective, cognitive, and motor processes

PubMed Central

Depue, Richard A.; Fu, Yu

2013-01-01

Research supports an association between extraversion and dopamine (DA) functioning. DA facilitates incentive motivation and the conditioning and incentive encoding of contexts that predict reward. Therefore, we assessed whether extraversion is related to the efficacy of acquiring conditioned contextual facilitation of three processes that are dependent on DA: motor velocity, positive affect, and visuospatial working memory. We exposed high and low extraverts to three days of association of drug reward (methylphenidate, MP) with a particular laboratory context (Paired group), a test day of conditioning, and three days of extinction in the same laboratory. A Placebo group and an Unpaired group (that had MP in a different laboratory context) served as controls. Conditioned contextual facilitation was assessed by (i) presenting video clips that varied in their pairing with drug and laboratory context and in inherent incentive value, and (ii) measuring increases from day 1 to Test day on the three processes above. Results showed acquisition of conditioned contextual facilitation across all measures to video clips that had been paired with drug and laboratory context in the Paired high extraverts, but no conditioning in the Paired low extraverts (nor in either of the control groups). Increases in the Paired high extraverts were correlated across the three measures. Also, conditioned facilitation was evident on the first day of extinction in Paired high extraverts, despite the absence of the unconditioned effects of MP. By the last day of extinction, responding returned to day 1 levels. The findings suggest that extraversion is associated with variation in the acquisition of contexts that predict reward. Over time, this variation may lead to differences in the breadth of networks of conditioned contexts. Thus, individual differences in extraversion may be maintained by activation of differentially encoded central representations of incentive contexts that predict reward. PMID:23785330

Increased ventral striatal BOLD activity during non-drug reward anticipation in cannabis users.

PubMed

Nestor, Liam; Hester, Robert; Garavan, Hugh

2010-01-01

Despite an increased understanding of the pharmacology and long-term cognitive effects of cannabis in humans, there has been no research to date examining its chronic effects upon reward processing in the brain. Motivational theories regarding long-term drug use posit contrasting predictions with respect to how drug users are likely to process non-drug incentives. The reward deficiency syndrome (RDS) of addiction posits that there are deficits in dopamine (DA) motivational circuitry for non-drug rewards, such that only drugs of abuse are capable of normalizing DA in the ventral striatum (VS). Alternatively, the opponent process theory (OPT) holds that in individuals prone to drug use, there exists some form of mesolimbic hyperactivity, in which there is a bias towards reward-centred behaviour concomitant with impulsivity. The current study examined BOLD responses during reward and loss anticipation and their outcome deliveries in 14 chronic cannabis users and 14 drug-naive controls during a monetary incentive delay (MID) task. Despite no significant behavioural differences between the two groups, cannabis users had significantly more right VS BOLD activity during reward anticipation. Correlation analyses demonstrated that this right VS BOLD response was significantly correlated with life-time use and reported life-time cannabis joints consumed. No correlations between cannabis abstinence and BOLD responses were observed. We also observed a number of group differences following outcome deliveries, most notably hypoactivity in the left insula cortex in response to loss and loss avoidance outcome notifications in the cannabis group. These results may suggest hypersensitivity during instrumental response anticipation for non-drug rewards and a hyposensitivity to loss outcomes in chronic cannabis users; the implications of which are discussed with respect to the potentially sensitizing effects of cannabis for other rewards.

Is Overeating Behavior Similar to Drug Addiction? (427th Brookhaven Lecture)

DOE Office of Scientific and Technical Information (OSTI.GOV)

Wang, Gene-Jack

2007-09-27

The increasing number of obese individuals in the U.S. and other countries world-wide adds urgency to the need to understand the mechanisms underlying pathological overeating. Research by the speaker and others at Brookhaven National Laboratory and elsewhere is compiling evidence that the brain circuits disrupted in obesity are similar to those involved in drug addiction. Using positron emission tomography (PET), the speaker and his colleagues have implicated brain dopamine in the normal and the pathological intake of food by humans. During the 427th Brookhaven Lecture, speaker will review the findings and implications of PET studies of obese subjects and thenmore » compare them to PET research involving drug-addicted individuals. For example, in pathologically obese subjects, it was found that reductions in striatal dopamine D2 receptors are similar to those observed in drug-addicted subjects. The speaker and his colleagues have postulated that decreased levels of dopamine receptors predisposed subjects to search for strongly rewarding reinforcers, be it drugs for the drug-addicted or food for the obese, as a means to compensate for decreased sensitivity of their dopamine-regulated reward circuits. As the speaker will summarize, multiple but similar brain circuits involved in reward, motivation, learning and inhibitory control are disrupted both in drug addiction and obesity, resulting in the need for a multimodal approach to the treatment of obesity.« less

Galanin and addiction.

PubMed

Picciotto, M R

2008-06-01

There has been increasing interest in the ability of neuropeptides involved in feeding to modulate circuits important for responses to drugs of abuse. A number of peptides with effects on hypothalamic function also modulate the mesolimbic dopamine system (ventral tegmental area and nucleus accumbens). Similarly, common stress-related pathways can modulate food intake, drug reward and symptoms of drug withdrawal. Galanin promotes food intake and the analgesic properties of opiates; thus it initially seemed possible that galanin might potentiate opiate reinforcement. Instead, galanin agonists decrease opiate reward, measured by conditioned place preference, and opiate withdrawal signs, whereas opiate reward and withdrawal are increased in knock-out mice lacking galanin. This is consistent with studies showing that galanin decreases activity-evoked dopamine release in striatal slices and decreases the firing rate of noradrenergic neurons in locus coeruleus, areas involved in drug reward and withdrawal, respectively. These data suggest that polymorphisms in genes encoding galanin or galanin receptors might be associated with susceptibility to opiate abuse. Further, galanin receptors might be potential targets for development of novel treatments for addiction.

Brain on Fire: Incentive Salience, Hedonic Hot Spots, Dopamine, Obesity, and Other Hunger Games.

PubMed

Cameron, Jameason D; Chaput, Jean-Philippe; Sjödin, Anders M; Goldfield, Gary S

2017-08-21

This review examines human feeding behavior in light of psychological motivational theory and highlights the importance of midbrain dopamine (DA). Prospective evidence of both reward surfeit and reward deficit pathways to increased body weight are evaluated, and we argue that it is more complex than an either/or scenario when examining DA's role in reward sensitivity, eating, and obesity. The Taq1A genotype is a common thread that ties the contrasting models of DA reward and obesity; this genotype related to striatal DA is not associated with obesity class per se but may nevertheless confer an increased risk of weight gain. We also critically examine the concept of so-called food addiction, and despite growing evidence, we argue that there is currently insufficient human data to warrant this diagnostic label. The surgical and pharmacological treatments of obesity are discussed, and evidence is presented for the selective use of DA-class drugs in obesity treatment.

Review. Neurobiological mechanisms for opponent motivational processes in addiction.

PubMed

Koob, George F; Le Moal, Michel

2008-10-12

The conceptualization of drug addiction as a compulsive disorder with excessive drug intake and loss of control over intake requires motivational mechanisms. Opponent process as a motivational theory for the negative reinforcement of drug dependence has long required a neurobiological explanation. Key neurochemical elements involved in reward and stress within basal forebrain structures involving the ventral striatum and extended amygdala are hypothesized to be dysregulated in addiction to convey the opponent motivational processes that drive dependence. Specific neurochemical elements in these structures include not only decreases in reward neurotransmission such as dopamine and opioid peptides in the ventral striatum, but also recruitment of brain stress systems such as corticotropin-releasing factor (CRF), noradrenaline and dynorphin in the extended amygdala. Acute withdrawal from all major drugs of abuse produces increases in reward thresholds, anxiety-like responses and extracellular levels of CRF in the central nucleus of the amygdala. CRF receptor antagonists block excessive drug intake produced by dependence. A brain stress response system is hypothesized to be activated by acute excessive drug intake, to be sensitized during repeated withdrawal, to persist into protracted abstinence and to contribute to stress-induced relapse. The combination of loss of reward function and recruitment of brain stress systems provides a powerful neurochemical basis for the long hypothesized opponent motivational processes responsible for the negative reinforcement driving addiction.

Dynamic nigrostriatal dopamine biases action selection

PubMed Central

Howard, Christopher D.; Li, Hao; Geddes, Claire E.; Jin, Xin

2017-01-01

Summary Dopamine is thought to play a critical role in reinforcement learning and goal-directed behavior, but its function in action selection remains largely unknown. Here, we demonstrate that nigrostriatal dopamine biases ongoing action selection. When mice were trained to dynamically switch the action selected at different time points, changes in firing rate of nigrostriatal dopamine neurons, as well as dopamine signaling in the dorsal striatum, were found to be associated with action selection. This dopamine profile is specific to behavioral choice, scalable with interval duration, and doesn’t reflect reward prediction error, timing, or value as single factors alone. Genetic deletion of NMDA receptors on dopamine or striatal neurons, or optogenetic manipulation of dopamine concentration, alters dopamine signaling and biases action selection. These results unveil a crucial role of nigrostriatal dopamine in integrating diverse information for regulating upcoming actions and have important implications for neurological disorders including Parkinson’s disease and substance dependence. PMID:28285820

Dynamic Nigrostriatal Dopamine Biases Action Selection.

PubMed

Howard, Christopher D; Li, Hao; Geddes, Claire E; Jin, Xin

2017-03-22

Dopamine is thought to play a critical role in reinforcement learning and goal-directed behavior, but its function in action selection remains largely unknown. Here we demonstrate that nigrostriatal dopamine biases ongoing action selection. When mice were trained to dynamically switch the action selected at different time points, changes in firing rate of nigrostriatal dopamine neurons, as well as dopamine signaling in the dorsal striatum, were found to be associated with action selection. This dopamine profile is specific to behavioral choice, scalable with interval duration, and doesn't reflect reward prediction error, timing, or value as single factors alone. Genetic deletion of NMDA receptors on dopamine or striatal neurons or optogenetic manipulation of dopamine concentration alters dopamine signaling and biases action selection. These results unveil a crucial role of nigrostriatal dopamine in integrating diverse information for regulating upcoming actions, and they have important implications for neurological disorders, including Parkinson's disease and substance dependence. Copyright © 2017 Elsevier Inc. All rights reserved.

The pleasures of play: pharmacological insights into social reward mechanisms.

PubMed

Trezza, Viviana; Baarendse, Petra J J; Vanderschuren, Louk J M J

2010-10-01

Like human children, most young mammals devote a significant amount of time and energy playing together, and social play is fun. Although social play is very pleasurable, it is more than just a frivolous activity: it is crucial for the development of behavioral flexibility, the acquisition of social and cognitive competence, and the maintenance of group cohesion. Social play is a natural reinforcer, and the neurotransmitter systems intimately implicated in the motivational, pleasurable and cognitive aspects of natural and drug rewards, such as opioids, endocannabinoids, dopamine and norepinephrine, play an important modulatory role in the performance of social play. In this review, we address the notion that social play is rewarding, and discuss recent developments in the neuropharmacology of this behavior. This provides a framework to understand how the brain processes social emotions, to make young individuals enjoy social play.

Dopamine neuronal loss contributes to memory and reward dysfunction in a model of Alzheimer's disease

PubMed Central

Nobili, Annalisa; Latagliata, Emanuele Claudio; Viscomi, Maria Teresa; Cavallucci, Virve; Cutuli, Debora; Giacovazzo, Giacomo; Krashia, Paraskevi; Rizzo, Francesca Romana; Marino, Ramona; Federici, Mauro; De Bartolo, Paola; Aversa, Daniela; Dell'Acqua, Maria Concetta; Cordella, Alberto; Sancandi, Marco; Keller, Flavio; Petrosini, Laura; Puglisi-Allegra, Stefano; Mercuri, Nicola Biagio; Coccurello, Roberto; Berretta, Nicola; D'Amelio, Marcello

2017-01-01

Alterations of the dopaminergic (DAergic) system are frequently reported in Alzheimer's disease (AD) patients and are commonly linked to cognitive and non-cognitive symptoms. However, the cause of DAergic system dysfunction in AD remains to be elucidated. We investigated alterations of the midbrain DAergic system in the Tg2576 mouse model of AD, overexpressing a mutated human amyloid precursor protein (APPswe). Here, we found an age-dependent DAergic neuron loss in the ventral tegmental area (VTA) at pre-plaque stages, although substantia nigra pars compacta (SNpc) DAergic neurons were intact. The selective VTA DAergic neuron degeneration results in lower DA outflow in the hippocampus and nucleus accumbens (NAc) shell. The progression of DAergic cell death correlates with impairments in CA1 synaptic plasticity, memory performance and food reward processing. We conclude that in this mouse model of AD, degeneration of VTA DAergic neurons at pre-plaque stages contributes to memory deficits and dysfunction of reward processing. PMID:28367951

Evaluating Dopamine Reward Pathway in ADHD

PubMed Central

Volkow, Nora D.; Wang, Gene-Jack; Kollins, Scott H.; Wigal, Tim L.; Newcorn, Jeffrey H.; Telang, Frank; Fowler, Joanna S.; Zhu, Wei; Logan, Jean; Ma, Yeming; Pradhan, Kith; Wong, Christopher; Swanson, James M.

2010-01-01

Context Attention-deficit/hyperactivity disorder (ADHD)—characterized by symptoms of inattention and hyperactivity-impulsivity—is the most prevalent childhood psychiatric disorder that frequently persists into adulthood, and there is increasing evidence of reward-motivation deficits in this disorder. Objective To evaluate biological bases that might underlie a reward/motivation deficit by imaging key components of the brain dopamine reward pathway (mesoaccumbens). Design, Setting, and Participants We used positron emission tomography to measure dopamine synaptic markers (transporters and D2/D3 receptors) in 53 nonmedicated adults with ADHD and 44 healthy controls between 2001–2009 at Brookhaven National Laboratory. Main Outcome Measures We measured specific binding of positron emission tomographic radioligands for dopamine transporters (DAT) using [11C]cocaine and for D2/D3 receptors using [11C]raclopride, quantified as binding potential (distribution volume ratio −1). Results For both ligands, statistical parametric mapping showed that specific binding was lower in ADHD than in controls (threshold for significance set at P<.005) in regions of the dopamine reward pathway in the left side of the brain. Region-of-interest analyses corroborated these findings. The mean (95% confidence interval [CI] of mean difference) for DAT in the nucleus accumbens for controls was 0.71 vs 0.63 for those with ADHD (95% CI, 0.03–0.13, P=.004) and in the midbrain for controls was 0.16 vs 0.09 for those with ADHD (95% CI, 0.03–0.12; P ≤ .001); for D2/D3 receptors, the mean accumbens for controls was 2.85 vs 2.68 for those with ADHD (95% CI, 0.06–0.30, P=.004); and in the midbrain, it was for controls 0.28 vs 0.18 for those with ADHD (95% CI, 0.02–0.17, P=.01). The analysis also corroborated differences in the left caudate: the mean DAT for controls was 0.66 vs 0.53 for those with ADHD (95% CI, 0.04–0.22; P=.003) and the mean D2/D3 for controls was 2.80 vs 2.47 for those with ADHD (95% CI, 0.10–0.56; P=.005) and differences in D2/D3 in the hypothalamic region, with controls having a mean of 0.12 vs 0.05 for those with ADHD (95% CI, 0.02–0.12; P=.004). Ratings of attention correlated with D2/D3 in the accumbens (r =0.35; 95% CI, 0.15–0.52; P =.001), midbrain (r=0.35; 95% CI, 0.14–0.52; P=.001), caudate (r=0.32; 95% CI, 0.11–0.50; P=.003), and hypothalamic (r=0.31; CI, 0.10–0.49; P=.003) regions and with DAT in the midbrain (r=0.37; 95% CI, 0.16–0.53; P ≤ .001). Conclusion A reduction in dopamine synaptic markers associated with symptoms of inattention was shown in the dopamine reward pathway of participants with ADHD. PMID:19738093

Neurochemical evidence that cocaine- and amphetamine-regulated transcript (CART) 55-102 peptide modulates the dopaminergic reward system by decreasing the dopamine release in the mouse nucleus accumbens.

PubMed

Rakovska, Angelina; Baranyi, Maria; Windisch, Katalin; Petkova-Kirova, Polina; Gagov, Hristo; Kalfin, Reni

2017-09-01

CART (Cocaine- and Amphetamine-Regulated Transcript) peptide is a neurotransmitter naturally occurring in the CNS and found mostly in nucleus accumbens, ventrotegmental area, ventral pallidum, amygdalae and striatum, brain regions associated with drug addiction. In the nucleus accumbens, known for its significant role in motivation, pleasure, reward and reinforcement learning, CART peptide inhibits cocaine and amphetamine-induced dopamine-mediated increases in locomotor activity and behavior, suggesting a CART peptide interaction with the dopaminergic system. Thus in the present study, we examined the effect of CART (55-102) peptide on the basal, electrical field stimulation-evoked (EFS-evoked) (30V, 2Hz, 120 shocks) and returning basal dopamine (DA) release and on the release of the DA metabolites 3,4-dihydroxyphenyl acetaldehyde (DOPAL), 3,4-dihydroxyphenylacetic acid (DOPAC), homovanillic acid (HVA), 3,4-dihydroxyphenylethanol (DOPET), 3-methoxytyramine (3-MT) as well as on norepinephrine (NE) and dopamine-o-quinone (Daq) in isolated mouse nucleus accumbens, in a preparation, in which any CART peptide effects on the dendrites or soma of ventral tegmental projection neurons have been excluded. We further extended our study to assess the effect of CART (55-102) peptide on basal cocaine-induced release of dopamine and its metabolites DOPAL, DOPAC, HVA, DOPET and 3-MT as well as on NE and Daq. To analyze the amount of [ 3 H]dopamine, dopamine metabolites, Daq and NE in the nucleus accumbens superfusate, a high-pressure liquid chromatography (HPLC), coupled with electrochemical, UV and radiochemical detections was used. CART (55-102) peptide, 0.1μM, added alone, exerted: (i) a significant decrease in the basal and EFS-evoked levels of extracellular dopamine (ii) a significant increase in the EFS-evoked and returning basal levels of the dopamine metabolites DOPAC and HVA, major products of dopamine degradation and (iii) a significant decrease in the returning basal levels of DOPET. At the same concentration, 0.1μM, CART (55-102) peptide did not have any effect on the release of noradrenaline. In the presence of CART (55-102) peptide, 0.1μM, the effect of cocaine, 30μM, on the basal dopamine release was inhibited and the effect on the basal DOPAC release substantially increased. To our knowledge, our findings are the first to show direct neurochemical evidence that CART (55-102) peptide plays a neuromodulatory role on the dopaminergic reward system by decreasing dopamine in the mouse nucleus accumbens and by attenuating cocaine-induced effects on dopamine release. Copyright © 2017 Elsevier Inc. All rights reserved.

Dorsal Raphe Dopamine Neurons Represent the Experience of Social Isolation

PubMed Central

Matthews, Gillian A.; Nieh, Edward H.; Vander Weele, Caitlin M.; Halbert, Sarah A.; Pradhan, Roma V.; Yosafat, Ariella S.; Glober, Gordon F.; Izadmehr, Ehsan M.; Thomas, Rain E.; Lacy, Gabrielle D.; Wildes, Craig P.; Ungless, Mark A.; Tye, Kay M.

2016-01-01

Summary The motivation to seek social contact may arise from either positive or negative emotional states, as social interaction can be rewarding and social isolation can be aversive. While ventral tegmental area (VTA) dopamine (DA) neurons may mediate social reward, a cellular substrate for the negative affective state of loneliness has remained elusive. Here, we identify a functional role for DA neurons in the dorsal raphe nucleus (DRN), in which we observe synaptic changes following acute social isolation. DRN DA neurons show increased activity upon social contact following isolation, revealed by in vivo calcium imaging. Optogenetic activation of DRN DA neurons increases social preference but causes place avoidance. Furthermore, these neurons are necessary for promoting rebound sociability following an acute period of isolation. Finally, the degree to which these neurons modulate behavior is predicted by social rank, together supporting a role for DRN dopamine neurons in mediating a loneliness-like state. PaperClip PMID:26871628

Segregated cholinergic transmission modulates dopamine neurons integrated in distinct functional circuits.

PubMed

Dautan, Daniel; Souza, Albert S; Huerta-Ocampo, Icnelia; Valencia, Miguel; Assous, Maxime; Witten, Ilana B; Deisseroth, Karl; Tepper, James M; Bolam, J Paul; Gerdjikov, Todor V; Mena-Segovia, Juan

2016-08-01

Dopamine neurons in the ventral tegmental area (VTA) receive cholinergic innervation from brainstem structures that are associated with either movement or reward. Whereas cholinergic neurons of the pedunculopontine nucleus (PPN) carry an associative/motor signal, those of the laterodorsal tegmental nucleus (LDT) convey limbic information. We used optogenetics and in vivo juxtacellular recording and labeling to examine the influence of brainstem cholinergic innervation of distinct neuronal subpopulations in the VTA. We found that LDT cholinergic axons selectively enhanced the bursting activity of mesolimbic dopamine neurons that were excited by aversive stimulation. In contrast, PPN cholinergic axons activated and changed the discharge properties of VTA neurons that were integrated in distinct functional circuits and were inhibited by aversive stimulation. Although both structures conveyed a reinforcing signal, they had opposite roles in locomotion. Our results demonstrate that two modes of cholinergic transmission operate in the VTA and segregate the neurons involved in different reward circuits.

Molecular imaging and neural networks in impulse control disorders in Parkinson's disease.

PubMed

Aracil-Bolaños, I; Strafella, A P

2016-01-01

Impulse control disorders (ICDs) may arise in Parkinson's disease (PD) in relation to the use of dopamine agonists (DA). A dysfunction of reward circuits is considered the main underlying mechanism. Neuroimaging has been largely used in this setting to understand the structure of the reward system and its abnormalities brought by exogenous stimulation in PD. Dopaminergic changes, such as increased dopamine release, reduced dopamine transporter activity and other changes, have been shown to be a consistent feature of ICDs in PD. Beyond the striatum, alterations of prefrontal cortical function may also impact an individuals' propensity for impulsivity. Neuroimaging is advancing our knowledge of the mechanisms involved in the development of these behavioral addictions. An increased understanding of these disorders may lead to the discovery of new therapeutic targets, or the identification of risk factors for the development of these disorders. Copyright © 2015 Elsevier Ltd. All rights reserved.

Unexpected rewards induce dopamine-dependent positive emotion-like state changes in bumblebees.

PubMed

Perry, Clint J; Baciadonna, Luigi; Chittka, Lars

2016-09-30

Whether invertebrates exhibit positive emotion-like states and what mechanisms underlie such states remain poorly understood. We demonstrate that bumblebees exhibit dopamine-dependent positive emotion-like states across behavioral contexts. After training with one rewarding and one unrewarding cue, bees that received pretest sucrose responded in a positive manner toward ambiguous cues. In a second experiment, pretest consumption of sucrose solution resulted in a shorter time to reinitiate foraging after a simulated predator attack. These behavioral changes were abolished with topical application of the dopamine antagonist fluphenazine. Further experiments established that pretest sucrose does not simply cause bees to become more exploratory. Our findings present a new opportunity for understanding the fundamental neural elements of emotions and may alter the view of how emotion states affect decision-making in animals. Copyright © 2016, American Association for the Advancement of Science.

The dopamine theory of addiction: 40 years of highs and lows.

PubMed

Nutt, David J; Lingford-Hughes, Anne; Erritzoe, David; Stokes, Paul R A

2015-05-01

For several decades, addiction has come to be viewed as a disorder of the dopamine neurotransmitter system; however, this view has not led to new treatments. In this Opinion article, we review the origins of the dopamine theory of addiction and discuss the ability of addictive drugs to elicit the release of dopamine in the human striatum. There is robust evidence that stimulants increase striatal dopamine levels and some evidence that alcohol may have such an effect, but little evidence, if any, that cannabis and opiates increase dopamine levels. Moreover, there is good evidence that striatal dopamine receptor availability and dopamine release are diminished in individuals with stimulant or alcohol dependence but not in individuals with opiate, nicotine or cannabis dependence. These observations have implications for understanding reward and treatment responses in various addictions.

Detection of phasic dopamine by D1 and D2 striatal medium spiny neurons.

PubMed

Yapo, Cedric; Nair, Anu G; Clement, Lorna; Castro, Liliana R; Hellgren Kotaleski, Jeanette; Vincent, Pierre

2017-12-15

Brief dopamine events are critical actors of reward-mediated learning in the striatum; the intracellular cAMP-protein kinase A (PKA) response of striatal medium spiny neurons to such events was studied dynamically using a combination of biosensor imaging in mouse brain slices and in silico simulations. Both D1 and D2 medium spiny neurons can sense brief dopamine transients in the sub-micromolar range. While dopamine transients profoundly change cAMP levels in both types of medium spiny neurons, the PKA-dependent phosphorylation level remains unaffected in D2 neurons. At the level of PKA-dependent phosphorylation, D2 unresponsiveness depends on protein phosphatase-1 (PP1) inhibition by DARPP-32. Simulations suggest that D2 medium spiny neurons could detect transient dips in dopamine level. The phasic release of dopamine in the striatum determines various aspects of reward and action selection, but the dynamics of the dopamine effect on intracellular signalling remains poorly understood. We used genetically encoded FRET biosensors in striatal brain slices to quantify the effect of transient dopamine on cAMP or PKA-dependent phosphorylation levels, and computational modelling to further explore the dynamics of this signalling pathway. Medium-sized spiny neurons (MSNs), which express either D 1 or D 2 dopamine receptors, responded to dopamine by an increase or a decrease in cAMP, respectively. Transient dopamine showed similar sub-micromolar efficacies on cAMP in both D1 and D2 MSNs, thus challenging the commonly accepted notion that dopamine efficacy is much higher on D 2 than on D 1 receptors. However, in D2 MSNs, the large decrease in cAMP level triggered by transient dopamine did not translate to a decrease in PKA-dependent phosphorylation level, owing to the efficient inhibition of protein phosphatase 1 by DARPP-32. Simulations further suggested that D2 MSNs can also operate in a 'tone-sensing' mode, allowing them to detect transient dips in basal dopamine. Overall, our results show that D2 MSNs may sense much more complex patterns of dopamine than previously thought. © 2017 The Authors. The Journal of Physiology © 2017 The Physiological Society.

Dopamine-Dependent Reinforcement of Motor Skill Learning: Evidence from Gilles de la Tourette Syndrome

ERIC Educational Resources Information Center

Palminteri, Stefano; Lebreton, Mael; Worbe, Yulia; Hartmann, Andreas; Lehericy, Stephane; Vidailhet, Marie; Grabli, David; Pessiglione, Mathias

2011-01-01

Reinforcement learning theory has been extensively used to understand the neural underpinnings of instrumental behaviour. A central assumption surrounds dopamine signalling reward prediction errors, so as to update action values and ensure better choices in the future. However, educators may share the intuitive idea that reinforcements not only…

Synergistic interaction between baclofen administration into the median raphe nucleus and inconsequential visual stimuli on investigatory behavior of rats

PubMed Central

Vollrath-Smith, Fiori R.; Shin, Rick

2011-01-01

Rationale Noncontingent administration of amphetamine into the ventral striatum or systemic nicotine increases responses rewarded by inconsequential visual stimuli. When these drugs are contingently administered, rats learn to self-administer them. We recently found that rats self-administer the GABAB receptor agonist baclofen into the median (MR) or dorsal (DR) raphe nuclei. Objectives We examined whether noncontingent administration of baclofen into the MR or DR increases rats’ investigatory behavior rewarded by a flash of light. Results Contingent presentations of a flash of light slightly increased lever presses. Whereas noncontingent administration of baclofen into the MR or DR did not reliably increase lever presses in the absence of visual stimulus reward, the same manipulation markedly increased lever presses rewarded by the visual stimulus. Heightened locomotor activity induced by intraperitoneal injections of amphetamine (3 mg/kg) failed to concur with increased lever pressing for the visual stimulus. These results indicate that the observed enhancement of visual stimulus seeking is distinct from an enhancement of general locomotor activity. Visual stimulus seeking decreased when baclofen was co-administered with the GABAB receptor antagonist, SCH 50911, confirming the involvement of local GABAB receptors. Seeking for visual stimulus also abated when baclofen administration was preceded by intraperitoneal injections of the dopamine antagonist, SCH 23390 (0.025 mg/kg), suggesting enhanced visual stimulus seeking depends on intact dopamine signals. Conclusions Baclofen administration into the MR or DR increased investigatory behavior induced by visual stimuli. Stimulation of GABAB receptors in the MR and DR appears to disinhibit the motivational process involving stimulus–approach responses. PMID:21904820

Hormonal gain control of a medial preoptic area social reward circuit

PubMed Central

McHenry, Jenna A.; Otis, James M.; Rossi, Mark A.; Robinson, J. Elliott; Kosyk, Oksana; Miller, Noah W.; McElligott, Zoe A.; Budygin, Evgeny A.; Rubinow, David R.; Stuber, Garret D.

2017-01-01

Neural networks that control reproduction must integrate social and hormonal signals, tune motivation, and invigorate social interactions. However, the neurocircuit mechanisms for these processes remain unresolved. The medial preoptic area (mPOA), an essential node for social behaviors and is comprised of molecularly-diverse neurons with widespread projections. Here, we identify a steroid-responsive subset of neurotensin (Nts) expressing mPOA neurons that interface with the ventral tegmental area (VTA) to form a socially-engaged reward circuit. Using in vivo 2-photon imaging in female mice, we show that mPOANts neurons preferentially encode attractive male cues compared to non-social appetitive stimuli. Ovarian hormone signals regulate both the physiological and cue encoding properties of these cells. Furthermore, optogenetic stimulation of mPOANts-VTA circuitry promotes rewarding phenotypes, social approach, and striatal dopamine release. Collectively, these data demonstrate that steroid-sensitive mPOA neurons encode ethologically-relevant stimuli and co-opt midbrain reward circuits to promote prosocial behavior critical for species survival. PMID:28135243

Anabolic-androgenic steroids and decision making: Probability and effort discounting in male rats.

PubMed

Wallin, Kathryn G; Alves, Jasmin M; Wood, Ruth I

2015-07-01

Anabolic-androgenic steroid (AAS) abuse is implicated in maladaptive behaviors such as increased aggression and risk taking. Impaired judgment due to changes in the mesocorticolimbic dopamine system may contribute to these behavioral changes. While AAS are known to influence dopamine function in mesocorticolimbic circuitry, the effects on decision making are unknown. This was the focus of the present study. Adolescent male Long-Evans rats were treated chronically with high-dose testosterone (7.5 mg/kg) or vehicle (13% cyclodextrin in water), and tested for cost/benefit decision making in two discounting paradigms. Rats chose between a small reward (1 sugar pellet) and a large discounted reward (3 or 4 pellets). Probability discounting (PD) measures sensitivity to reward uncertainty by decreasing the probability (100, 75, 50, 25, 0%) of receiving the large reward in successive blocks of each daily session. Effort discounting (ED) measures sensitivity to a work cost by increasing the lever presses required to earn the large reward (1, 2, 5, 10, 15 presses). In PD, testosterone-treated rats selected the large/uncertain reward significantly less than vehicle-treated controls. However, during ED, testosterone-treated rats selected the large/high effort reward significantly more than controls. These studies show that testosterone has divergent effects on different aspects of decision making. Specifically, testosterone increases aversion to uncertainty but decreases sensitivity to the output of effort for reward. These results have implications for understanding maladaptive behavioral changes in human AAS users. Copyright © 2015 Elsevier Ltd. All rights reserved.

An Update on the Role of Serotonin and its Interplay with Dopamine for Reward.

PubMed

Fischer, Adrian G; Ullsperger, Markus

2017-01-01

The specific role of serotonin and its interplay with dopamine (DA) in adaptive, reward guided behavior as well as drug dependance, still remains elusive. Recently, novel methods allowed cell type specific anatomical, functional and interventional analyses of serotonergic and dopaminergic circuits, promising significant advancement in understanding their functional roles. Furthermore, it is increasingly recognized that co-release of neurotransmitters is functionally relevant, understanding of which is required in order to interpret results of pharmacological studies and their relationship to neural recordings. Here, we review recent animal studies employing such techniques with the aim to connect their results to effects observed in human pharmacological studies and subjective effects of drugs. It appears that the additive effect of serotonin and DA conveys significant reward related information and is subjectively highly euphorizing. Neither DA nor serotonin alone have such an effect. This coincides with optogenetically targeted recordings in mice, where the dopaminergic system codes reward prediction errors (PE), and the serotonergic system mainly unsigned PE. Overall, this pattern of results indicates that joint activity between both systems carries essential reward information and invites parallel investigation of both neurotransmitter systems.

Lateral hypothalamus, nucleus accumbens, and ventral pallidum roles in eating and hunger: interactions between homeostatic and reward circuitry

PubMed Central

Castro, Daniel C.; Cole, Shannon L.; Berridge, Kent C.

2015-01-01

The study of the neural bases of eating behavior, hunger, and reward has consistently implicated the lateral hypothalamus (LH) and its interactions with mesocorticolimbic circuitry, such as mesolimbic dopamine projections to nucleus accumbens (NAc) and ventral pallidum (VP), in controlling motivation to eat. The NAc and VP play special roles in mediating the hedonic impact (“liking”) and motivational incentive salience (“wanting”) of food rewards, and their interactions with LH help permit regulatory hunger/satiety modulation of food motivation and reward. Here, we review some progress that has been made regarding this circuitry and its functions: the identification of localized anatomical hedonic hotspots within NAc and VP for enhancing hedonic impact; interactions of NAc/VP hedonic hotspots with specific LH signals such as orexin; an anterior-posterior gradient of sites in NAc shell for producing intense appetitive eating vs. intense fearful reactions; and anatomically distributed appetitive functions of dopamine and mu opioid signals in NAc shell and related structures. Such findings help improve our understanding of NAc, VP, and LH interactions in mediating affective and motivation functions, including “liking” and “wanting” for food rewards. PMID:26124708

Cocaine self-administration disrupts mesolimbic dopamine circuit function and attenuates dopaminergic responsiveness to cocaine.

PubMed

Siciliano, Cody A; Ferris, Mark J; Jones, Sara R

2015-08-01

Dopaminergic projections from the ventral midbrain to the nucleus accumbens (NAc) have long been implicated in encoding associations between reward availability and environmental stimuli. As such, this circuit is instrumental in guiding behaviors towards obtaining maximal rewards based on previous experience. Cocaine acts on the dopamine system to exert its reinforcing effects and it is thought that cocaine-induced dysregulation of dopamine neurotransmission contributes to the difficulty that cocaine addicts exhibit in selecting environmentally appropriate behaviors. Here we used cocaine self-administration combined with in vivo fast scan cyclic voltammetry in anesthetised rats to examine the function of the ventral tegmental area to NAc projection neurons. Over 5 days of cocaine self-administration (fixed-ratio 1; 1.5 mg/kg/injection; 40 injections/day), animals increased their rate of intake. Following cocaine self-administration, there was a marked reduction in ventral tegmental area-stimulated NAc dopamine release. Additionally, there was a decreased augmentation of stimulated dopamine overflow in response to a cocaine challenge. These findings demonstrate that cocaine induces a hypodopaminergic state, which may contribute to the inflexible drug-taking and drug-seeking behaviors observed in cocaine abusers. Additionally, tolerance to the ability of cocaine to elevate dopamine may lead to increased cocaine intake in order to overcome decreased effects, another hallmark of cocaine abuse. © 2015 Federation of European Neuroscience Societies and John Wiley & Sons Ltd.

Dopamine efflux in response to ultraviolet radiation in addicted sunbed users

PubMed Central

Aubert, Pamela M.; Seibyl, John P.; Price, Julianne L.; Harris, Thomas S.; Filbey, Francesca M.; Jacobe, Heidi; Devous, Michael D.; Adinoff, Bryon

2017-01-01

Compulsive tanning despite awareness of ultraviolet radiation (UVR) carcinogenicity may represent an “addictive” behavior. Many addictive disorders are associated with alterations in dopamine (D2/D3) receptor binding and dopamine reactivity in the brain’s reward pathway. To determine if compulsive tanners exhibited neurobiologic responses similar to other addictive disorders, this study assessed basal striatal D2/D3 binding and UVR-induced striatal dopamine efflux in ten addicted and ten infrequent tanners. In a double-blind crossover trial, UVR or sham UVR was administered in separate sessions during brain imaging with single photon emission computerized tomography (SPECT). Basal D2/D3 receptor density and UVR-induced dopamine efflux in the caudate were assessed using 123I-iodobenzamide (123I-IBZM) binding potential non-displaceable (BPnd). Basal BPnd did not significantly differ between addicted and infrequent tanners. Whereas neither UVR nor sham UVR induced significant changes in bilateral caudate BPnd in either group, post-hoc analyses revealed left caudate BPnd significantly decreased (reflecting increased dopamine efflux) in the addicted tanners – but not the infrequent tanners –during the UVR session only. Bilateral ΔBPnd correlated with tanning severity only in the addicted tanners. These preliminary findings are consistent with a stronger neural rewarding response to UVR in addicted tanners, supporting a cutaneous-neural connection driving excessive sunbed use. PMID:27085608

Addiction and the brain antireward system.

PubMed

Koob, George F; Le Moal, Michel

2008-01-01

A neurobiological model of the brain emotional systems has been proposed to explain the persistent changes in motivation that are associated with vulnerability to relapse in addiction, and this model may generalize to other psychopathology associated with dysregulated motivational systems. In this framework, addiction is conceptualized as a cycle of decreased function of brain reward systems and recruitment of antireward systems that progressively worsen, resulting in the compulsive use of drugs. Counteradaptive processes, such as opponent process, that are part of the normal homeostatic limitation of reward function fail to return within the normal homeostatic range and are hypothesized to repeatedly drive the allostatic state. Excessive drug taking thus results in not only the short-term amelioration of the reward deficit but also suppression of the antireward system. However, in the long term, there is worsening of the underlying neurochemical dysregulations that ultimately form an allostatic state (decreased dopamine and opioid peptide function, increased corticotropin-releasing factor activity). This allostatic state is hypothesized to be reflected in a chronic deviation of reward set point that is fueled not only by dysregulation of reward circuits per se but also by recruitment of brain and hormonal stress responses. Vulnerability to addiction may involve genetic comorbidity and developmental factors at the molecular, cellular, or neurocircuitry levels that sensitize the brain antireward systems.

Computer and video game addiction-a comparison between game users and non-game users.

PubMed

Weinstein, Aviv Malkiel

2010-09-01

Computer game addiction is excessive or compulsive use of computer and video games that may interfere with daily life. It is not clear whether video game playing meets diagnostic criteria for Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV). First objective is to review the literature on computer and video game addiction over the topics of diagnosis, phenomenology, epidemiology, and treatment. Second objective is to describe a brain imaging study measuring dopamine release during computer game playing. Article search of 15 published articles between 2000 and 2009 in Medline and PubMed on computer and video game addiction. Nine abstinent "ecstasy" users and 8 control subjects were scanned at baseline and after performing on a motorbike riding computer game while imaging dopamine release in vivo with [123I] IBZM and single photon emission computed tomography (SPECT). Psycho-physiological mechanisms underlying computer game addiction are mainly stress coping mechanisms, emotional reactions, sensitization, and reward. Computer game playing may lead to long-term changes in the reward circuitry that resemble the effects of substance dependence. The brain imaging study showed that healthy control subjects had reduced dopamine D2 receptor occupancy of 10.5% in the caudate after playing a motorbike riding computer game compared with baseline levels of binding consistent with increased release and binding to its receptors. Ex-chronic "ecstasy" users showed no change in levels of dopamine D2 receptor occupancy after playing this game. This evidence supports the notion that psycho-stimulant users have decreased sensitivity to natural reward. Computer game addicts or gamblers may show reduced dopamine response to stimuli associated with their addiction presumably due to sensitization.

Modulation of the mesolimbic dopamine system by leptin.

PubMed

Opland, Darren M; Leinninger, Gina M; Myers, Martin G

2010-09-02

Nutritional status modulates many forms of reward-seeking behavior, with caloric restriction increasing the drive for drugs of abuse as well as for food. Understanding the interactions between the mesolimbic dopamine (DA) system (which mediates the incentive salience of natural and artificial rewards) and the neural and hormonal systems that sense and regulate energy balance is thus of significant importance. Leptin, which is produced by adipocytes in proportion to fat content as a hormonal signal of long-term energy stores, acts via its receptor (LepRb) on multiple populations of central nervous system neurons to modulate neural circuits in response to body energy stores. Leptin suppresses feeding and plays a central role in the control of energy balance. In addition to demonstrating that leptin modulates hypothalamic and brainstem circuits to promote satiety, recent work has begun to explore the mechanisms by which leptin influences the mesolimbic DA system and related behaviors. Indeed, leptin diminishes several measures of drug and food reward, and promotes a complex set of changes in the mesolimbic DA system. While many of the details remain to be worked out, several lines of evidence suggest that leptin regulates the mesolimbic DA system via multiple neural pathways and processes, and that distinct sets of LepRb neurons each modulate unique aspects of the mesolimbic DA system and behavior in response to leptin. 2010 Elsevier B.V. All rights reserved.

Dopamine D3 Receptor Availability Is Associated with Inflexible Decision Making.

PubMed

Groman, Stephanie M; Smith, Nathaniel J; Petrullli, J Ryan; Massi, Bart; Chen, Lihui; Ropchan, Jim; Huang, Yiyun; Lee, Daeyeol; Morris, Evan D; Taylor, Jane R

2016-06-22

Dopamine D2/3 receptor signaling is critical for flexible adaptive behavior; however, it is unclear whether D2, D3, or both receptor subtypes modulate precise signals of feedback and reward history that underlie optimal decision making. Here, PET with the radioligand [(11)C]-(+)-PHNO was used to quantify individual differences in putative D3 receptor availability in rodents trained on a novel three-choice spatial acquisition and reversal-learning task with probabilistic reinforcement. Binding of [(11)C]-(+)-PHNO in the midbrain was negatively related to the ability of rats to adapt to changes in rewarded locations, but not to the initial learning. Computational modeling of choice behavior in the reversal phase indicated that [(11)C]-(+)-PHNO binding in the midbrain was related to the learning rate and sensitivity to positive, but not negative, feedback. Administration of a D3-preferring agonist likewise impaired reversal performance by reducing the learning rate and sensitivity to positive feedback. These results demonstrate a previously unrecognized role for D3 receptors in select aspects of reinforcement learning and suggest that individual variation in midbrain D3 receptors influences flexible behavior. Our combined neuroimaging, behavioral, pharmacological, and computational approach implicates the dopamine D3 receptor in decision-making processes that are altered in psychiatric disorders. Flexible decision-making behavior is dependent upon dopamine D2/3 signaling in corticostriatal brain regions. However, the role of D3 receptors in adaptive, goal-directed behavior has not been thoroughly investigated. By combining PET imaging with the D3-preferring radioligand [(11)C]-(+)-PHNO, pharmacology, a novel three-choice probabilistic discrimination and reversal task and computational modeling of behavior in rats, we report that naturally occurring variation in [(11)C]-(+)-PHNO receptor availability relates to specific aspects of flexible decision making. We confirm these relationships using a D3-preferring agonist, thus identifying a unique role of midbrain D3 receptors in decision-making processes. Copyright © 2016 the authors 0270-6474/16/366732-10$15.00/0.

Cerebral dopaminergic and glutamatergic transmission relate to different subjective responses of acute alcohol intake: an in vivo multimodal imaging study.

PubMed

Leurquin-Sterk, Gil; Ceccarini, Jenny; Crunelle, Cleo Lina; Weerasekera, Akila; de Laat, Bart; Himmelreich, Uwe; Bormans, Guy; Van Laere, Koen

2018-05-01

Converging preclinical evidence links extrastriatal dopamine release and glutamatergic transmission via the metabotropic glutamate receptor 5 (mGluR5) to the rewarding properties of alcohol. To date, human evidence is lacking on how and where in the brain these processes occur. Mesocorticolimbic dopamine release upon intravenous alcohol administration and mGluR5 availability were measured in 11 moderate social drinkers by single-session [ 18 F]fallypride and [ 18 F]FPEB positron emission tomography, respectively. Additionally, baseline and postalcohol glutamate and glutamine levels in the anterior cingulate cortex (ACC) were measured by using proton-magnetic resonance spectroscopy. To investigate differences in reward domains linked to both neurotransmitters, regional imaging data were related to subjective alcohol responses. Alcohol induced significant [ 18 F]fallypride displacement in the prefrontal cortex (PFC), temporal and parietal cortices and thalamus (P < 0.05, corrected for multiple comparisons). Dopamine release in the ACC and orbitofrontal and ventromedial PFCs were correlated with subjective 'liking' and 'wanting' effects (P < 0.05). In contrast, baseline mGluR5 availability was positively correlated with the 'high' effect of alcohol in dorsolateral, ventrolateral and ventromedial PFCs and in the medial temporal lobe, thalamus and caudate nucleus (P < 0.05). Although neither proton-magnetic resonance spectroscopy glutamate nor glutamine levels were affected by alcohol, baseline ACC glutamate levels were negatively associated with the alcohol 'liking' effect (P < 0.003). These data reveal new mechanistic understanding and differential neurobiological underpinnings of the effects of acute alcohol consumption on human behavior. Specifically, prefrontal dopamine release may encode alcohol 'liking' and 'wanting' effects in specific areas underlying value processing and motivation, whereas mGluR5 availability in distinct prefrontal-temporal-subcortical regions is more related to the alcohol 'high' effect. © 2017 Society for the Study of Addiction.

Modulation of frontostriatal interaction aligns with reduced primary reward processing under serotonergic drugs.

PubMed

Abler, Birgit; Grön, Georg; Hartmann, Antonie; Metzger, Coraline; Walter, Martin

2012-01-25

Recently, functional interactions between anteroventral prefrontal cortex and nucleus accumbens (NAcc) have been shown to relate to behavior counteracting reward-desiring (Diekhof and Gruber, 2010). Downregulation of the reward system by serotonin has also been suggested as the mode of action accounting for unsatisfactory effects of serotonin reuptake inhibitors (SSRIs) such as insufficient alleviation or even increase of anhedonia, and loss of interest. However, understanding of the in vivo mechanisms of SSRI-related alteration of the human reward system is still incomplete. Using functional magnetic resonance imaging (fMRI) within a double-blind cross-over within-subjects study design and administering the SSRI paroxetine, the dopamine/norepinephrine reuptake inhibitor bupropione, and placebo for 7 d each, we investigated a group of 18 healthy male subjects. Under paroxetine, subjects showed significantly decreased activation of the bilateral NAcc during processing of primary rewards (erotic videos), but not under bupropion. Similar to the previous study, analysis of psychophysiological interactions revealed that this downregulation relied on negative interactions between left and right NAcc fMRI signals and the bilateral anteroventral prefrontal cortex that now were significantly enhanced under paroxetine and reduced under bupropion. Individual drug-dependent modulations of interacting brain regions were significantly associated with individual expressions of impulsivity as a personality trait. Our results corroborate and extend previous insights on interregional crosstalk from secondary to primary rewards and demonstrate parallels between active inhibitory control of and serotonergic effects on the dopaminergic reward system's activity.

Dietary triglycerides as signaling molecules that influence reward and motivation

PubMed Central

Berland, Chloé; Cansell, Céline; Hnasko, Thomas S.; Magnan, Christophe; Luquet, Serge

2017-01-01

The reinforcing and motivational aspects of food are tied to the release of the dopamine in the mesolimbic system (ML). Free fatty acids from triglyceride (TG)-rich particles are released upon action of TG-lipases found at high levels in peripheral oxidative tissue (muscle, heart), but also in the ML. This suggests that local TG-hydrolysis in the ML might regulate food seeking and reward. Indeed, evidence now suggests that dietary TG directly target the ML to regulate amphetamine-induced locomotion and reward seeking behavior. Though the cellular mechanisms of TG action are unresolved, TG act in part through ML lipoprotein lipase, upstream of dopamine 2 receptor (D2R), and show desensitization in conditions of chronically elevated plasma TG as occur in obesity. TG sensing in the ML therefore represents a new mechanism by which chronic consumption of dietary fat might lead to adaptations in the ML and dysregulated feeding behaviors. PMID:28191490

A local circuit model of learned striatal and dopamine cell responses under probabilistic schedules of reward.

PubMed

Tan, Can Ozan; Bullock, Daniel

2008-10-01

Recently, dopamine (DA) neurons of the substantia nigra pars compacta (SNc) were found to exhibit sustained responses related to reward uncertainty, in addition to the phasic responses related to reward-prediction errors (RPEs). Thus, cue-dependent anticipations of the timing, magnitude, and uncertainty of rewards are learned and reflected in components of DA signals. Here we simulate a local circuit model to show how learned uncertainty responses are generated, along with phasic RPE responses, on single trials. Both types of simulated DA responses exhibit the empirically observed dependencies on conditional probability, expected value of reward, and time since onset of the reward-predicting cue. The model's three major pathways compute expected values of cues, timed predictions of reward magnitudes, and uncertainties associated with these predictions. The first two pathways' computations refine those modeled by Brown et al. (1999). The third, newly modeled, pathway involves medium spiny projection neurons (MSPNs) of the striatal matrix, whose axons corelease GABA and substance P, both at synapses with GABAergic neurons in the substantia nigra pars reticulata (SNr) and with distal dendrites (in SNr) of DA neurons whose somas are located in ventral SNc. Corelease enables efficient computation of uncertainty responses that are a nonmonotonic function of the conditional probability of reward, and variability in striatal cholinergic transmission can explain observed individual differences in the amplitudes of uncertainty responses. The involvement of matricial MSPNs and cholinergic transmission within the striatum implies a relation between uncertainty in cue-reward contingencies and action-selection functions of the basal ganglia.

Dopamine and Pain Sensitivity: Neither Sulpiride nor Acute Phenylalanine and Tyrosine Depletion Have Effects on Thermal Pain Sensations in Healthy Volunteers

PubMed Central

Becker, Susanne; Ceko, Marta; Louis-Foster, Mytsumi; Elfassy, Nathaniel M.; Leyton, Marco; Shir, Yoram; Schweinhardt, Petra

2013-01-01

Based on animal studies and some indirect clinical evidence, dopamine has been suggested to have anti-nociceptive effects. Here, we investigated directly the effects of increased and decreased availability of extracellular dopamine on pain perception in healthy volunteers. In Study 1, participants ingested, in separate sessions, a placebo and a low dose of the centrally acting D2-receptor antagonist sulpiride, intended to increase synaptic dopamine via predominant pre-synaptic blockade. No effects were seen on thermal pain thresholds, tolerance, or temporal summation. Study 2 used the acute phenylalanine and tyrosine depletion (APTD) method to transiently decrease dopamine availability. In one session participants ingested a mixture that depletes the dopamine amino acid precursors, phenylalanine and tyrosine. In the other session they ingested a nutritionally balanced control mixture. APTD led to a small mood-lowering response following aversive thermal stimulation, but had no effects on the perception of cold, warm, or pain stimuli. In both studies the experimental manipulation of dopaminergic neurotransmission was successful as indicated by manipulation checks. The results contradict proposals that dopamine has direct anti-nociceptive effects in acute experimental pain. Based on dopamine’s well-known role in reward processing, we hypothesize that also in the context of pain, dopamine acts on stimulus salience and might play a role in the initiation of avoidance behavior rather than having direct antinociceptive effects in acute experimental pain. PMID:24236199

Basal ganglia and Dopamine Contributions to Probabilistic Category Learning

PubMed Central

Shohamy, D.; Myers, C.E.; Kalanithi, J.; Gluck, M.A.

2009-01-01

Studies of the medial temporal lobe and basal ganglia memory systems have recently been extended towards understanding the neural systems contributing to category learning. The basal ganglia, in particular, have been linked to probabilistic category learning in humans. A separate parallel literature in systems neuroscience has emerged, indicating a role for the basal ganglia and related dopamine inputs in reward prediction and feedback processing. Here, we review behavioral, neuropsychological, functional neuroimaging, and computational studies of basal ganglia and dopamine contributions to learning in humans. Collectively, these studies implicate the basal ganglia in incremental, feedback-based learning that involves integrating information across multiple experiences. The medial temporal lobes, by contrast, contribute to rapid encoding of relations between stimuli and support flexible generalization of learning to novel contexts and stimuli. By breaking down our understanding of the cognitive and neural mechanisms contributing to different aspects of learning, recent studies are providing insight into how, and when, these different processes support learning, how they may interact with each other, and the consequence of different forms of learning for the representation of knowledge. PMID:18061261

Dopamine Receptor-Specific Contributions to the Computation of Value.

PubMed

Burke, Christopher J; Soutschek, Alexander; Weber, Susanna; Raja Beharelle, Anjali; Fehr, Ernst; Haker, Helene; Tobler, Philippe N

2018-05-01

Dopamine is thought to play a crucial role in value-based decision making. However, the specific contributions of different dopamine receptor subtypes to the computation of subjective value remain unknown. Here we demonstrate how the balance between D1 and D2 dopamine receptor subtypes shapes subjective value computation during risky decision making. We administered the D2 receptor antagonist amisulpride or placebo before participants made choices between risky options. Compared with placebo, D2 receptor blockade resulted in more frequent choice of higher risk and higher expected value options. Using a novel model fitting procedure, we concurrently estimated the three parameters that define individual risk attitude according to an influential theoretical account of risky decision making (prospect theory). This analysis revealed that the observed reduction in risk aversion under amisulpride was driven by increased sensitivity to reward magnitude and decreased distortion of outcome probability, resulting in more linear value coding. Our data suggest that different components that govern individual risk attitude are under dopaminergic control, such that D2 receptor blockade facilitates risk taking and expected value processing.

Lack of association between alcohol-dependence and D3 dopamine receptor gene in three independent samples

DOE Office of Scientific and Technical Information (OSTI.GOV)

Gorwood, P.; Feingold, J.; Ades, J.

1995-12-18

Numerous studies on the involvement of dopamine receptors in the genetics of alcoholism focused on associations between a polymorphism of the D2 dopamine receptor (DRD2) gene and alcohol dependence. However, the results of these studies are conflicting. Another receptor, the D3 dopamine receptor (DRD3), may be of additional interest since it is specifically located in the limbic area, and in particular in the nucleus accumbens which plays a significant role in the reward process of addiction behavior. We thus tested the association in three independent samples of alcoholic patients, with different origins and various inclusion criteria. No difference in themore » DRD3 gene polymorphism emerged between controls and alcoholic patients, regardless of their origin, inclusion criteria, or presence or absence of the DRD2 TaqI A1-allele. Despite the fact that more information could have been considered and that association studies provide limited information, there is good evidence that this DRD3 polymorphism does not play a major role in the genetic component of alcoholism. 17 refs., 2 tabs.« less

The role of orgasm in the development and shaping of partner preferences

PubMed Central

Coria-Avila, Genaro A.; Herrera-Covarrubias, Deissy; Ismail, Nafissa; Pfaus, James G.

2016-01-01

Background The effect of orgasm on the development and shaping of partner preferences may involve a catalysis of the neurochemical mechanisms of bonding. Therefore, understanding such process is relevant for neuroscience and psychology. Methods A systematic review was carried out using the terms Orgasm, Sexual Reward, Partner Preference, Pair Bonding, Brain, Learning, Sex, Copulation. Results In humans, concentrations of arousing neurotransmitters and potential bonding neurotransmitters increase during orgasm in the cerebrospinal fluid and the bloodstream. Similarly, studies in animals indicate that those neurotransmitters (noradrenaline, oxytocin, prolactin) and others (e.g. dopamine, opioids, serotonin) modulate the appetitive and consummatory phases of sexual behavior and reward. This suggests a link between the experience of orgasm/sexual reward and the neurochemical mechanisms of pair bonding. Orgasm/reward functions as an unconditioned stimulus (UCS). Some areas in the nervous system function as UCS-detection centers, which become activated during orgasm. Partner-related cues function as conditioned stimuli (CS) and are processed in CS-detector centers. Conclusions Throughout the article, we discuss how UCS- and CS-detection centers must interact to facilitate memory consolidation and produce recognition and motivation during future social encounters. PMID:27799080

Affective neuroscience of pleasure: reward in humans and animals

PubMed Central

2010-01-01

Introduction Pleasure and reward are generated by brain circuits that are largely shared between humans and other animals. Discussion Here, we survey some fundamental topics regarding pleasure mechanisms and explicitly compare humans and animals. Conclusion Topics surveyed include liking, wanting, and learning components of reward; brain coding versus brain causing of reward; subjective pleasure versus objective hedonic reactions; roles of orbitofrontal cortex and related cortex regions; subcortical hedonic hotspots for pleasure generation; reappraisals of dopamine and pleasure-electrode controversies; and the relation of pleasure to happiness. PMID:18311558

The Role of Dopamine and Its Dysfunction as a Consequence of Oxidative Stress

PubMed Central

Juárez Olguín, Hugo; Calderón Guzmán, David; Hernández García, Ernestina; Barragán Mejía, Gerardo

2016-01-01

Dopamine is a neurotransmitter that is produced in the substantia nigra, ventral tegmental area, and hypothalamus of the brain. Dysfunction of the dopamine system has been implicated in different nervous system diseases. The level of dopamine transmission increases in response to any type of reward and by a large number of strongly additive drugs. The role of dopamine dysfunction as a consequence of oxidative stress is involved in health and disease. Introduce new potential targets for the development of therapeutic interventions based on antioxidant compounds. The present review focuses on the therapeutic potential of antioxidant compounds as a coadjuvant treatment to conventional neurological disorders is discussed. PMID:26770661

Reinforcement Learning Using a Continuous Time Actor-Critic Framework with Spiking Neurons

PubMed Central

Frémaux, Nicolas; Sprekeler, Henning; Gerstner, Wulfram

2013-01-01

Animals repeat rewarded behaviors, but the physiological basis of reward-based learning has only been partially elucidated. On one hand, experimental evidence shows that the neuromodulator dopamine carries information about rewards and affects synaptic plasticity. On the other hand, the theory of reinforcement learning provides a framework for reward-based learning. Recent models of reward-modulated spike-timing-dependent plasticity have made first steps towards bridging the gap between the two approaches, but faced two problems. First, reinforcement learning is typically formulated in a discrete framework, ill-adapted to the description of natural situations. Second, biologically plausible models of reward-modulated spike-timing-dependent plasticity require precise calculation of the reward prediction error, yet it remains to be shown how this can be computed by neurons. Here we propose a solution to these problems by extending the continuous temporal difference (TD) learning of Doya (2000) to the case of spiking neurons in an actor-critic network operating in continuous time, and with continuous state and action representations. In our model, the critic learns to predict expected future rewards in real time. Its activity, together with actual rewards, conditions the delivery of a neuromodulatory TD signal to itself and to the actor, which is responsible for action choice. In simulations, we show that such an architecture can solve a Morris water-maze-like navigation task, in a number of trials consistent with reported animal performance. We also use our model to solve the acrobot and the cartpole problems, two complex motor control tasks. Our model provides a plausible way of computing reward prediction error in the brain. Moreover, the analytically derived learning rule is consistent with experimental evidence for dopamine-modulated spike-timing-dependent plasticity. PMID:23592970

Reinforcement learning using a continuous time actor-critic framework with spiking neurons.

PubMed

Frémaux, Nicolas; Sprekeler, Henning; Gerstner, Wulfram

2013-04-01

Animals repeat rewarded behaviors, but the physiological basis of reward-based learning has only been partially elucidated. On one hand, experimental evidence shows that the neuromodulator dopamine carries information about rewards and affects synaptic plasticity. On the other hand, the theory of reinforcement learning provides a framework for reward-based learning. Recent models of reward-modulated spike-timing-dependent plasticity have made first steps towards bridging the gap between the two approaches, but faced two problems. First, reinforcement learning is typically formulated in a discrete framework, ill-adapted to the description of natural situations. Second, biologically plausible models of reward-modulated spike-timing-dependent plasticity require precise calculation of the reward prediction error, yet it remains to be shown how this can be computed by neurons. Here we propose a solution to these problems by extending the continuous temporal difference (TD) learning of Doya (2000) to the case of spiking neurons in an actor-critic network operating in continuous time, and with continuous state and action representations. In our model, the critic learns to predict expected future rewards in real time. Its activity, together with actual rewards, conditions the delivery of a neuromodulatory TD signal to itself and to the actor, which is responsible for action choice. In simulations, we show that such an architecture can solve a Morris water-maze-like navigation task, in a number of trials consistent with reported animal performance. We also use our model to solve the acrobot and the cartpole problems, two complex motor control tasks. Our model provides a plausible way of computing reward prediction error in the brain. Moreover, the analytically derived learning rule is consistent with experimental evidence for dopamine-modulated spike-timing-dependent plasticity.

Effects of dopamine D1 receptor blockade in the prelimbic prefrontal cortex or lateral dorsal striatum on frontostriatal function in Wistar and Spontaneously Hypertensive Rats.

PubMed

Gauthier, Jamie M; Tassin, David H; Dwoskin, Linda P; Kantak, Kathleen M

2014-07-15

Attention Deficit Hyperactivity Disorder (ADHD) is associated with dysfunctional prefrontal and striatal circuitry and dysregulated dopamine neurotransmission. Spontaneously Hypertensive Rats (SHR), a heuristically useful animal model of ADHD, were evaluated against normotensive Wistar (WIS) controls to determine whether dopamine D1 receptor blockade of either prelimbic prefrontal cortex (plPFC) or lateral dorsal striatum (lDST) altered learning functions of both interconnected sites. A strategy set shifting task measured plPFC function (behavioral flexibility/executive function) and a reward devaluation task measured lDST function (habitual responding). Prior to tests, rats received bilateral infusions of SCH 23390 (1.0 μg/side) or vehicle into plPFC or lDST. Following vehicle, SHR exhibited longer lever press reaction times, more trial omissions, and fewer completed trials during the set shift test compared to WIS, indicating slower decision-making and attentional/motivational impairment in SHR. After reward devaluation, vehicle-treated SHR responded less than WIS, indicating relatively less habitual responding in SHR. After SCH 23390 infusions into plPFC, WIS expressed the same behavioral phenotype as vehicle-treated SHR during set shift and reward devaluation tests. In SHR, SCH 23390 infusions into plPFC exacerbated behavioral deficits in the set shift test and maintained the lower rate of responding in the reward devaluation test. SCH 23390 infusions into lDST did not modify set shifting in either strain, but produced lower rates of responding than vehicle infusions after reward devaluation in WIS. This research provides pharmacological evidence for unidirectional interactions between prefrontal and striatal brain regions, which has implications for the neurological basis of ADHD and its treatment. Copyright © 2014 Elsevier B.V. All rights reserved.

Chronic CRH depletion from GABAergic, long-range projection neurons in the extended amygdala reduces dopamine release and increases anxiety.

PubMed

Dedic, Nina; Kühne, Claudia; Jakovcevski, Mira; Hartmann, Jakob; Genewsky, Andreas J; Gomes, Karina S; Anderzhanova, Elmira; Pöhlmann, Max L; Chang, Simon; Kolarz, Adam; Vogl, Annette M; Dine, Julien; Metzger, Michael W; Schmid, Bianca; Almada, Rafael C; Ressler, Kerry J; Wotjak, Carsten T; Grinevich, Valery; Chen, Alon; Schmidt, Mathias V; Wurst, Wolfgang; Refojo, Damian; Deussing, Jan M

2018-06-01

The interplay between corticotropin-releasing hormone (CRH) and the dopaminergic system has predominantly been studied in addiction and reward, while CRH-dopamine interactions in anxiety are scarcely understood. We describe a new population of CRH-expressing, GABAergic, long-range-projecting neurons in the extended amygdala that innervate the ventral tegmental area and alter anxiety following chronic CRH depletion. These neurons are part of a distinct CRH circuit that acts anxiolytically by positively modulating dopamine release.

Phasic dopamine release in the nucleus accumbens in response to pro-social 50 kHz ultrasonic vocalizations in rats.

PubMed

Willuhn, Ingo; Tose, Amanda; Wanat, Matthew J; Hart, Andrew S; Hollon, Nick G; Phillips, Paul E M; Schwarting, Rainer K W; Wöhr, Markus

2014-08-06

Rats emit ultrasonic vocalizations (USVs) that are thought to serve as situation-dependent affective signals and accomplish important communicative functions. In appetitive situations, rats produce 50 kHz USVs, whereas 22 kHz USVs occur in aversive situations. Reception of 50 kHz USVs induces social approach behavior, while 22 kHz USVs lead to freezing behavior. These opposite behavioral responses are paralleled by distinct brain activation patterns, with 50 kHz USVs, but not 22 kHz USVs, activating neurons in the nucleus accumbens (NAcc). The NAcc mediates appetitive behavior and is critically modulated by dopaminergic afferents that are known to encode the value of reward. Therefore, we hypothesized that 50 kHz USVs, but not 22 kHz USVs, elicit NAcc dopamine release. While recording dopamine signaling with fast-scan cyclic voltammetry, freely moving rats were exposed to playback of four acoustic stimuli via an ultrasonic speaker in random order: (1) 50 kHz USVs, (2) 22 kHz USVs, (3) time- and amplitude-matched white noise, and (4) background noise. Only presentation of 50 kHz USVs induced phasic dopamine release and elicited approach behavior toward the speaker. Both of these effects, neurochemical and behavioral, were most pronounced during initial playback, but then declined rapidly with subsequent presentations, indicating a close temporal relationship between the two measures. Moreover, the magnitudes of these effects during initial playback were significantly correlated. Collectively, our findings show that NAcc dopamine release encodes pro-social 50 kHz USVs, but not alarming 22 kHz USVs. Thus, our results support the hypothesis that these call types are processed in distinct neuroanatomical regions and establish a functional link between pro-social communicative signals and reward-related neurotransmission. Copyright © 2014 the authors 0270-6474/14/3410616-08$15.00/0.

Noradrenergic modulation of risk/reward decision making.

PubMed

Montes, David R; Stopper, Colin M; Floresco, Stan B

2015-08-01

Catecholamine transmission modulates numerous cognitive and reward-related processes that can subserve more complex functions such as cost/benefit decision making. Dopamine has been shown to play an integral role in decisions involving reward uncertainty, yet there is a paucity of research investigating the contributions of noradrenaline (NA) transmission to these functions. The present study was designed to elucidate the contribution of NA to risk/reward decision making in rats, assessed with a probabilistic discounting task. We examined the effects of reducing noradrenergic transmission with the α2 agonist clonidine (10-100 μg/kg), and increasing activity at α2A receptor sites with the agonist guanfacine (0.1-1 mg/kg), the α2 antagonist yohimbine (1-3 mg/kg), and the noradrenaline transporter (NET) inhibitor atomoxetine (0.3-3 mg/kg) on probabilistic discounting. Rats chose between a small/certain reward and a larger/risky reward, wherein the probability of obtaining the larger reward either decreased (100-12.5 %) or increased (12.5-100 %) over a session. In well-trained rats, clonidine reduced risky choice by decreasing reward sensitivity, whereas guanfacine did not affect choice behavior. Yohimbine impaired adjustments in decision biases as reward probability changed within a session by altering negative feedback sensitivity. In a subset of rats that displayed prominent discounting of probabilistic rewards, the lowest dose of atomoxetine increased preference for the large/risky reward when this option had greater long-term utility. These data highlight an important and previously uncharacterized role for noradrenergic transmission in mediating different aspects of risk/reward decision making and mediating reward and negative feedback sensitivity.

Generational Association Studies of Dopaminergic Genes in Reward Deficiency Syndrome (RDS) Subjects: Selecting Appropriate Phenotypes for Reward Dependence Behaviors

PubMed Central

Blum, Kenneth; Chen, Amanda L. C.; Oscar-Berman, Marlene; Chen, Thomas J. H.; Lubar, Joel; White, Nancy; Lubar, Judith; Bowirrat, Abdalla; Braverman, Eric; Schoolfield, John; Waite, Roger L.; Downs, Bernard W.; Madigan, Margaret; Comings, David E.; Davis, Caroline; Kerner, Mallory M.; Knopf, Jennifer; Palomo, Tomas; Giordano, John J.; Morse, Siobhan A.; Fornari, Frank; Barh, Debmalya; Femino, John; Bailey, John A.

2011-01-01

Abnormal behaviors involving dopaminergic gene polymorphisms often reflect an insufficiency of usual feelings of satisfaction, or Reward Deficiency Syndrome (RDS). RDS results from a dysfunction in the “brain reward cascade,” a complex interaction among neurotransmitters (primarily dopaminergic and opioidergic). Individuals with a family history of alcoholism or other addictions may be born with a deficiency in the ability to produce or use these neurotransmitters. Exposure to prolonged periods of stress and alcohol or other substances also can lead to a corruption of the brain reward cascade function. We evaluated the potential association of four variants of dopaminergic candidate genes in RDS (dopamine D1 receptor gene [DRD1]; dopamine D2 receptor gene [DRD2]; dopamine transporter gene [DAT1]; dopamine beta-hydroxylase gene [DBH]). Methodology: We genotyped an experimental group of 55 subjects derived from up to five generations of two independent multiple-affected families compared to rigorously screened control subjects (e.g., N = 30 super controls for DRD2 gene polymorphisms). Data related to RDS behaviors were collected on these subjects plus 13 deceased family members. Results: Among the genotyped family members, the DRD2 Taq1 and the DAT1 10/10 alleles were significantly (at least p < 0.015) more often found in the RDS families vs. controls. The TaqA1 allele occurred in 100% of Family A individuals (N = 32) and 47.8% of Family B subjects (11 of 23). No significant differences were found between the experimental and control positive rates for the other variants. Conclusions: Although our sample size was limited, and linkage analysis is necessary, the results support the putative role of dopaminergic polymorphisms in RDS behaviors. This study shows the importance of a nonspecific RDS phenotype and informs an understanding of how evaluating single subset behaviors of RDS may lead to spurious results. Utilization of a nonspecific “reward” phenotype may be a paradigm shift in future association and linkage studies involving dopaminergic polymorphisms and other neurotransmitter gene candidates. PMID:22408582

Nicotine Withdrawal Induces Neural Deficits in Reward Processing.

PubMed

Oliver, Jason A; Evans, David E; Addicott, Merideth A; Potts, Geoffrey F; Brandon, Thomas H; Drobes, David J

2017-06-01

Nicotine withdrawal reduces neurobiological responses to nonsmoking rewards. Insight into these reward deficits could inform the development of targeted interventions. This study examined the effect of withdrawal on neural and behavioral responses during a reward prediction task. Smokers (N = 48) attended two laboratory sessions following overnight abstinence. Withdrawal was manipulated by having participants smoke three regular nicotine (0.6 mg yield; satiation) or very low nicotine (0.05 mg yield; withdrawal) cigarettes. Electrophysiological recordings of neural activity were obtained while participants completed a reward prediction task that involved viewing four combinations of predictive and reward-determining stimuli: (1) Unexpected Reward; (2) Predicted Reward; (3) Predicted Punishment; (4) Unexpected Punishment. The task evokes a medial frontal negativity that mimics the phasic pattern of dopaminergic firing in ventral tegmental regions associated with reward prediction errors. Nicotine withdrawal decreased the amplitude of the medial frontal negativity equally across all trial types (p < .001). Exploratory analyses indicated withdrawal increased time to initiate the next trial following unexpected punishment trials (p < .001) and response time on reward trials during withdrawal was positively related to nicotine dependence (p < .001). Nicotine withdrawal had equivocal impact across trial types, suggesting reward processing deficits are unlikely to stem from changes in phasic dopaminergic activity during prediction errors. Effects on tonic activity may be more pronounced. Pharmacological interventions directly targeting the dopamine system and behavioral interventions designed to increase reward motivation and responsiveness (eg, behavioral activation) may aid in mitigating withdrawal symptoms and potentially improving smoking cessation outcomes. Findings from this study indicate nicotine withdrawal impacts reward processing signals that are observable in smokers' neural activity. This may play a role in the subjective aversive experience of nicotine withdrawal and potentially contribute to smoking relapse. Interventions that address abnormal responding to both pleasant and unpleasant stimuli may be particularly effective for alleviating nicotine withdrawal. © The Author 2017. Published by Oxford University Press on behalf of the Society for Research on Nicotine and Tobacco. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

CB1-Dependent Long-Term Depression in Ventral Tegmental Area GABA Neurons: A Novel Target for Marijuana.

PubMed

Friend, Lindsey; Weed, Jared; Sandoval, Philip; Nufer, Teresa; Ostlund, Isaac; Edwards, Jeffrey G

2017-11-08

The VTA is necessary for reward behavior with dopamine cells critically involved in reward signaling. Dopamine cells in turn are innervated and regulated by neighboring inhibitory GABA cells. Using whole-cell electrophysiology in juvenile-adolescent GAD67-GFP male mice, we examined excitatory plasticity in fluorescent VTA GABA cells. A novel CB1-dependent LTD was induced in GABA cells that was dependent on metabotropic glutamate receptor 5, and cannabinoid receptor 1 (CB1). LTD was absent in CB1 knock-out mice but preserved in heterozygous littermates. Bath applied Δ 9 -tetrahydrocannabinol depressed GABA cell activity, therefore downstream dopamine cells will be disinhibited; and thus, this could potentially result in increased reward. Chronic injections of Δ 9 -tetrahydrocannabinol occluded LTD compared with vehicle injections; however, a single exposure was insufficient to do so. As synaptic modifications by drugs of abuse are often tied to addiction, these data suggest a possible mechanism for the addictive effects of Δ 9 -tetrahydrocannabinol in juvenile-adolescents, by potentially altering reward behavioral outcomes. SIGNIFICANCE STATEMENT The present study identifies a novel form of glutamatergic synaptic plasticity in VTA GABA neurons, a currently understudied cell type that is critical for the brain's reward circuit, and how Δ 9 -tetrahydrocannabinol occludes this plasticity. This study specifically addresses a potential unifying mechanism whereby marijuana could exert rewarding and addictive/withdrawal effects. Marijuana use and legalization are a pressing issue for many states in the United States. Although marijuana is the most commonly abused illicit drug, the implications of legalized, widespread, or continued usage are speculative. This study in juvenile-adolescent aged mice identifies a novel form of synaptic plasticity in VTA GABA cells, and the synaptic remodeling that can occur after Δ 9 -tetrahydrocannabinol use. Copyright © 2017 the authors 0270-6474/17/3710943-12$15.00/0.

A Transient Dopamine Signal Represents Avoidance Value and Causally Influences the Demand to Avoid

PubMed Central

Pultorak, Katherine J.; Schelp, Scott A.; Isaacs, Dominic P.; Krzystyniak, Gregory

2018-01-01

Abstract While an extensive literature supports the notion that mesocorticolimbic dopamine plays a role in negative reinforcement, recent evidence suggests that dopamine exclusively encodes the value of positive reinforcement. In the present study, we employed a behavioral economics approach to investigate whether dopamine plays a role in the valuation of negative reinforcement. Using rats as subjects, we first applied fast-scan cyclic voltammetry (FSCV) to determine that dopamine concentration decreases with the number of lever presses required to avoid electrical footshock (i.e., the economic price of avoidance). Analysis of the rate of decay of avoidance demand curves, which depict an inverse relationship between avoidance and increasing price, allows for inference of the worth an animal places on avoidance outcomes. Rapidly decaying demand curves indicate increased price sensitivity, or low worth placed on avoidance outcomes, while slow rates of decay indicate reduced price sensitivity, or greater worth placed on avoidance outcomes. We therefore used optogenetics to assess how inducing dopamine release causally modifies the demand to avoid electrical footshock in an economic setting. Increasing release at an avoidance predictive cue made animals more sensitive to price, consistent with a negative reward prediction error (i.e., the animal perceives they received a worse outcome than expected). Increasing release at avoidance made animals less sensitive to price, consistent with a positive reward prediction error (i.e., the animal perceives they received a better outcome than expected). These data demonstrate that transient dopamine release events represent the value of avoidance outcomes and can predictably modify the demand to avoid. PMID:29766047

Hyperresponsivity and impaired prefrontal control of the mesolimbic reward system in schizophrenia.

PubMed

Richter, Anja; Petrovic, Aleksandra; Diekhof, Esther K; Trost, Sarah; Wolter, Sarah; Gruber, Oliver

2015-12-01

Schizophrenia is characterized by substantial dysfunctions of reward processing, leading to detrimental consequences for decision-making. The neurotransmitter dopamine is responsible for the transmission of reward signals and also known to be involved in the mechanism of psychosis. Using functional magnetic resonance imaging (fMRI), sixteen medicated patients with schizophrenia and sixteen healthy controls performed the 'desire-reason dilemma' (DRD) paradigm. This paradigm allowed us to directly investigate reward-related brain activations depending on the interaction of bottom-up and top-down mechanisms, when a previously conditioned reward stimulus had to be rejected to achieve a superordinate long-term goal. Both patients and controls showed significant activations in the mesolimbic reward system. In patients with schizophrenia, however, we found a significant hyperactivation of the left ventral striatum (vStr) when they were allowed to accept the conditioned reward stimuli, and a reduced top-down regulation of activation in the ventral striatum (vStr) and ventral tegmental area (VTA) while having to reject the immediate reward to pursue the superordinate task-goal. Moreover, while healthy subjects exhibited a negative functional coupling of the vStr with both the anteroventral prefrontal cortex (avPFC) and the ventromedial prefrontal cortex (VMPFC) in the dilemma situation, this functional coupling was significantly impaired in the patient group. These findings provide evidence for an increased ventral striatal activation to reward stimuli and an impaired top-down control of reward signals by prefrontal brain regions in schizophrenia. Copyright © 2015 Elsevier Ltd. All rights reserved.

Activation of dopamine D3 receptors inhibits reward-related learning induced by cocaine.

PubMed

Kong, H; Kuang, W; Li, S; Xu, M

2011-03-10

Memories of learned associations between the rewarding properties of drugs and environmental cues contribute to craving and relapse in humans. The mesocorticolimbic dopamine (DA) system is involved in reward-related learning induced by drugs of abuse. DA D3 receptors are preferentially expressed in mesocorticolimbic DA projection areas. Genetic and pharmacological studies have shown that DA D3 receptors suppress locomotor-stimulant effects of cocaine and reinstatement of cocaine-seeking behaviors. Activation of the extracellular signal-regulated kinase (ERK) induced by acute cocaine administration is also inhibited by D3 receptors. How D3 receptors modulate cocaine-induced reward-related learning and associated changes in cell signaling in reward circuits in the brain, however, have not been fully investigated. In the present study, we show that D3 receptor mutant mice exhibit potentiated acquisition of conditioned place preference (CPP) at low doses of cocaine compared to wild-type mice. Activation of ERK and CaMKIIα, but not the c-Jun N-terminal kinase and p38, in the nucleus accumbens, amygdala and prefrontal cortex is also potentiated in D3 receptor mutant mice compared to that in wild-type mice following CPP expression. These results support a model in which D3 receptors modulate reward-related learning induced by low doses of cocaine by inhibiting activation of ERK and CaMKIIα in reward circuits in the brain. Copyright © 2011 IBRO. Published by Elsevier Ltd. All rights reserved.

Subjective perception of cocaine reward in mice assessed by a single exposure place preference (sePP) paradigm.

PubMed

Runegaard, Annika H; Jensen, Kathrine Louise; Dencker, Ditte; Wörtwein, Gitta; Gether, Ulrik

2017-09-01

The potential of abused drugs to induce addiction and compulsive drug-related behavior is associated with their ability to alter dopamine signaling. Dopamine plays a key role in reward signaling and it has been of great interest to investigate how various drugs of abuse alter reward-related behavior. In rodents, the rewarding effects of drugs have often been assessed in self-administration or place preference paradigms; both involving repeated drug exposure and weeks of training and testing. Our investigation describes a valid approach to assess the initial rewarding effects of cocaine in mice with a single exposure place preference (sePP) paradigm, avoiding repeated drug injections. We present the sePP paradigm with a 3-day protocol to assess the initial rewarding effects of cocaine. Interestingly, only male mice exhibit sePP to cocaine. To assess subsequent drug-related behavior, the protocol was extended by 3days of extinction followed by reinstatement on day 10. The sePP paradigm provides a reliable and convenient approach to assess the initial rewarding effects of cocaine, circumventing the need for repeated drug injections. The sePP protocol allows further dissection of the mechanism and influence of initial cocaine exposure on subsequent drug-related behaviors by including extinction and reinstatement. The lack of sePP in female mice may reflect a biologically relevant sex difference in the initial subjective perception of cocaine-induced reward. This could relate to and explain why males and females have been reported to respond differently to cocaine and cocaine-associated cues. Copyright © 2017 Elsevier B.V. All rights reserved.

The Sensory Features of a Food Cue Influence Its Ability to Act as an Incentive Stimulus and Evoke Dopamine Release in the Nucleus Accumbens Core

ERIC Educational Resources Information Center

Singer, Bryan F.; Bryan, Myranda A.; Popov, Pavlo; Scarff, Raymond; Carter, Cody; Wright, Erin; Aragona, Brandon J.; Robinson, Terry E.

2016-01-01

The sensory properties of a reward-paired cue (a conditioned stimulus; CS) may impact the motivational value attributed to the cue, and in turn influence the form of the conditioned response (CR) that develops. A cue with multiple sensory qualities, such as a moving lever-CS, may activate numerous neural pathways that process auditory and visual…

Speed/accuracy trade-off between the habitual and the goal-directed processes.

PubMed

Keramati, Mehdi; Dezfouli, Amir; Piray, Payam

2011-05-01

Instrumental responses are hypothesized to be of two kinds: habitual and goal-directed, mediated by the sensorimotor and the associative cortico-basal ganglia circuits, respectively. The existence of the two heterogeneous associative learning mechanisms can be hypothesized to arise from the comparative advantages that they have at different stages of learning. In this paper, we assume that the goal-directed system is behaviourally flexible, but slow in choice selection. The habitual system, in contrast, is fast in responding, but inflexible in adapting its behavioural strategy to new conditions. Based on these assumptions and using the computational theory of reinforcement learning, we propose a normative model for arbitration between the two processes that makes an approximately optimal balance between search-time and accuracy in decision making. Behaviourally, the model can explain experimental evidence on behavioural sensitivity to outcome at the early stages of learning, but insensitivity at the later stages. It also explains that when two choices with equal incentive values are available concurrently, the behaviour remains outcome-sensitive, even after extensive training. Moreover, the model can explain choice reaction time variations during the course of learning, as well as the experimental observation that as the number of choices increases, the reaction time also increases. Neurobiologically, by assuming that phasic and tonic activities of midbrain dopamine neurons carry the reward prediction error and the average reward signals used by the model, respectively, the model predicts that whereas phasic dopamine indirectly affects behaviour through reinforcing stimulus-response associations, tonic dopamine can directly affect behaviour through manipulating the competition between the habitual and the goal-directed systems and thus, affect reaction time.

Assaying the Effect of Levodopa on the Evaluation of Risk in Healthy Humans

PubMed Central

Symmonds, Mkael; Wright, Nicholas D.; Fagan, Elizabeth; Dolan, Raymond J.

2013-01-01

In humans, dopamine is implicated in reward and risk-based decision-making. However, the specific effects of dopamine augmentation on risk evaluation are unclear. Here we sought to measure the effect of 100 mg oral levodopa, which enhances synaptic release of dopamine, on choice behaviour in healthy humans. We use a paradigm without feedback or learning, which solely isolates effects on risk evaluation. We present two studies (n = 20; n = 20) employing a randomised, placebo-controlled, within-subjects design. We manipulated different dimensions of risk in a controlled economic paradigm. We test effects on risk-reward tradeoffs, assaying both aversion to variance (the spread of possible outcomes) and preference for relative losses and gains (asymmetry of outcomes - skewness), dissociating this from potential non-specific effects on choice randomness using behavioural modelling. There were no systematic effects of levodopa on risk attitudes, either for variance or skewness. However, there was a drift towards more risk-averse behaviour over time, indicating that this paradigm was sensitive to detect changes in risk-preferences. These findings suggest that levodopa administration does not change the evaluation of risk. One possible reason is that dopaminergic influences on decision making may be due to changing the response to reward feedback. PMID:23844168

Increased dopamine DRD4 receptor mRNA expression in lymphocytes of musicians and autistic individuals: bridging the music-autism connection.

PubMed

Emanuele, Enzo; Boso, Marianna; Cassola, Francesco; Broglia, Davide; Bonoldi, Ilaria; Mancini, Lara; Marini, Mara; Politi, Pierluigi

2010-01-01

People with autistic spectrum disorder (ASD) are affected by a long-life disabling condition, characterized by communication deficits, severe impairments in social functioning, and stereotyped behaviors. Although ASD individuals display several problems in interactions, it has been reported that they may show a peculiar interest in music. Previous studies have suggested a pivotal role for the dopaminergic system in the psychobiology of reward, including the pleasure of music. In the present study, we sought to investigate dopamine DRD3 and DRD4 receptor expression in peripheral blood lymphocytes of adult healthy musicians and age- and gender-matched patients with ASD against the background hypothesis that the dopaminergic system may contribute a biological cause to the reward dimensions of the musical experience in both healthy and autistic individuals. ANOVA showed significant differences in DRD4 mRNA expression between the groups (P = 0.008). Post-hoc analysis showed significant differences between the control group and both musicians (P < 0.05) and ASD individuals (P < 0.05). No differences were found for DRD3 mRNA expression between the groups. Our current results provide intriguing preliminary evidence for a possible molecular link between dopamine DRD4 receptor, music and autism, possibly via mechanisms involving the reward system and the appraisal of emotions.

Presynaptic D2 dopamine receptors control long-term depression expression and memory processes in the temporal hippocampus.

PubMed

Rocchetti, Jill; Isingrini, Elsa; Dal Bo, Gregory; Sagheby, Sara; Menegaux, Aurore; Tronche, François; Levesque, Daniel; Moquin, Luc; Gratton, Alain; Wong, Tak Pan; Rubinstein, Marcelo; Giros, Bruno

2015-03-15

Dysfunctional mesocorticolimbic dopamine signaling has been linked to alterations in motor and reward-based functions associated with psychiatric disorders. Converging evidence from patients with psychiatric disorders and use of antipsychotics suggests that imbalance of dopamine signaling deeply alters hippocampal functions. However, given the lack of full characterization of a functional mesohippocampal pathway, the precise role of dopamine transmission in memory deficits associated with these disorders and their dedicated therapies is unknown. In particular, the positive outcome of antipsychotic treatments, commonly antagonizing D2 dopamine receptors (D2Rs), on cognitive deficits and memory impairments remains questionable. Following pharmacologic and genetic manipulation of dopamine transmission, we performed anatomic, neurochemical, electrophysiologic, and behavioral investigations to uncover the role of D2Rs in hippocampal-dependent plasticity and learning. Naïve mice (n = 4-21) were used in the different procedures. Dopamine modulated both long-term potentiation and long-term depression in the temporal hippocampus as well as spatial and recognition learning and memory in mice through D2Rs. Although genetic deletion or pharmacologic blockade of D2Rs led to the loss of long-term potentiation expression, the specific genetic removal of presynaptic D2Rs impaired long-term depression and performances on spatial memory tasks. Presynaptic D2Rs in dopamine fibers of the temporal hippocampus tightly modulate long-term depression expression and play a major role in the regulation of hippocampal learning and memory. This direct role of mesohippocampal dopamine input as uncovered here adds a new dimension to dopamine involvement in the physiology underlying deficits associated with neuropsychiatric disorders. Copyright © 2015 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.

Dynamic fluctuations in dopamine efflux in the prefrontal cortex and nucleus accumbens during risk-based decision making.

PubMed

St Onge, Jennifer R; Ahn, Soyon; Phillips, Anthony G; Floresco, Stan B

2012-11-21

Mesocorticolimbic dopamine (DA) has been implicated in cost/benefit decision making about risks and rewards. The prefrontal cortex (PFC) and nucleus accumbens (NAc) are two DA terminal regions that contribute to decision making in distinct manners. However, how fluctuations of tonic DA levels may relate to different aspects of decision making remains to be determined. The present study measured DA efflux in the PFC and NAc with microdialysis in well trained rats performing a probabilistic discounting task. Selection of a small/certain option always delivered one pellet, whereas another, large/risky option yielded four pellets, with probabilities that decreased (100-12.5%) or increased (12.5-100%) across four blocks of trials. Yoked-reward groups were also included to control for reward delivery. PFC DA efflux during decision making decreased or increased over a session, corresponding to changes in large/risky reward probabilities. Similar profiles were observed from yoked-rewarded rats, suggesting that fluctuations in PFC DA reflect changes in the relative rate of reward received. NAc DA efflux also showed decreasing/increasing trends over the session during both tasks. However, DA efflux was higher during decision making on free- versus forced-choice trials and during periods of greater reward uncertainty. Moreover, changes in NAc DA closely tracked shifts in choice biases. These data reveal dynamic and dissociable fluctuations in PFC and NAc DA transmission associated with different aspects of risk-based decision making. PFC DA may signal changes in reward availability that facilitates modification of choice biases, whereas NAc DA encodes integrated signals about reward rates, uncertainty, and choice, reflecting implementation of decision policies.

Reward sensitivity deficits modulated by dopamine are associated with apathy in Parkinson’s disease

PubMed Central

Manohar, Sanjay; Ben Yehuda, Michael; Chong, Trevor T.-J.; Tofaris, George; Lennox, Graham; Bogdanovic, Marko; Hu, Michele; Husain, Masud

2016-01-01

Abstract Apathy is a debilitating and under-recognized condition that has a significant impact in many neurodegenerative disorders. In Parkinson’s disease, it is now known to contribute to worse outcomes and a reduced quality of life for patients and carers, adding to health costs and extending disease burden. However, despite its clinical importance, there remains limited understanding of mechanisms underlying apathy. Here we investigated if insensitivity to reward might be a contributory factor and examined how this relates to severity of clinical symptoms. To do this we created novel ocular measures that indexed motivation level using pupillary and saccadic response to monetary incentives, allowing reward sensitivity to be evaluated objectively. This approach was tested in 40 patients with Parkinson’s disease, 31 elderly age-matched control participants and 20 young healthy volunteers. Thirty patients were examined ON and OFF their dopaminergic medication in two counterbalanced sessions, so that the effect of dopamine on reward sensitivity could be assessed. Pupillary dilation to increasing levels of monetary reward on offer provided quantifiable metrics of motivation in healthy subjects as well as patients. Moreover, pupillary reward sensitivity declined with age. In Parkinson’s disease, reduced pupillary modulation by incentives was predictive of apathy severity, and independent of motor impairment and autonomic dysfunction as assessed using overnight heart rate variability measures. Reward sensitivity was further modulated by dopaminergic state, with blunted sensitivity when patients were OFF dopaminergic drugs, both in pupillary response and saccadic peak velocity response to reward. These findings suggest that reward insensitivity may be a contributory mechanism to apathy and provide potential new clinical measures for improved diagnosis and monitoring of apathy. 10.1093/brain/aww188_video_abstractaww188_video_abstract PMID:27452600

Receptor-specific modulation of risk-based decision making by nucleus accumbens dopamine.

PubMed

Stopper, Colin M; Khayambashi, Shahin; Floresco, Stan B

2013-04-01

The nucleus accumbens (NAc) serves as an integral node within cortico-limbic circuitry that regulates various forms of cost-benefit decision making. The dopamine (DA) system has also been implicated in enabling organisms to overcome a variety of costs to obtain more valuable rewards. However, it remains unclear how DA activity within the NAc may regulate decision making involving reward uncertainty. This study investigated the contribution of different DA receptor subtypes in the NAc to risk-based decision making, assessed with a probabilistic discounting task. In well-trained rats, D1 receptor blockade with SCH 23,390 decreased preference for larger, uncertain rewards, which was associated with enhanced negative-feedback sensitivity (ie, an increased tendency to select a smaller/certain option after an unrewarded risky choice). Treatment with a D1 agonist (SKF 81,297) optimized decision making, increasing choice of the risky option when reward probability was high, and decreasing preference under low probability conditions. In stark contrast, neither blockade of NAc D2 receptors with eticlopride, nor stimulation of these receptors with quinpirole or bromocriptine influenced risky choice. In comparison, infusion of the D3-preferring agonist PD 128,907 decreased reward sensitivity and risky choice. Collectively, these results show that mesoaccumbens DA refines risk-reward decision biases via dissociable mechanisms recruiting D1 and D3, but not D2 receptors. D1 receptor activity mitigates the effect of reward omissions on subsequent choices to promote selection of reward options that may have greater long-term utility, whereas excessive D3 receptor activity blunts the impact that larger/uncertain rewards have in promoting riskier choices.

Honey bee foraging induces upregulation of early growth response protein 1, hormone receptor 38 and candidate downstream genes of the ecdysteroid signalling pathway.

PubMed

Singh, A S; Shah, A; Brockmann, A

2018-02-01

In honey bees, continuous foraging at an artificial feeder induced a sustained upregulation of the immediate early genes early growth response protein 1 (Egr-1) and hormone receptor 38 (Hr38). This gene expression response was accompanied by an upregulation of several Egr-1 candidate downstream genes: ecdysone receptor (EcR), dopamine/ecdysteroid receptor (DopEcR), dopamine decarboxylase and dopamine receptor 2. Hr38, EcR and DopEcR are components of the ecdysteroid signalling pathway, which is highly probably involved in learning and memory processes in honey bees and other insects. Time-trained foragers still showed an upregulation of Egr-1 when the feeder was presented at an earlier time of the day, suggesting that the genomic response is more dependent on the food reward than training time. However, presentation of the feeder at the training time without food was still capable of inducing a transient increase in Egr-1 expression. Thus, learnt feeder cues, or even training time, probably affect Egr-1 expression. In contrast, whole brain Egr-1 expression changes did not differ between dancing and nondancing foragers. On the basis of our results we propose that food reward induced continuous foraging ultimately elicits a genomic response involving Egr-1 and Hr38 and their downstream genes. Furthermore this genomic response is highly probably involved in foraging-related learning and memory responses. © 2017 The Royal Entomological Society.

Targeting circuits of sexual desire as a treatment strategy for hypoactive sexual desire disorder.

PubMed

Stahl, Stephen M

2010-07-01

Hypoactive sexual desire disorder (HSDD) is hypothesized to be a disorder of the brain's reward circuitry. Neurotransmitters in reward circuits are thus therapeutic targets for improving sexual desire. Novel treatment strategies are to enhance dopamine (DA) actions, reduce serotonin (5-HT) actions, or both. (c) Copyright 2010 Physicians Postgraduate Press, Inc.

Neural coding of basic reward terms of animal learning theory, game theory, microeconomics and behavioural ecology.

PubMed

Schultz, Wolfram

2004-04-01

Neurons in a small number of brain structures detect rewards and reward-predicting stimuli and are active during the expectation of predictable food and liquid rewards. These neurons code the reward information according to basic terms of various behavioural theories that seek to explain reward-directed learning, approach behaviour and decision-making. The involved brain structures include groups of dopamine neurons, the striatum including the nucleus accumbens, the orbitofrontal cortex and the amygdala. The reward information is fed to brain structures involved in decision-making and organisation of behaviour, such as the dorsolateral prefrontal cortex and possibly the parietal cortex. The neural coding of basic reward terms derived from formal theories puts the neurophysiological investigation of reward mechanisms on firm conceptual grounds and provides neural correlates for the function of rewards in learning, approach behaviour and decision-making.

Role of dopamine D2 receptors in optimizing choice strategy in a dynamic and uncertain environment

PubMed Central

Kwak, Shinae; Huh, Namjung; Seo, Ji-Seon; Lee, Jung-Eun; Han, Pyung-Lim; Jung, Min W.

2014-01-01

In order to investigate roles of dopamine receptor subtypes in reward-based learning, we examined choice behavior of dopamine D1 and D2 receptor-knockout (D1R-KO and D2R-KO, respectively) mice in an instrumental learning task with progressively increasing reversal frequency and a dynamic two-armed bandit task. Performance of D2R-KO mice was progressively impaired in the former as the frequency of reversal increased and profoundly impaired in the latter even with prolonged training, whereas D1R-KO mice showed relatively minor performance deficits. Choice behavior in the dynamic two-armed bandit task was well explained by a hybrid model including win-stay-lose-switch and reinforcement learning terms. A model-based analysis revealed increased win-stay, but impaired value updating and decreased value-dependent action selection in D2R-KO mice, which were detrimental to maximizing rewards in the dynamic two-armed bandit task. These results suggest an important role of dopamine D2 receptors in learning from past choice outcomes for rapid adjustment of choice behavior in a dynamic and uncertain environment. PMID:25389395

Fischer 344 and Lewis Rat Strains as a Model of Genetic Vulnerability to Drug Addiction

PubMed Central

Cadoni, Cristina

2016-01-01

Today it is well acknowledged that both nature and nurture play important roles in the genesis of psychopathologies, including drug addiction. Increasing evidence suggests that genetic factors contribute for at least 40–60% of the variation in liability to drug dependence. Human genetic studies suggest that multiple genes of small effect, rather than single genes, contribute to the genesis of behavioral psychopathologies. Therefore, the use of inbred rat strains might provide a valuable tool to identify differences, linked to genotype, important in liability to addiction and related disorders. In this regard, Lewis and Fischer 344 inbred rats have been proposed as a model of genetic vulnerability to drug addiction, given their innate differences in sensitivity to the reinforcing and rewarding effects of drugs of abuse, as well their different responsiveness to stressful stimuli. This review will provide evidence in support of this model for the study of the genetic influence on addiction vulnerability, with particular emphasis on differences in mesolimbic dopamine (DA) transmission, rewarding and emotional function. It will be highlighted that Lewis and Fischer 344 rats differ not only in several indices of DA transmission and adaptive changes following repeated drug exposure, but also in hypothalamic-pituitary-adrenal (HPA) axis responsiveness, influencing not only the ability of the individual to cope with stressful events, but also interfering with rewarding and motivational processes, given the influence of corticosteroids on dopamine neuron functionality. Further differences between the two strains, as impulsivity or anxiousness, might contribute to their different proneness to addiction, and likely these features might be linked to their different DA neurotransmission plasticity. Although differences in other neurotransmitter systems might deserve further investigation, results from the reviewed studies might open new vistas in understanding aberrant deviations in reward and motivational functions. PMID:26903787

Cholinergic modulation of mesolimbic dopamine function and reward.

PubMed

Mark, Gregory P; Shabani, Shkelzen; Dobbs, Lauren K; Hansen, Stephen T

2011-07-25

The substantial health risk posed by obesity and compulsive drug use has compelled a serious research effort to identify the neurobiological substrates that underlie the development these pathological conditions. Despite substantial progress, an understanding of the neurochemical systems that mediate the motivational aspects of drug-seeking and craving remains incomplete. Important work from the laboratory of Bart Hoebel has provided key information on neurochemical systems that interact with dopamine (DA) as potentially important components in both the development of addiction and the expression of compulsive behaviors such as binge eating. One such modulatory system appears to be cholinergic pathways that interact with DA systems at all levels of the reward circuit. Cholinergic cells in the pons project to DA-rich cell body regions in the ventral tegmental area (VTA) and substantial nigra (SN) where they modulate the activity of dopaminergic neurons and reward processing. The DA terminal region of the nucleus accumbens (NAc) contains a small but particularly important group of cholinergic interneurons, which have extensive dendritic arbors that make synapses with a vast majority of NAc neurons and afferents. Together with acetylcholine (ACh) input onto DA cell bodies, cholinergic systems could serve a vital role in gating information flow concerning the motivational value of stimuli through the mesolimbic system. In this report we highlight evidence that CNS cholinergic systems play a pivotal role in behaviors that are motivated by both natural and drug rewards. We argue that the search for underlying neurochemical substrates of compulsive behaviors, as well as attempts to identify potential pharmacotherapeutic targets to combat them, must include a consideration of central cholinergic systems. Copyright © 2011 Elsevier Inc. All rights reserved.

Fischer 344 and Lewis Rat Strains as a Model of Genetic Vulnerability to Drug Addiction.

PubMed

Cadoni, Cristina

2016-01-01

Today it is well acknowledged that both nature and nurture play important roles in the genesis of psychopathologies, including drug addiction. Increasing evidence suggests that genetic factors contribute for at least 40-60% of the variation in liability to drug dependence. Human genetic studies suggest that multiple genes of small effect, rather than single genes, contribute to the genesis of behavioral psychopathologies. Therefore, the use of inbred rat strains might provide a valuable tool to identify differences, linked to genotype, important in liability to addiction and related disorders. In this regard, Lewis and Fischer 344 inbred rats have been proposed as a model of genetic vulnerability to drug addiction, given their innate differences in sensitivity to the reinforcing and rewarding effects of drugs of abuse, as well their different responsiveness to stressful stimuli. This review will provide evidence in support of this model for the study of the genetic influence on addiction vulnerability, with particular emphasis on differences in mesolimbic dopamine (DA) transmission, rewarding and emotional function. It will be highlighted that Lewis and Fischer 344 rats differ not only in several indices of DA transmission and adaptive changes following repeated drug exposure, but also in hypothalamic-pituitary-adrenal (HPA) axis responsiveness, influencing not only the ability of the individual to cope with stressful events, but also interfering with rewarding and motivational processes, given the influence of corticosteroids on dopamine neuron functionality. Further differences between the two strains, as impulsivity or anxiousness, might contribute to their different proneness to addiction, and likely these features might be linked to their different DA neurotransmission plasticity. Although differences in other neurotransmitter systems might deserve further investigation, results from the reviewed studies might open new vistas in understanding aberrant deviations in reward and motivational functions.

Molecular role of dopamine in anhedonia linked to reward deficiency syndrome (RDS) and anti- reward systems.

PubMed

Gold, Mark S; Blum, Kenneth; Febo, Marcelo; Baron, David; Modestino, Edward Justin; Elman, Igor; Badgaiyan, Rajendra D

2018-03-01

Anhedonia is a condition that leads to the loss of feelings pleasure in response to natural reinforcers like food, sex, exercise, and social activities. This disorder occurs in addiction, and an array of related neuropsychiatric syndromes, including schizophrenia, depression, and Post Traumatic Stress Disorder (PTSD). Anhedonia may by due to derangements in mesolimbic dopaminergic pathways and their terminal fields (e.g., striatum, amygdala, and prefrontal cortex) that persist long after the traces of the causative drugs are eliminated (pharmacokinetically). Here we postulate that anhedonia is not a distinct entity but is rather an epiphenomenon of hypodopaminergic states and traits arising from the interaction of genetic traits and epigenetic neurobiological alterations in response to environmental influences. Moreover, dopaminergic activity is rather complex, and so it may give rise to differential pathophysiological processes such as incentive sensitization, aberrant learning and stress-like "anti-reward" phenomena. These processes may have additive, synergistic or antagonistic interactions with the concurrent reward deficiency states leading in some instances to more severe and long-lasting symptoms. Operant understanding of the neurogenetic antecedents to reward deficiency syndrome (RDS) and the elucidation of reward gene polymorphisms may provide a map for accessing an individual's genetic risk for developing Anhedonia. Prevention techniques that can restore homeostatic balance via physiological activation of dopaminergic receptors (D2/D3) may be instrumental for targeting not only anhedonia per se but also drug craving and relapse.

Genetic inhibition of neurotransmission reveals role of glutamatergic input to dopamine neurons in high-effort behavior.

PubMed

Hutchison, M A; Gu, X; Adrover, M F; Lee, M R; Hnasko, T S; Alvarez, V A; Lu, W

2018-05-01

Midbrain dopamine neurons are crucial for many behavioral and cognitive functions. As the major excitatory input, glutamatergic afferents are important for control of the activity and plasticity of dopamine neurons. However, the role of glutamatergic input as a whole onto dopamine neurons remains unclear. Here we developed a mouse line in which glutamatergic inputs onto dopamine neurons are specifically impaired, and utilized this genetic model to directly test the role of glutamatergic inputs in dopamine-related functions. We found that while motor coordination and reward learning were largely unchanged, these animals showed prominent deficits in effort-related behavioral tasks. These results provide genetic evidence that glutamatergic transmission onto dopaminergic neurons underlies incentive motivation, a willingness to exert high levels of effort to obtain reinforcers, and have important implications for understanding the normal function of the midbrain dopamine system.

Functional evidence for a direct excitatory projection from the lateral habenula to the ventral tegmental area in the rat

PubMed Central

Shepard, Paul D.

2016-01-01

The lateral habenula, a phylogenetically conserved epithalamic structure, is activated by aversive stimuli and reward omission. Excitatory efferents from the lateral habenula predominately inhibit midbrain dopamine neuronal firing through a disynaptic, feedforward inhibitory mechanism involving the rostromedial tegmental nucleus. However, the lateral habenula also directly targets dopamine neurons within the ventral tegmental area, suggesting that opposing actions may result from increased lateral habenula activity. In the present study, we tested the effect of habenular efferent stimulation on dopamine and nondopamine neurons in the ventral tegmental area of Sprague-Dawley rats using a parasagittal brain slice preparation. Single pulse stimulation of the fasciculus retroflexus excited 48% of dopamine neurons and 51% of nondopamine neurons in the ventral tegmental area of rat pups. These proportions were not altered by excision of the rostromedial tegmental nucleus and were evident in both cortical- and striatal-projecting dopamine neurons. Glutamate receptor antagonists blocked this excitation, and fasciculus retroflexus stimulation elicited evoked excitatory postsynaptic potentials with a nearly constant onset latency, indicative of a monosynaptic, glutamatergic connection. Comparison of responses in rat pups and young adults showed no significant difference in the proportion of neurons excited by fasciculus retroflexus stimulation. Our data indicate that the well-known, indirect inhibitory effect of lateral habenula activation on midbrain dopamine neurons is complemented by a significant, direct excitatory effect. This pathway may contribute to the role of midbrain dopamine neurons in processing aversive stimuli and salience. PMID:27358317

Functional evidence for a direct excitatory projection from the lateral habenula to the ventral tegmental area in the rat.

PubMed

Brown, P Leon; Shepard, Paul D

2016-09-01

The lateral habenula, a phylogenetically conserved epithalamic structure, is activated by aversive stimuli and reward omission. Excitatory efferents from the lateral habenula predominately inhibit midbrain dopamine neuronal firing through a disynaptic, feedforward inhibitory mechanism involving the rostromedial tegmental nucleus. However, the lateral habenula also directly targets dopamine neurons within the ventral tegmental area, suggesting that opposing actions may result from increased lateral habenula activity. In the present study, we tested the effect of habenular efferent stimulation on dopamine and nondopamine neurons in the ventral tegmental area of Sprague-Dawley rats using a parasagittal brain slice preparation. Single pulse stimulation of the fasciculus retroflexus excited 48% of dopamine neurons and 51% of nondopamine neurons in the ventral tegmental area of rat pups. These proportions were not altered by excision of the rostromedial tegmental nucleus and were evident in both cortical- and striatal-projecting dopamine neurons. Glutamate receptor antagonists blocked this excitation, and fasciculus retroflexus stimulation elicited evoked excitatory postsynaptic potentials with a nearly constant onset latency, indicative of a monosynaptic, glutamatergic connection. Comparison of responses in rat pups and young adults showed no significant difference in the proportion of neurons excited by fasciculus retroflexus stimulation. Our data indicate that the well-known, indirect inhibitory effect of lateral habenula activation on midbrain dopamine neurons is complemented by a significant, direct excitatory effect. This pathway may contribute to the role of midbrain dopamine neurons in processing aversive stimuli and salience. Copyright © 2016 the American Physiological Society.

Dorsal Raphe Dopamine Neurons Represent the Experience of Social Isolation.

PubMed

Matthews, Gillian A; Nieh, Edward H; Vander Weele, Caitlin M; Halbert, Sarah A; Pradhan, Roma V; Yosafat, Ariella S; Glober, Gordon F; Izadmehr, Ehsan M; Thomas, Rain E; Lacy, Gabrielle D; Wildes, Craig P; Ungless, Mark A; Tye, Kay M

2016-02-11

The motivation to seek social contact may arise from either positive or negative emotional states, as social interaction can be rewarding and social isolation can be aversive. While ventral tegmental area (VTA) dopamine (DA) neurons may mediate social reward, a cellular substrate for the negative affective state of loneliness has remained elusive. Here, we identify a functional role for DA neurons in the dorsal raphe nucleus (DRN), in which we observe synaptic changes following acute social isolation. DRN DA neurons show increased activity upon social contact following isolation, revealed by in vivo calcium imaging. Optogenetic activation of DRN DA neurons increases social preference but causes place avoidance. Furthermore, these neurons are necessary for promoting rebound sociability following an acute period of isolation. Finally, the degree to which these neurons modulate behavior is predicted by social rank, together supporting a role for DRN dopamine neurons in mediating a loneliness-like state. PAPERCLIP. Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.

Adolescent Stimulation of D2 Receptors Alters the Maturation of Dopamine-dependent Goal-Directed Behavior

PubMed Central

Naneix, Fabien; Marchand, Alain R; Pichon, Anaïs; Pape, Jean- Rémi; Coutureau, Etienne

2013-01-01

Adolescence is a period of high sensitivity to drugs and rewards, characterized by the immaturity of decision-making abilities. A chronic stimulation of reward systems during this period might constitute a factor of vulnerability to the development of psychiatric disorders. However, the long-term consequences of such an exposure have seldom been explored. Here, we investigate at the adult age the effects of chronic dopamine (DA) stimulation during adolescence on both the maturation of DA systems and the cognitive processes underlying goal-directed actions. We first demonstrate that chronic stimulation of D2 receptors by quinpirole during adolescence alters the development of DA systems. This treatment has particularly prominent effects on the mesocortical DA pathway where it decreases DA fibers density, DA concentration, and DA receptors expression. Furthermore, we show that quinpirole-treated rats exhibit specific impairments in instrumental goal-directed behavior, as they fail to adapt their action when action–outcome relationships change in a contingency degradation procedure. These results therefore highlight the vulnerability of DA system and prefrontal areas to prolonged stimulation during adolescence, and its potential long-term impact on cognitive functions. PMID:23443719

A Dynamic Connectome Supports the Emergence of Stable Computational Function of Neural Circuits through Reward-Based Learning.

PubMed

Kappel, David; Legenstein, Robert; Habenschuss, Stefan; Hsieh, Michael; Maass, Wolfgang

2018-01-01

Synaptic connections between neurons in the brain are dynamic because of continuously ongoing spine dynamics, axonal sprouting, and other processes. In fact, it was recently shown that the spontaneous synapse-autonomous component of spine dynamics is at least as large as the component that depends on the history of pre- and postsynaptic neural activity. These data are inconsistent with common models for network plasticity and raise the following questions: how can neural circuits maintain a stable computational function in spite of these continuously ongoing processes, and what could be functional uses of these ongoing processes? Here, we present a rigorous theoretical framework for these seemingly stochastic spine dynamics and rewiring processes in the context of reward-based learning tasks. We show that spontaneous synapse-autonomous processes, in combination with reward signals such as dopamine, can explain the capability of networks of neurons in the brain to configure themselves for specific computational tasks, and to compensate automatically for later changes in the network or task. Furthermore, we show theoretically and through computer simulations that stable computational performance is compatible with continuously ongoing synapse-autonomous changes. After reaching good computational performance it causes primarily a slow drift of network architecture and dynamics in task-irrelevant dimensions, as observed for neural activity in motor cortex and other areas. On the more abstract level of reinforcement learning the resulting model gives rise to an understanding of reward-driven network plasticity as continuous sampling of network configurations.

A Dynamic Connectome Supports the Emergence of Stable Computational Function of Neural Circuits through Reward-Based Learning

PubMed Central

Habenschuss, Stefan; Hsieh, Michael

2018-01-01

Synaptic connections between neurons in the brain are dynamic because of continuously ongoing spine dynamics, axonal sprouting, and other processes. In fact, it was recently shown that the spontaneous synapse-autonomous component of spine dynamics is at least as large as the component that depends on the history of pre- and postsynaptic neural activity. These data are inconsistent with common models for network plasticity and raise the following questions: how can neural circuits maintain a stable computational function in spite of these continuously ongoing processes, and what could be functional uses of these ongoing processes? Here, we present a rigorous theoretical framework for these seemingly stochastic spine dynamics and rewiring processes in the context of reward-based learning tasks. We show that spontaneous synapse-autonomous processes, in combination with reward signals such as dopamine, can explain the capability of networks of neurons in the brain to configure themselves for specific computational tasks, and to compensate automatically for later changes in the network or task. Furthermore, we show theoretically and through computer simulations that stable computational performance is compatible with continuously ongoing synapse-autonomous changes. After reaching good computational performance it causes primarily a slow drift of network architecture and dynamics in task-irrelevant dimensions, as observed for neural activity in motor cortex and other areas. On the more abstract level of reinforcement learning the resulting model gives rise to an understanding of reward-driven network plasticity as continuous sampling of network configurations. PMID:29696150

Development of a Dual Tracer PET Method for Imaging Dopaminergic Neuromodulation

NASA Astrophysics Data System (ADS)

Converse, Alexander K.; Dejesus, Onofre T.; Flores, Leo G.; Holden, James E.; Kelley, Ann E.; Moirano, Jeffrey M.; Nickles, Robert J.; Oakes, Terrence R.; Roberts, Andrew D.; Ruth, Thomas J.; Vandehey, Nicholas T.; Davidson, Richard J.

2006-04-01

The modulatory neurotransmittor dopamine (DA) is involved in movement and reward behaviors, and malfunctions in the dopamine system are implicated in a variety of prevalent and debilitating pathologies including Parkinson's disease, attention deficit/hyperactivity disorder, schizophrenia, and addiction. Positron emission tomography (PET) has been used to separately measure changes in DA receptor occupancy and blood flow in response to various interventions. Here we describe a dual tracer PET method to simultaneously measure both responses with the aim of comparing DA release in particular areas of the brain and associated alterations in neural activity throughout the brain. Significant correlations between reductions in DA receptor occupancy and blood flow alterations would be potential signs of dopaminergic modulation, i.e. modifications in signal processing due to increased levels of extracellular DA. Methodological development has begun with rats undergoing an amphetamine challenge while being scanned with the blood flow tracer [17F]fluoromethane and the dopamine D2 receptor tracer [18F]desmethoxyfallypride.

Direct Midbrain Dopamine Input to the Suprachiasmatic Nucleus Accelerates Circadian Entrainment.

PubMed

Grippo, Ryan M; Purohit, Aarti M; Zhang, Qi; Zweifel, Larry S; Güler, Ali D

2017-08-21

Dopamine (DA) neurotransmission controls behaviors important for survival, including voluntary movement, reward processing, and detection of salient events, such as food or mate availability. Dopaminergic tone also influences circadian physiology and behavior. Although the evolutionary significance of this input is appreciated, its precise neurophysiological architecture remains unknown. Here, we identify a novel, direct connection between the DA neurons of the ventral tegmental area (VTA) and the suprachiasmatic nucleus (SCN). We demonstrate that D1 dopamine receptor (Drd1) signaling within the SCN is necessary for properly timed resynchronization of activity rhythms to phase-shifted light:dark cycles and that elevation of DA tone through selective activation of VTA DA neurons accelerates photoentrainment. Our findings demonstrate a previously unappreciated role for direct DA input to the master circadian clock and highlight the importance of an evolutionarily significant relationship between the circadian system and the neuromodulatory circuits that govern motivational behaviors. Copyright © 2017 Elsevier Ltd. All rights reserved.

Isolated Flinders Sensitive Line rats have decreased dopamine D2 receptor mRNA.

PubMed

Bjørnebekk, Astrid; Mathé, Aleksander A; Brené, Stefan

2007-07-02

Social isolation has profound effects on animal behavior and dopamine systems. We investigated the effect of social isolation on the dopamine receptor and neuropeptide mRNAs in the brain reward system in an animal model of depression, the Flinders Sensitive Line rats and Sprague-Dawley controls. We demonstrate that socially isolated but not group housed Flinders sensitive line rats had lower dopamine D2 receptor mRNA levels compared with Sprague-Dawley rats. Isolated and group housed Flinders Sensitive Line rats had higher levels of dopamine D1 receptor and substance P and enkephalin but not dynorphin mRNAs when compared with Sprague-Dawley rats. Our findings of decreased dopamine D2 receptor levels in socially isolated Flinders Sensitive Line rats suggest that low D2 receptor expression may play a role in pathophysiology of depression.

Amphetamine primes enhanced motivation toward uncertain choices in rats with genetic alcohol preference.

PubMed

Oinio, Ville; Sundström, Mikko; Bäckström, Pia; Uhari-Väänänen, Johanna; Kiianmaa, Kalervo; Raasmaja, Atso; Piepponen, Petteri

2018-05-01

Comorbidity with gambling disorder (GD) and alcohol use disorder (AUD) is well documented. The purpose of our study was to examine the influence of genetic alcohol drinking tendency on reward-guided decision making behavior of rats and the impact of dopamine releaser D-amphetamine on this behavior. In this study, Alko alcohol (AA) and Wistar rats went through long periods of operant lever pressing training where the task was to choose the profitable of two options. The lever choices were guided by different-sized sucrose rewards (one or three pellets), and the probability of gaining the larger reward was slowly changed to a level where choosing the smaller reward would be the most profitable in the long run. After training, rats were injected (s.c.) with dopamine releaser D-amphetamine (0.3, 1.0 mg/kg) to study the impact of rapid dopamine release on this learned decision making behavior. Administration of D-amphetamine promoted unprofitable decision making of AA rats more robustly when compared to Wistar rats. At the same time, D-amphetamine reduced lever pressing responses. Interestingly, we found that this reduction in lever pressing was significantly greater in Wistar rats than in AA rats and it was not linked to motivation to consume sucrose. Our results indicate that conditioning to the lever pressing in uncertain environments is more pronounced in AA than in Wistar rats and indicate that the reinforcing effects of a gambling-like environment act as a stronger conditioning factor for rats that exhibit a genetic tendency for high alcohol drinking.

Dietary triglycerides act on mesolimbic structures to regulate the rewarding and motivational aspects of feeding

PubMed Central

Cansell, Céline; Castel, Julien; Denis, Raphaël G. P.; Rouch, Claude; Delbes, Anne-Sophie; Martinez, Sarah; Mestivier, Denis; Finan, Brian; Maldonado-Aviles, Jaime G.; Rijnsburger, Merel; Tschöp, Matthias H.; DiLeone, Ralph J.; Eckel, Robert H.; la Fleur, Susanne E.; Magnan, Christophe; Hnasko, Thomas S.; Luquet, Serge

2014-01-01

Circulating triglycerides (TG) normally increase after a meal but are altered in pathophysiological conditions such as obesity. Although TG metabolism in the brain remains poorly understood, several brain structures express enzymes that process TG-enriched particles, including mesolimbic structures. For this reason, and because consumption of high fat diet alters dopamine signaling, we tested the hypothesis that TG might directly target mesolimbic reward circuits to control reward-seeking behaviors. We found that the delivery of small amounts of TG to the brain through the carotid artery rapidly reduced both spontaneous and amphetamine-induced locomotion, abolished preference for palatable food, and reduced the motivation to engage in food-seeking behavior. Conversely, targeted disruption of the TG-hydrolyzing enzyme lipoprotein lipase specifically in the nucleus accumbens increased palatable food preference and food seeking behavior. Finally, prolonged TG perfusion resulted in a return to normal palatable food preference despite continued locomotor suppression, suggesting that adaptive mechanisms occur. These findings reveal new mechanisms by which dietary fat may alter mesolimbic circuit function and reward seeking. PMID:24732670

Neuromodulation of reward-based learning and decision making in human aging

PubMed Central

Eppinger, Ben; Hämmerer, Dorothea; Li, Shu-Chen

2013-01-01

In this paper, we review the current literature to highlight relations between age-associated declines in dopaminergic and serotonergic neuromodulation and adult age differences in adaptive goal-directed behavior. Specifically, we focus on evidence suggesting that deficits in neuromodulation contribute to older adults’ behavioral disadvantages in learning and decision making. These deficits are particularly pronounced when reward information is uncertain or the task context requires flexible adaptations to changing stimulus–reward contingencies. Moreover, emerging evidence points to age-related differences in the sensitivity to rewarding and aversive outcomes during learning and decision making if the acquisition of behavior critically depends on outcome processing. These age-related asymmetries in outcome valuation may be explained by age differences in the interplay of dopaminergic and serotonergic neuromodulation. This hypothesis is based on recent neurocomputational and psychopharmacological approaches, which suggest that dopamine and serotonin serve opponent roles in regulating the balance between approach behavior and inhibitory control. Studying adaptive regulation of behavior across the adult life span may shed new light on how the aging brain changes functionally in response to its diminishing resources. PMID:22023564

Mood, food, and obesity.

PubMed

Singh, Minati

2014-01-01

Food is a potent natural reward and food intake is a complex process. Reward and gratification associated with food consumption leads to dopamine (DA) production, which in turn activates reward and pleasure centers in the brain. An individual will repeatedly eat a particular food to experience this positive feeling of gratification. This type of repetitive behavior of food intake leads to the activation of brain reward pathways that eventually overrides other signals of satiety and hunger. Thus, a gratification habit through a favorable food leads to overeating and morbid obesity. Overeating and obesity stems from many biological factors engaging both central and peripheral systems in a bi-directional manner involving mood and emotions. Emotional eating and altered mood can also lead to altered food choice and intake leading to overeating and obesity. Research findings from human and animal studies support a two-way link between three concepts, mood, food, and obesity. The focus of this article is to provide an overview of complex nature of food intake where various biological factors link mood, food intake, and brain signaling that engages both peripheral and central nervous system signaling pathways in a bi-directional manner in obesity.

Dopaminergic dysfunction in schizophrenia: salience attribution revisited.

PubMed

Heinz, Andreas; Schlagenhauf, Florian

2010-05-01

A dysregulation of the mesolimbic dopamine system in schizophrenia patients may lead to aberrant attribution of incentive salience and contribute to the emergence of psychopathological symptoms like delusions. The dopaminergic signal has been conceptualized to represent a prediction error that indicates the difference between received and predicted reward. The incentive salience hypothesis states that dopamine mediates the attribution of "incentive salience" to conditioned cues that predict reward. This hypothesis was initially applied in the context of drug addiction and then transferred to schizophrenic psychosis. It was hypothesized that increased firing (chaotic or stress associated) of dopaminergic neurons in the striatum of schizophrenia patients attributes incentive salience to otherwise irrelevant stimuli. Here, we review recent neuroimaging studies directly addressing this hypothesis. They suggest that neuronal functions associated with dopaminergic signaling, such as the attribution of salience to reward-predicting stimuli and the computation of prediction errors, are indeed altered in schizophrenia patients and that this impairment appears to contribute to delusion formation.

Noradrenaline and dopamine neurons in the reward/effort trade-off: a direct electrophysiological comparison in behaving monkeys.

PubMed

Varazzani, Chiara; San-Galli, Aurore; Gilardeau, Sophie; Bouret, Sebastien

2015-05-20

Motivation determines multiple aspects of behavior, including action selection and energization of behavior. Several components of the underlying neural systems have been examined closely, but the specific role of the different neuromodulatory systems in motivation remains unclear. Here, we compare directly the activity of dopaminergic neurons from the substantia nigra pars compacta and noradrenergic neurons from the locus coeruleus in monkeys performing a task manipulating the reward/effort trade-off. Consistent with previous reports, dopaminergic neurons encoded the expected reward, but we found that they also anticipated the upcoming effort cost in connection with its negative influence on action selection. Conversely, the firing of noradrenergic neurons increased with both pupil dilation and effort production in relation to the energization of behavior. Therefore, this work underlines the contribution of dopamine to effort-based decision making and uncovers a specific role of noradrenaline in energizing behavior to face challenges. Copyright © 2015 the authors 0270-6474/15/357866-12$15.00/0.

NAD+ cellular redox and SIRT1 regulate the diurnal rhythms of tyrosine hydroxylase and conditioned cocaine reward.

PubMed

Logan, Ryan W; Parekh, Puja K; Kaplan, Gabrielle N; Becker-Krail, Darius D; Williams, Wilbur P; Yamaguchi, Shintaro; Yoshino, Jun; Shelton, Micah A; Zhu, Xiyu; Zhang, Hui; Waplinger, Spencer; Fitzgerald, Ethan; Oliver-Smith, Jeffrey; Sundarvelu, Poornima; Enwright, John F; Huang, Yanhua H; McClung, Colleen A

2018-05-04

The diurnal regulation of dopamine is important for normal physiology and diseases such as addiction. Here we find a novel role for the CLOCK protein to antagonize CREB-mediated transcriptional activity at the tyrosine hydroxylase (TH) promoter, which is mediated by the interaction with the metabolic sensing protein, Sirtuin 1 (SIRT1). Additionally, we demonstrate that the transcriptional activity of TH is modulated by the cellular redox state, and daily rhythms of redox balance in the ventral tegmental area (VTA), along with TH transcription, are highly disrupted following chronic cocaine administration. Furthermore, CLOCK and SIRT1 are important for regulating cocaine reward and dopaminergic (DAergic) activity, with interesting differences depending on whether DAergic activity is in a heightened state and if there is a functional CLOCK protein. Taken together, we find that rhythms in cellular metabolism and circadian proteins work together to regulate dopamine synthesis and the reward value for drugs of abuse.

Tyrosine hydroxylase in the ventral tegmental area of rams with high or low libido-A role for dopamine.

PubMed

Kramer, A C; Mirto, A J; Austin, K J; Roselli, C E; Alexander, B M

2017-12-01

Dopamine synthesis in the ventral tegmental area (VTA) is necessary for the reinforcement of sexual behavior. The objective of this study determined if sexual stimuli initiates reward, and whether reward is attenuated in sexually inactive rams. Sexually active rams were exposed to urine from estrous (n=4) or ovariectomized (n=3) ewes with inactive rams (n=3) exposed to urine from estrous ewes. Following exposure, rams were exsanguinated and brains perfused. Alternating sections of the VTA were stained for Fos related antigens (FRA), tyrosine hydroxylase, and dopamine beta-hydroxylase activity. Forebrain tissue, mid-sagittal ventral to the anterior corpus callosum, was stained for dopamine D 2 receptors. Concentrations of cortisol was determined prior to and following exposure. Exposure to ovariectomized-ewe urine in sexually active rams did not influence (P=0.6) FRA expression, but fewer (P<0.05) neurons were positive for tyrosine hydroxylase in the VTA. Sexually inactive rams had fewer (P<0.05) FRA and tyrosine hydroxylase positive neurons in the VTA than sexually active rams following exposure to estrous ewe urine. VTA neurons staining positive for dopamine beta-hydroxylase did not differ by sexual activity (P=0.44) or urine exposure (P=0.07). Exposure to stimulus did not influence (P=0.46) numbers of forebrain neurons staining positive for dopamine D2 receptors in sexually active rams, but fewer (P=0.04) neurons stain positive in inactive rams. Serum concentrations of cortisol did not differ (P≥0.52) among rams prior to or following stimulus. In conclusion sexual inactivity is unlikely due to stress, but may be partially a result of decreased tyrosine hydroxylase and/or the response to dopamine. Copyright © 2017 Elsevier B.V. All rights reserved.

Cytokine effects on the basal ganglia and dopamine function: the subcortical source of inflammatory malaise.

PubMed

Felger, Jennifer C; Miller, Andrew H

2012-08-01

Data suggest that cytokines released during the inflammatory response target subcortical structures including the basal ganglia as well as dopamine function to acutely induce behavioral changes that support fighting infection and wound healing. However, chronic inflammation and exposure to inflammatory cytokines appears to lead to persisting alterations in the basal ganglia and dopamine function reflected by anhedonia, fatigue, and psychomotor slowing. Moreover, reduced neural responses to hedonic reward, decreased dopamine metabolites in the cerebrospinal fluid and increased presynaptic dopamine uptake and decreased turnover have been described. This multiplicity of changes in the basal ganglia and dopamine function suggest fundamental effects of inflammatory cytokines on dopamine synthesis, packaging, release and/or reuptake, which may sabotage and circumvent the efficacy of current treatment approaches. Thus, examination of the mechanisms by which cytokines alter the basal ganglia and dopamine function will yield novel insights into the treatment of cytokine-induced behavioral changes and inflammatory malaise. Copyright © 2012 Elsevier Inc. All rights reserved.

The Impact of Selective Dopamine D2, D3 and D4 Ligands on the Rat Gambling Task.

PubMed

Di Ciano, Patricia; Pushparaj, Abhiram; Kim, Aaron; Hatch, Jessica; Masood, Talal; Ramzi, Abby; Khaled, Maram A T M; Boileau, Isabelle; Winstanley, Catherine A; Le Foll, Bernard

2015-01-01

Gambling is an addictive disorder with serious societal and personal costs. To-date, there are no approved pharmacological treatments for gambling disorder. Evidence suggests a role for dopamine in gambling disorder and thus may provide a therapeutic target. The present study therefore aimed to investigate the effects of selective antagonists and agonists of D2, D3 and D4 receptors in a rodent analogue of the Iowa gambling task used clinically. In this rat gambling task (rGT), animals are trained to associate different response holes with different magnitudes and probabilities of food pellet rewards and punishing time-out periods. As in the Iowa gambling task, the optimal strategy is to avoid the tempting high-risk high-reward options, and instead favor those linked to smaller per-trial rewards but also lower punishments, thereby maximizing the amount of reward earned over time. Administration of those selective ligands did not affect decision making under the rGT. Only the D4 drug had modest effects on latency measures suggesting that D4 may contribute in some ways to decision making under this task.

The effects of intranasal oxytocin on reward circuitry responses in children with autism spectrum disorder.

PubMed

Greene, R K; Spanos, M; Alderman, C; Walsh, E; Bizzell, J; Mosner, M G; Kinard, J L; Stuber, G D; Chandrasekhar, T; Politte, L C; Sikich, L; Dichter, G S

2018-03-27

Intranasal oxytocin (OT) has been shown to improve social communication functioning of individuals with autism spectrum disorder (ASD) and, thus, has received considerable interest as a potential ASD therapeutic agent. Although preclinical research indicates that OT modulates the functional output of the mesocorticolimbic dopamine system that processes rewards, no clinical brain imaging study to date has examined the effects of OT on this system using a reward processing paradigm. To address this, we used an incentive delay task to examine the effects of a single dose of intranasal OT, versus placebo (PLC), on neural responses to social and nonsocial rewards in children with ASD. In this placebo-controlled double-blind study, 28 children and adolescents with ASD (age: M = 13.43 years, SD = 2.36) completed two fMRI scans, one after intranasal OT administration and one after PLC administration. During both scanning sessions, participants completed social and nonsocial incentive delay tasks. Task-based neural activation and connectivity were examined to assess the impact of OT relative to PLC on mesocorticolimbic brain responses to social and nonsocial reward anticipation and outcomes. Central analyses compared the OT and PLC conditions. During nonsocial reward anticipation, there was greater activation in the right nucleus accumbens (NAcc), left anterior cingulate cortex (ACC), bilateral orbital frontal cortex (OFC), left superior frontal cortex, and right frontal pole (FP) during the OT condition relative to PLC. Alternatively, during social reward anticipation and outcomes, there were no significant increases in brain activation during the OT condition relative to PLC. A Treatment Group × Reward Condition interaction revealed relatively greater activation in the right NAcc, right caudate nucleus, left ACC, and right OFC during nonsocial relative to social reward anticipation during the OT condition relative to PLC. Additionally, these analyses revealed greater activation during nonsocial reward outcomes during the OT condition relative to PLC in the right OFC and left FP. Finally, functional connectivity analyses generally revealed changes in frontostriatal connections during the OT condition relative to PLC in response to nonsocial, but not social, rewards. The effects of intranasal OT administration on mesocorticolimbic brain systems that process rewards in ASD were observable primarily during the processing of nonsocial incentive salience stimuli. These findings have implications for understanding the effects of OT on neural systems that process rewards, as well as for experimental trials of novel ASD treatments developed to ameliorate social communication impairments in ASD.

Dopamine D5 receptor modulates male and female sexual behavior in mice.

PubMed

Kudwa, A E; Dominguez-Salazar, E; Cabrera, D M; Sibley, D R; Rissman, E F

2005-07-01

Dopamine exerts its actions through at least five receptor (DAR) isoforms. In female rats, D5 DAR may be involved in expression of sexual behavior. We used a D5 knockout (D5KO) mouse to assess the role of D5 DAR in mouse sexual behavior. Both sexes of D5KO mice are fertile and exhibit only minor disruptions in exploratory locomotion, startle, and prepulse inhibition responses. This study was conducted to characterize the sexual behavior of male and female D5KO mice relative to their WT littermates. Female WT and D5KO littermates were ovariectomized and given a series of sexual behavior tests after treatment with estradiol benzoate (EB) and progesterone (P). Once sexual performance was optimal the dopamine agonist, apomorphine (APO), was substituted for P. Male mice were observed in pair- and trio- sexual behavior tests. To assess whether the D5 DAR is involved in rewarding aspects of sexual behavior, WT and D5KO male mice were tested for conditioned place preference. Both WT and D5KO females can display receptivity after treatment with EB and P, but APO was only able to facilitate receptivity in EB-primed WT, not in D5KO, mice. Male D5KO mice display normal masculine sexual behavior in mating tests. In conditioned preference tests, WT males formed a conditioned preference for context associated with either intromissions alone or ejaculation as the unconditioned stimulus. In contrast, D5KO males only showed a place preference when ejaculation was paired with the context. In females, the D5 DAR is essential for the actions of dopamine on receptivity. In males, D5 DAR influences rewarding aspects of intromissions. Taken together, the work suggests that the D5 receptor mediates dopamine's action on sexual behavior in both sexes, perhaps via a reward pathway.

A new synthetic drug 5-(2-aminopropyl)indole (5-IT) induces rewarding effects and increases dopamine D1 receptor and dopamine transporter mRNA levels.

PubMed

Botanas, Chrislean Jun; Yoon, Seong Shoon; de la Peña, June Bryan; Dela Peña, Irene Joy; Kim, Mikyung; Custodio, Raly James; Woo, Taeseon; Seo, Joung-Wook; Jang, Choon-Gon; Yang, Ji Seul; Yoon, Yoon Mi; Lee, Yong Sup; Kim, Hee Jin; Cheong, Jae Hoon

2018-04-02

In recent years, there has been a marked increase in the use of recreational synthetic psychoactive substances, which is a cause of concern among healthcare providers and legal authorities. In particular, there have been reports on the misuse of 5-(2-aminopropyl)indole (5-API; 5-IT), a new synthetic drug, and of fatal and non-fatal intoxication. Despite these reports, little is known about its psychopharmacological effects and abuse potential. Here, we investigated the abuse potential of 5-IT by evaluating its rewarding and reinforcing effects through conditioned place preference (CPP) (1, 10, and 30 mg/kg, i.p.) in mice and self-administration test (0.1, 0.3, 1, and 3 mg/kg/inf., i.v.) in rats. We also examined whether 5-IT (1, 3, and 10 mg/kg, i.p.) induces locomotor sensitization in mice following a 7-day treatment and drug challenge. Then, we explored the effects of 5-IT (10 mg/kg, i.p.) on dopamine-related genes in the striatum, prefrontal cortex (PFC), and substantia nigra pars compacta (SNc)/ventral tegmental (VTA) of mice by quantitative real-time polymerase chain reaction. 5-IT produced CPP in mice but was not reliably self-administered by rats. 5-IT also induced locomotor sensitization following repeated administration and drug challenge. Moreover, 5-IT increased mRNA levels of dopamine D1 receptor in the striatum and PFC and dopamine transporter in the SNc/VTA of mice. These results indicate that 5-IT has psychostimulant and rewarding properties, which may be attributed to its ability to affect the dopaminergic system in the brain. These findings suggest that 5-IT poses a substantial risk for abuse and addiction in humans. Copyright © 2017 Elsevier B.V. All rights reserved.

Striatal dopamine D2 receptor availability predicts the thalamic and medial prefrontal responses to reward in cocaine abusers three years later

DOE Office of Scientific and Technical Information (OSTI.GOV)

Asensio, S.; Goldstein, R.; Asensio, S.

Low levels of dopamine (DA) D2 receptor availability at a resting baseline have been previously reported in drug addicted individuals and have been associated with reduced ventral and dorsal prefrontal metabolism. The reduction in DA D2 receptor availability along with the reduced ventral frontal metabolism is thought to underlie compromised sensitivity to nondrug reward, a core characteristic of drug addiction. We therefore hypothesized that variability in DA D2 receptor availability at baseline will covary with dynamic responses to monetary reward in addicted individuals. Striatal DA D2 receptor availability was measured with [{sup 11}C]raclopride and positron emission tomography and response tomore » monetary reward was measured (an average of three years later) with functional magnetic resonance imaging in seven cocaine-addicted individuals. Results show that low DA D2 receptor availability in the dorsal striatum was associated with decreased thalamic response to monetary reward; while low availability in ventral striatum was associated with increased medial prefrontal (Brodmann Area 6/8/32) response to monetary reward. These preliminary results, that need to be replicated in larger sample sizes and validated with healthy controls, suggest that resting striatal DA D2 receptor availability predicts variability in functional responses to a nondrug reinforcer (money) in prefrontal cortex, implicated in behavioral monitoring, and in thalamus, implicated in conditioned responses and expectation, in cocaine-addicted individuals.« less

Emotional Eating Phenotype is Associated with Central Dopamine D2 Receptor Binding Independent of Body Mass Index

PubMed Central

Eisenstein, Sarah A.; Bischoff, Allison N.; Gredysa, Danuta M.; Antenor-Dorsey, Jo Ann V.; Koller, Jonathan M.; Al-Lozi, Amal; Pepino, Marta Y.; Klein, Samuel; Perlmutter, Joel S.; Moerlein, Stephen M.; Black, Kevin J.; Hershey, Tamara

2015-01-01

PET studies have provided mixed evidence regarding central D2/D3 dopamine receptor binding and its relationship with obesity as measured by body mass index (BMI). Other aspects of obesity may be more tightly coupled to the dopaminergic system. We characterized obesity-associated behaviors and determined if these related to central D2 receptor (D2R) specific binding independent of BMI. Twenty-two obese and 17 normal-weight participants completed eating- and reward-related questionnaires and underwent PET scans using the D2R-selective and nondisplaceable radioligand (N-[11C]methyl)benperidol. Questionnaires were grouped by domain (eating related to emotion, eating related to reward, non-eating behavior motivated by reward or sensitivity to punishment). Normalized, summed scores for each domain were compared between obese and normal-weight groups and correlated with striatal and midbrain D2R binding. Compared to normal-weight individuals, the obese group self-reported higher rates of eating related to both emotion and reward (p < 0.001), greater sensitivity to punishment (p = 0.06), and lower non-food reward behavior (p < 0.01). Across normal-weight and obese participants, self-reported emotional eating and non-food reward behavior positively correlated with striatal (p < 0.05) and midbrain (p < 0.05) D2R binding, respectively. In conclusion, an emotional eating phenotype may reflect altered central D2R function better than other commonly used obesity-related measures such as BMI. PMID:26066863

Striatal dopamine D2 receptor availability predicts the thalamic and medial prefrontal responses to reward in cocaine abusers three years later

PubMed Central

Asensio, Samuel; Romero, Maria J.; Romero, Francisco J.; Wong, Christopher; Alia-Klein, Nelly; Tomasi, Dardo; Wang, Gene-Jack; Telang, Frank; Volkow, Nora D.; Goldstein, Rita Z.

2009-01-01

Low levels of dopamine (DA) D2 receptor availability at a resting baseline have been previously reported in drug addicted individuals and have been associated with reduced ventral and dorsal prefrontal metabolism. The reduction in DA D2 receptor availability along with the reduced ventral frontal metabolism is thought to underlie compromised sensitivity to non-drug reward, a core characteristic of drug addiction. We therefore hypothesized that variability in DA D2 receptor availability at baseline will covary with dynamic responses to monetary reward in addicted individuals. Striatal DA D2 receptor availability was measured with [11C]raclopride and positron emission tomography and response to monetary reward was measured (an average of 3 years later) with functional magnetic resonance imaging in seven cocaine addicted individuals. Results show that low DA D2 receptor availability in the dorsal striatum was associated with decreased thalamic response to monetary reward; while low availability in ventral striatum was associated with increased medial prefrontal (Brodmann Area 6/8/32) response to monetary reward. These preliminary results, that need to be replicated in larger sample sizes and validated with healthy controls, suggest that resting striatal DA D2 receptor availability predicts variability in functional responses to a non-drug reinforcer (money) in prefrontal cortex, implicated in behavioral monitoring, and in thalamus, implicated in conditioned responses and expectation, in cocaine addicted individuals. PMID:20034014

DOE Office of Scientific and Technical Information (OSTI.GOV)

Volkow, N.D.; Wang, G.; Volkow, N.D.

Attention-deficit/hyperactivity disorder (ADHD) - characterized by symptoms of inattention and hyperactivity-impulsivity - is the most prevalent childhood psychiatric disorder that frequently persists into adulthood, and there is increasing evidence of reward-motivation deficits in this disorder. To evaluate biological bases that might underlie a reward/motivation deficit by imaging key components of the brain dopamine reward pathway (mesoaccumbens). We used positron emission tomography to measure dopamine synaptic markers (transporters and D{sub 2}/D{sub 3} receptors) in 53 nonmedicated adults with ADHD and 44 healthy controls between 2001-2009 at Brookhaven National Laboratory. We measured specific binding of positron emission tomographic radioligands for dopamine transportersmore » (DAT) using [{sup 11}C]cocaine and for D{sub 2}/D{sub 3} receptors using [{sup 11}C]raclopride, quantified as binding potential (distribution volume ratio -1). For both ligands, statistical parametric mapping showed that specific binding was lower in ADHD than in controls (threshold for significance set at P < .005) in regions of the dopamine reward pathway in the left side of the brain. Region-of-interest analyses corroborated these findings. The mean (95% confidence interval [CI] of mean difference) for DAT in the nucleus accumbens for controls was 0.71 vs 0.63 for those with ADHD (95% CI, 0.03-0.13, P = .004) and in the midbrain for controls was 0.16 vs 0.09 for those with ADHD (95% CI, 0.03-0.12; P {le} .001); for D{sub 2}/D{sub 3} receptors, the mean accumbens for controls was 2.85 vs 2.68 for those with ADHD (95% CI, 0.06-0.30, P = .004); and in the midbrain, it was for controls 0.28 vs 0.18 for those with ADHD (95% CI, 0.02-0.17, P = .01). The analysis also corroborated differences in the left caudate: the mean DAT for controls was 0.66 vs 0.53 for those with ADHD (95% CI, 0.04-0.22; P = .003) and the mean D{sub 2}/D{sub 3} for controls was 2.80 vs 2.47 for those with ADHD (95% CI, 0.10-0.56; P = .005) and differences in D{sub 2}/D{sub 3} in the hypothalamic region, with controls having a mean of 0.12 vs 0.05 for those with ADHD (95% CI, 0.02-0.12; P = .004). Ratings of attention correlated with D{sub 2}/D{sub 3} in the accumbens (r = 0.35; 95% CI, 0.15-0.52; P = .001), midbrain (r = 0.35; 95% CI, 0.14-0.52; P = .001), caudate (r = 0.32; 95% CI, 0.11-0.50; P = .003), and hypothalamic (r = 0.31; CI, 0.10-0.49; P = .003) regions and with DAT in the midbrain (r = 0.37; 95% CI, 0.16-0.53; P {le} .001). A reduction in dopamine synaptic markers associated with symptoms of inattention was shown in the dopamine reward pathway of participants with ADHD.« less

Learning Reward Uncertainty in the Basal Ganglia

PubMed Central

Bogacz, Rafal

2016-01-01

Learning the reliability of different sources of rewards is critical for making optimal choices. However, despite the existence of detailed theory describing how the expected reward is learned in the basal ganglia, it is not known how reward uncertainty is estimated in these circuits. This paper presents a class of models that encode both the mean reward and the spread of the rewards, the former in the difference between the synaptic weights of D1 and D2 neurons, and the latter in their sum. In the models, the tendency to seek (or avoid) options with variable reward can be controlled by increasing (or decreasing) the tonic level of dopamine. The models are consistent with the physiology of and synaptic plasticity in the basal ganglia, they explain the effects of dopaminergic manipulations on choices involving risks, and they make multiple experimental predictions. PMID:27589489

Adaptive increase in D3 dopamine receptors in the brain reward circuits of human cocaine fatalities.

PubMed

Staley, J K; Mash, D C

1996-10-01

The mesolimbic dopaminergic system plays a primary role in mediating the euphoric and rewarding effects of most abused drugs. Chronic cocaine use is associated with an increase in dopamine neurotransmission resulting from the blockade of dopamine uptake and is mediated by the activation of dopamine receptors. Recent studies have suggested that the D3 receptor subtype plays a pivotal role in the reinforcing effects of cocaine. The D3 receptor-preferring agonist 7-hydroxy-N,N-di-n-propyl-2-aminotetralin (7-OH-DPAT) is a reinforcer in rhesus monkeys trained to self-administer cocaine, but not in cocainenaive monkeys. In vitro autoradiographic localization of [3H]-(+)-7-OH-DPAT binding in the human brain demonstrated that D3 receptors were prevalent and highly localized over the ventromedial sectors of the striatum. Pharmacological characterization of [3H]-(+)-7-OH-DPAT binding to the human nucleus accumbens demonstrated a rank order of potency similar to that observed for binding to the cloned D3 receptor expressed in transfected cell lines. Region-of-interest analysis of [3H]-(+)-7-OH-DPAT binding to the D3 receptor demonstrated a one- to threefold elevation in the number of binding sites over particular sectors of the striatum and substantia nigra in cocaine overdose victims as compared with age-matched and drug-free control subjects. The elevated number of [3H]-(+)-7-OH-DPAT binding sites demonstrates that adaptive changes in the D3 receptor in the reward circuitry of the brain are associated with chronic cocaine abuse. These results suggest that the D3 receptor may be a useful target for drug development of anticocaine medications.

Hypothesizing That Neuropharmacological and Neuroimaging Studies of Glutaminergic-Dopaminergic Optimization Complex (KB220Z) Are Associated With "Dopamine Homeostasis" in Reward Deficiency Syndrome (RDS).

PubMed

Blum, Kenneth; Febo, Marcelo; Fried, Lyle; Li, Mona; Dushaj, Kristina; Braverman, Eric R; McLaughlin, Thomas; Steinberg, Bruce; Badgaiyan, Rajendra D

2017-03-21

There is need for better treatments of addictive behaviors, both substance and non-substance related, termed Reward Deficiency Syndrome (RDS). While the FDA has approved pharmaceuticals under the umbrella term Medication Assisted Treatment (MAT), these drugs are not optimal. It is our contention that these drugs work well in the short-term by blocking dopamine function leading to psychological extinction. However, use of buprenorphine/Naloxone over a long period of time results in unwanted addiction liability, reduced emotional affect, and mood changes including suicidal ideation. We are thus proposing a paradigm shift in addiction treatment, with the long-term goal of achieving "Dopamine Homeostasis." While this may be a laudable goal, it is very difficult to achieve. Nevertheless, this commentary briefly reviews past history of developing and subsequently, utilizing a glutaminergic-dopaminergic optimization complex [Kb220Z] shown to be beneficial in at least 20 human clinical trials and in a number of published and unpublished studies. It is our opinion that, while additional required studies could confirm these findings to date, the cited studies are indicative of achieving enhanced resting state functional connectivity, connectivity volume, and possibly, neuroplasticity. Conclusions/Importance: We are proposing a Reward Deficiency Solution System (RDSS) that includes: Genetic Addiction Risk Score (GARS); Comprehensive Analysis of Reported Drugs (CARD); and a glutaminergic-dopaminergic optimization complex (Kb220Z). Continued investigation of this novel strategy may lead to a better-targeted approach in the long-term, causing dopamine regulation by balancing the glutaminergic-dopaminergic pathways. This may potentially change the landscape of treating all addictions leading us to the promised land.

Estradiol increases the sensitivity of ventral tegmental area dopamine neurons to dopamine and ethanol.

PubMed

Vandegrift, Bertha J; You, Chang; Satta, Rosalba; Brodie, Mark S; Lasek, Amy W

2017-01-01

Gender differences in psychiatric disorders such as addiction may be modulated by the steroid hormone estrogen. For instance, 17β-estradiol (E2), the predominant form of circulating estrogen in pre-menopausal females, increases ethanol consumption, suggesting that E2 may affect the rewarding properties of ethanol and thus the development of alcohol use disorder in females. The ventral tegmental area (VTA) is critically involved in the rewarding and reinforcing effects of ethanol. In order to determine the role of E2 in VTA physiology, gonadally intact female mice were sacrificed during diestrus II (high E2) or estrus (low E2) for electrophysiology recordings. We measured the excitation by ethanol and inhibition by dopamine (DA) of VTA DA neurons and found that both excitation by ethanol and inhibition by dopamine were greater in diestrus II compared with estrus. Treatment of VTA slices from mice in diestrus II with an estrogen receptor antagonist (ICI 182,780) reduced ethanol-stimulated neuronal firing, but had no effect on ethanol-stimulated firing of neurons in slices from mice in estrus. Surprisingly, ICI 182,780 did not affect the inhibition by DA, indicating different mechanisms of action of estrogen receptors in altering ethanol and DA responses. We also examined the responses of VTA DA neurons to ethanol and DA in ovariectomized mice treated with E2 and found that E2 treatment enhanced the responses to ethanol and DA in a manner similar to what we observed in mice in diestrus II. Our data indicate that E2 modulates VTA neuron physiology, which may contribute to both the enhanced reinforcing and rewarding effects of alcohol and the development of other psychiatric disorders in females that involve alterations in DA neurotransmission.

Hypothesizing That Neuropharmacological and Neuroimaging Studies of Glutaminergic-Dopaminergic Optimization Complex (KB220Z) Are Associated With “Dopamine Homeostasis” in Reward Deficiency Syndrome (RDS)

PubMed Central

Blum, Kenneth; Febo, Marcelo; Fried, Lyle; Li, Mona; Dushaj, Kristina; Braverman, Eric R.; McLaughlin, Thomas; Steinberg, Bruce; Badgaiyan, Rajendra D.

2017-01-01

Background There is need for better treatments of addictive behaviors, both substance and non-substance related, termed “Reward Deficiency Syndrome” (RDS). While the FDA has approved pharmaceuticals under the umbrella term Medication Assisted Treatment (MAT), these drugs are not optimal. Objectives It is our contention that these drugs work well in the short-term by blocking dopamine function leading to psychological extinction. However, use of buprenorphine/Naloxone over a long period of time results in unwanted addiction liability, reduced emotional affect, and mood changes including suicidal ideation. Methods We are thus proposing a paradigm shift in addiction treatment, with the long-term goal of achieving “Dopamine Homeostasis.” While this may be a laudable goal, it is very difficult to achieve. Nevertheless, this commentary briefly reviews past history of developing and subsequently, utilizing a glutaminergic-dopaminergic optimization complex [Kb220Z] shown to be beneficial in at least 20 human clinical trials and in a number of published and unpublished studies. Results It is our opinion that, while additional required studies could confirm these findings to date, the cited studies are indicative of achieving enhanced resting state functional connectivity, connectivity volume, and possibly, neuroplasticity. Conclusions/Importance We are proposing a Reward Deficiency Solution System (RDSS) that includes: Genetic Addiction Risk Score (GARS); Comprehensive Analysis of Reported Drugs (CARD); and a glutaminergic-dopaminergic optimization complex (Kb220Z). Continued investigation of this novel strategy may lead to a better-targeted approach in the long-term, causing dopamine regulation by balancing the glutaminergic-dopaminergic pathways. This may potentially change the landscape of treating all addictions leading us to the promised land. PMID:28033474

Estradiol increases the sensitivity of ventral tegmental area dopamine neurons to dopamine and ethanol

PubMed Central

Vandegrift, Bertha J.; You, Chang; Satta, Rosalba; Brodie, Mark S.

2017-01-01

Gender differences in psychiatric disorders such as addiction may be modulated by the steroid hormone estrogen. For instance, 17β-estradiol (E2), the predominant form of circulating estrogen in pre-menopausal females, increases ethanol consumption, suggesting that E2 may affect the rewarding properties of ethanol and thus the development of alcohol use disorder in females. The ventral tegmental area (VTA) is critically involved in the rewarding and reinforcing effects of ethanol. In order to determine the role of E2 in VTA physiology, gonadally intact female mice were sacrificed during diestrus II (high E2) or estrus (low E2) for electrophysiology recordings. We measured the excitation by ethanol and inhibition by dopamine (DA) of VTA DA neurons and found that both excitation by ethanol and inhibition by dopamine were greater in diestrus II compared with estrus. Treatment of VTA slices from mice in diestrus II with an estrogen receptor antagonist (ICI 182,780) reduced ethanol-stimulated neuronal firing, but had no effect on ethanol-stimulated firing of neurons in slices from mice in estrus. Surprisingly, ICI 182,780 did not affect the inhibition by DA, indicating different mechanisms of action of estrogen receptors in altering ethanol and DA responses. We also examined the responses of VTA DA neurons to ethanol and DA in ovariectomized mice treated with E2 and found that E2 treatment enhanced the responses to ethanol and DA in a manner similar to what we observed in mice in diestrus II. Our data indicate that E2 modulates VTA neuron physiology, which may contribute to both the enhanced reinforcing and rewarding effects of alcohol and the development of other psychiatric disorders in females that involve alterations in DA neurotransmission. PMID:29107956

Dual roles of dopamine in food- and drug-seeking: the drive-reward paradox

PubMed Central

Wise, Roy A.

2012-01-01

The question of whether (or to what degree) obesity reflects addiction to high energy foods often narrows to the question of whether the overeating of these foods causes the same long-term neuroadaptations as are identified with the late stages of addiction. Of equal or perhaps greater interest is the question of whether common brain mechanisms mediate the acquisition and development of eating and drug-taking habits. The earliest evidence on this question is rooted in early studies of brain stimulation reward. Lateral hypothalamic electrical stimulation can be reinforcing in some conditions and can motivate feeding in others. That stimulation of the same brain region should be both reinforcing and drive-inducing is paradoxical; why should an animal work to induce a drive-like state such as hunger? This is known as the “drive-reward paradox.” Insights into the substrates of the drive-reward paradox suggest an answer to the controversial question of whether the dopamine system—a system “downstream” from the stimulated fibers of the lateral hypothalamus—is more critically involved in “wanting” or in “liking” of various rewards including food and addictive drugs. That the same brain circuitry is implicated in the motivation for and the reinforcement by both food and addictive drugs extends the argument for a common mechanism underlying compulsive overeating and compulsive drug-taking. PMID:23044182

The 5-HT1A/1B-receptor agonist eltoprazine increases both catecholamine release in the prefrontal cortex and dopamine release in the nucleus accumbens and decreases motivation for reward and "waiting" impulsivity, but increases "stopping" impulsivity.

PubMed

Korte, S Mechiel; Prins, Jolanda; Van den Bergh, Filip S; Oosting, Ronald S; Dupree, Rudy; Korte-Bouws, Gerdien A H; Westphal, Koen G C; Olivier, Berend; Denys, Damiaan A; Garland, Alexis; Güntürkün, Onur

2017-01-05

The 5-HT 1A/1B -receptor agonist eltoprazine has a behavioral drug signature that resembles that of a variety of psychostimulant drugs, despite the differences in receptor binding profile. These psychostimulants are effective in treating impulsivity disorders, most likely because they increase norepinephrine (NE) and dopamine (DA) levels in the prefrontal cortex. Both amphetamine and methylphenidate, however, also increase dopamine levels in the nucleus accumbens (NAc), which has a significant role in motivation, pleasure, and reward. How eltoprazine affects monoamine release in the medial prefrontal cortex (mPFC), the orbitofrontal cortex (OFC), and the NAc is unknown. It is also unknown whether eltoprazine affects different forms of impulsivity and brain reward mechanisms. Therefore, in the present study, we investigate the effects of eltoprazine in rats in the following sequence: 1) the activity of the monoaminergic systems using in vivo microdialysis, 2) motivation for reward measured using the intracranial self-stimulation (ICSS) procedure, and finally, 3) "waiting" impulsivity in the delay-aversion task, and the "stopping" impulsivity in the stop-signal task. The microdialysis studies clearly showed that eltoprazine increased DA and NE release in both the mPFC and OFC, but only increased DA concentration in the NAc. In contrast, eltoprazine decreased 5-HT release in the mPFC and NAc (undetectable in the OFC). Remarkably, eltoprazine decreased impulsive choice, but increased impulsive action. Furthermore, brain stimulation was less rewarding following eltoprazine treatment. These results further support the long-standing hypothesis that "waiting" and "stopping" impulsivity are regulated by distinct neural circuits, because 5-HT 1A/1B -receptor activation decreases impulsive choice, but increases impulsive action. Copyright © 2016 Elsevier B.V. All rights reserved.

A translational systems biology approach in both animals and humans identifies a functionally related module of accumbal genes involved in the regulation of reward processing and binge drinking in males.

PubMed

Stacey, David; Lourdusamy, Anbarasu; Ruggeri, Barbara; Maroteaux, Matthieu; Jia, Tianye; Cattrell, Anna; Nymberg, Charlotte; Banaschewski, Tobias; Bhattacharyya, Sohinee; Band, Hamid; Barker, Gareth; Bokde, Arun; Buchel, Christian; Carvalho, Fabiana; Conrod, Patricia; Desrivieres, Sylvane; Easton, Alanna; Fauth-Buehler, Mira; Fernandez-Medarde, Alberto; Flor, Herta; Frouin, Vincent; Gallinat, Jurgen; Garavanh, Hugh; Heinz, Andreas; Ittermann, Bernd; Lathrop, Mark; Lawrence, Claire; Loth, Eva; Mann, Karl; Martinot, Jean-Luc; Nees, Frauke; Paus, Tomas; Pausova, Zdenka; Rietschel, Marcella; Rotter, Andrea; Santos, Eugenio; Smolka, Michael; Sommer, Wolfgang; Mameli, Manuel; Spanagel, Rainer; Girault, Jean-Antoine; Mueller, Christian; Schumann, Gunter

2016-04-01

The mesolimbic dopamine system, composed primarily of dopaminergic neurons in the ventral tegmental area that project to striatal structures, is considered to be the key mediator of reinforcement-related mechanisms in the brain. Prompted by a genome-wide association meta-analysis implicating the Ras-specific guanine nucleotide-releasing factor 2 (RASGRF2) gene in the regulation of alcohol intake in men, we have recently shown that male Rasgrf2(-/-) mice exhibit reduced ethanol intake and preference accompanied by a perturbed mesolimbic dopamine system. We therefore propose that these mice represent a valid model to further elucidate the precise genes and mechanisms regulating mesolimbic dopamine functioning. Transcriptomic data from the nucleus accumbens (NAcc) of male Rasgrf2(-/-) mice and wild-type controls were analyzed by weighted gene coexpression network analysis (WGCNA). We performed follow-up genetic association tests in humans using a sample of male adolescents from the IMAGEN study characterized for binge drinking (n = 905) and ventral striatal activation during an fMRI reward task (n = 608). The WGCNA analyses using accumbal transcriptomic data revealed 37 distinct "modules," or functionally related groups of genes. Two of these modules were significantly associated with Rasgrf2 knockout status: M5 (p < 0.001) and M6 (p < 0.001). In follow-up translational analyses we found that human orthologues for the M5 module were significantly (p < 0.01) enriched with genetic association signals for binge drinking in male adolescents. Furthermore, the most significant locus, originating from the EH-domain containing 4 (EHD4) gene (p < 0.001), was also significantly associated with altered ventral striatal activity in male adolescents performing an fMRI reward task (pempirical < 0.001). It was not possible to determine the extent to which the M5 module was dysregulated in Rasgrf2(-/-) mice by perturbed mesolimbic dopamine signalling or by the loss of Rasgrf2 function in the NAcc. Taken together, our findings indicate that the accumbal M5 module, initially identified as being dysregulated in male Rasgrf2(-/-) mice, is also relevant for human alcohol-related phenotypes potentially through the modulation of reinforcement mechanisms in the NAcc. We therefore propose that the genes comprising this module represent important candidates for further elucidation within the context of alcohol-related phenotypes.

Running on Empty: Leptin Signaling in VTA Regulates Reward from Physical Activity.

PubMed

Chen, Zuxin; Kenny, Paul J

2015-10-06

Hunger increases physical activity and stamina to support food-directed foraging behaviors, but underlying mechanisms are unclear. In this issue, Fernandes et al. (2015) show that disruption of leptin-regulated STAT3 signaling in midbrain dopamine neurons increases the rewarding effects of running in mice, which could explain the "high" experienced by endurance runners. Copyright © 2015 Elsevier Inc. All rights reserved.

Appetitive Cue-Evoked ERK Signaling in the Nucleus Accumbens Requires NMDA and D1 Dopamine Receptor Activation and Regulates CREB Phosphorylation

ERIC Educational Resources Information Center

Kirschmann, Erin K. Z.; Mauna, Jocelyn C.; Willis, Cory M.; Foster, Rebecca L.; Chipman, Amanda M.; Thiels, Edda

2014-01-01

Conditioned stimuli (CS) can modulate reward-seeking behavior. This modulatory effect can be maladaptive and has been implicated in excessive reward seeking and relapse to drug addiction. We previously demonstrated that exposure to an appetitive CS causes an increase in the activation of extracellular signal-regulated kinase (ERK) and cyclic-AMP…

Nicotine-induced Conditional Place Preference is Affected by Head Injury: Correlation with Dopamine Release in the Nucleus Accumbens Shell.

PubMed

Yuan-Hao, Chen; Kuo, Tung-Tai; Huang, Eagle Yi-Kung; Hoffer, Barry J; Kao, Jen-Hsin; Chou, Yu-Ching; Chiang, Yung-Hsiao; Miller, Jonathan

2018-06-14

Traumatic brain injury (TBI) is known to impact dopamine-mediated reward pathways, but the underlying mechanisms have not been fully established. Nicotine-induced conditional place preference (CPP) was used to study rats exposed to a 6-psi fluid percussion injury (FPI) with and without prior exposure to nicotine. Preference was quantified as a score defined as (C1-C2) / (C1+C2), where C1 is time in the nicotine-paired compartment and C2 is time in the saline-paired compartment. Subsequent fast-scan cyclic voltammetry (FSCV) was used to analyze the impact of nicotine infusion on dopamine release in the shell portion of the nucleus accumbens (NAc). To further determine the influence of brain injury on nicotine withdrawal, nicotine infusion was administered to the rats after FPI. The effects of FPI on CPP after prior exposure to nicotine and abstinence or withdrawal from nicotine were also assessed. After TBI, dopamine release was reduced in the NAc shell, and nicotine-induced CPP preference was significantly impaired. Preference scores of control, sham-injured, and FPI groups were 0.1627 ± 0.04204, 0.1515 ± 0.03806, and -0.001300 ± 0.04286, respectively. Nicotine-induced CPP was also seen in animals after nicotine pre-treatment, with a CPP score of 0.07805 ± 0.02838. Nicotine pre-exposure substantially increased tonic dopamine release in sham-injured animals, but it did not change phasic release; nicotine exposure after FPI enhanced phasic release, though not to the same levels seen in sham-injured rats. Conditioned preference was related not only to phasic dopamine release (r= 0.8110) but also to the difference between tonic and phasic dopamine levels (r= 0.9521). TBI suppresses dopamine release from the shell portion of the NAc, which in turn significantly alters reward-seeking behavior. These results have important implications for tobacco and drug use after TBI.

Implications for glycine receptors and astrocytes in ethanol-induced elevation of dopamine levels in the nucleus accumbens.

PubMed

Adermark, Louise; Clarke, Rhona B C; Olsson, Torsten; Hansson, Elisabeth; Söderpalm, Bo; Ericson, Mia

2011-01-01

Elevated dopamine levels are believed to contribute to the rewarding sensation of ethanol (EtOH), and previous research has shown that strychnine-sensitive glycine receptors in the nucleus accumbens (nAc) are involved in regulating dopamine release and in mediating the reinforcing effects of EtOH. Furthermore, the osmoregulator taurine, which is released from astrocytes treated with EtOH, can act as an endogenous ligand for the glycine receptor, and increase extracellular dopamine levels. The aim of this study was to address if EtOH-induced swelling of astrocytes could contribute to elevated dopamine levels by increasing the extracellular concentration of taurine. Cell swelling was estimated by optical sectioning of fluorescently labeled astrocytes in primary cultures from rat, and showed that EtOH (25-150 mM) increased astrocyte cell volumes in a concentration- and ion-dependent manner. The EtOH-induced cell swelling was inhibited in cultures treated with the Na(+) /K(+) /2Cl⁻ cotransporter blocker furosemide (1 mM), Na(+) /K(+) -ATPase inhibitor ouabain (0.1 mM), potassium channel inhibitor BaCl₂ (50 µM) and in cultures containing low extracellular sodium concentration (3 mM). In vivo microdialysis performed in the nAc of awake and freely moving rats showed that local treatment with EtOH enhanced the concentrations of dopamine and taurine in the microdialysate, while glycine and β-alanine levels were not significantly modulated. EtOH-induced dopamine release was antagonized by local treatment with the glycine receptor antagonist strychnine (20 µM) or furosemide (100 µM or 1 mM). Furosemide also prevented EtOH-induced taurine release in the nAc. In conclusion, our data suggest that extracellular concentrations of dopamine and taurine are interconnected and that swelling of astrocytes contributes to the acute rewarding sensation of EtOH. © 2010 The Authors, Addiction Biology © 2010 Society for the Study of Addiction.

A functional neuroimaging study assessing gender differences in the neural mechanisms underlying the ability to resist impulsive desires.

PubMed

Diekhof, Esther K; Keil, Maria; Obst, Katrin U; Henseler, Ilona; Dechent, Peter; Falkai, Peter; Gruber, Oliver

2012-09-14

There is ample evidence of gender differences in neural processes and behavior. Differences in reward-related behaviors have been linked to either temporary or permanent organizational influences of gonadal hormones on the mesolimbic dopamine system and reward-related activation. Still, little is known about the association between biological gender and the neural underpinnings of the ability to resist reward-related impulses. Here we assessed with functional magnetic resonance imaging which neural processes enable men and women to successfully control their desire for immediate reward when this is required by a higher-order goal (i.e., during a 'desire-reason dilemma'; Diekhof and Gruber, 2010). Thirty-two participants (16 females) were closely matched for age, personality characteristics (e.g., novelty seeking) and behavioral performance in the 'desire-reason task'. On the neural level, men and women showed similarities in the general response of the nucleus accumbens and of the ventral tegmental area to predictors of immediate reward, but they differed in additional brain mechanisms that enabled self-controlled decisions against the preference for immediate reward. Firstly, men exhibited a stronger reduction of activation in the ventral pallidum, putamen, temporal pole and pregenual anterior cingulate cortex during the 'desire-reason dilemma'. Secondly, connectivity analyses revealed a significant change in the direction of the connectivity between anteroventral prefrontal cortex and nucleus accumbens during decisions counteracting the reward-related impulse when comparing men and women. Together, these findings support the view of a sexual dimorphism that manifested in the recruitment of gender-specific neural resources during the successful deployment of self-control. Copyright © 2012 Elsevier B.V. All rights reserved.

Dopaminergic control of cognitive flexibility in humans and animals

PubMed Central

Klanker, Marianne; Feenstra, Matthijs; Denys, Damiaan

2013-01-01

Striatal dopamine (DA) is thought to code for learned associations between cues and reinforcers and to mediate approach behavior toward a reward. Less is known about the contribution of DA to cognitive flexibility—the ability to adapt behavior in response to changes in the environment. Altered reward processing and impairments in cognitive flexibility are observed in psychiatric disorders such as obsessive compulsive disorder (OCD). Patients with this disorder show a disruption of functioning in the frontostriatal circuit and alterations in DA signaling. In this review we summarize findings from animal and human studies that have investigated the involvement of striatal DA in cognitive flexibility. These findings may provide a better understanding of the role of dopaminergic dysfunction in cognitive inflexibility in psychiatric disorders, such as OCD. PMID:24204329

Application of fast-scan cyclic voltammetry for the in vivo characterization of optically evoked dopamine in the olfactory tubercle of the rat brain.

PubMed

Wakabayashi, Ken T; Bruno, Michael J; Bass, Caroline E; Park, Jinwoo

2016-06-21

The olfactory tubercle (OT), as a component of the ventral striatum, serves as an important multisensory integration center for reward-related processes in the brain. Recent studies show that dense dopaminergic innervation from the ventral tegmental area (VTA) into the OT may play an outsized role in disorders such as psychostimulant addiction and disorders of motivation, increasing recent scientific interest in this brain region. However, due to its anatomical inaccessibility, relative small size, and proximity to other dopamine-rich structures, neurochemical assessments using conventional methods cannot be readily employed. Here, we investigated dopamine (DA) regulation in the OT of urethane-anesthetized rats using in vivo fast-scan voltammetry (FSCV) coupled with carbon-fiber microelectrodes, following optogenetic stimulation of the VTA. The results were compared with DA regulation in the nucleus accumbens (NAc), a structure located adjacent to the OT and which also receives dense DA innervation from the VTA. FSCV coupled with optically evoked release allowed us to investigate the spatial distribution of DA in the OT and characterize OT DA dynamics (release and clearance) with subsecond temporal and micrometer spatial resolution for the first time. In this study, we demonstrated that DA transporters play an important role in regulating DA in the OT. However, the control of extracellular DA by uptake in the OT was less than in the NAc. The difference in DA transmission in the terminal fields of the OT and NAc may be involved in region-specific responses to drugs of abuse and contrasting roles in mediating reward-related behavior.

The dopamine hypothesis of bipolar affective disorder: the state of the art and implications for treatment

PubMed Central

Ashok, A H; Marques, T R; Jauhar, S; Nour, M M; Goodwin, G M; Young, A H; Howes, O D

2017-01-01

Bipolar affective disorder is a common neuropsychiatric disorder. Although its neurobiological underpinnings are incompletely understood, the dopamine hypothesis has been a key theory of the pathophysiology of both manic and depressive phases of the illness for over four decades. The increased use of antidopaminergics in the treatment of this disorder and new in vivo neuroimaging and post-mortem studies makes it timely to review this theory. To do this, we conducted a systematic search for post-mortem, pharmacological, functional magnetic resonance and molecular imaging studies of dopamine function in bipolar disorder. Converging findings from pharmacological and imaging studies support the hypothesis that a state of hyperdopaminergia, specifically elevations in D2/3 receptor availability and a hyperactive reward processing network, underlies mania. In bipolar depression imaging studies show increased dopamine transporter levels, but changes in other aspects of dopaminergic function are inconsistent. Puzzlingly, pharmacological evidence shows that both dopamine agonists and antidopaminergics can improve bipolar depressive symptoms and perhaps actions at other receptors may reconcile these findings. Tentatively, this evidence suggests a model where an elevation in striatal D2/3 receptor availability would lead to increased dopaminergic neurotransmission and mania, whilst increased striatal dopamine transporter (DAT) levels would lead to reduced dopaminergic function and depression. Thus, it can be speculated that a failure of dopamine receptor and transporter homoeostasis might underlie the pathophysiology of this disorder. The limitations of this model include its reliance on pharmacological evidence, as these studies could potentially affect other monoamines, and the scarcity of imaging evidence on dopaminergic function. This model, if confirmed, has implications for developing new treatment strategies such as reducing the dopamine synthesis and/or release in mania and DAT blockade in bipolar depression. PMID:28289283

Increased dopamine receptor expression and anti-depressant response following deep brain stimulation of the medial forebrain bundle.

PubMed

Dandekar, Manoj P; Luse, Dustin; Hoffmann, Carson; Cotton, Patrick; Peery, Travis; Ruiz, Christian; Hussey, Caroline; Giridharan, Vijayasree V; Soares, Jair C; Quevedo, Joao; Fenoy, Albert J

2017-08-01

Among several potential neuroanatomical targets pursued for deep brain stimulation (DBS) for treating those with treatment-resistant depression (TRD), the superolateral-branch of the medial forebrain bundle (MFB) is emerging as a privileged location. We investigated the antidepressant-like phenotypic and chemical changes associated with reward-processing dopaminergic systems in rat brains after MFB-DBS. Male Wistar rats were divided into three groups: sham-operated, DBS-Off, and DBS-On. For DBS, a concentric bipolar electrode was stereotactically implanted into the right MFB. Exploratory activity and depression-like behavior were evaluated using the open-field and forced-swimming test (FST), respectively. MFB-DBS effects on the dopaminergic system were evaluated using immunoblotting for tyrosine hydroxylase (TH), dopamine transporter (DAT), and dopamine receptors (D1-D5), and high-performance liquid chromatography for quantifying dopamine, 3,4-dihydroxyphenylacetic acid (DOPAC), and homovanillic acid (HVA) in brain homogenates of prefrontal cortex (PFC), hippocampus, amygdala, and nucleus accumbens (NAc). Animals receiving MFB-DBS showed a significant increase in swimming time without alterations in locomotor activity, relative to the DBS-Off (p<0.039) and sham-operated groups (p<0.014), indicating an antidepressant-like response. MFB-DBS led to a striking increase in protein levels of dopamine D2 receptors and DAT in the PFC and hippocampus, respectively. However, we did not observe appreciable differences in the expression of other dopamine receptors, TH, or in the concentrations of dopamine, DOPAC, and HVA in PFC, hippocampus, amygdala, and NAc. This study was not performed on an animal model of TRD. MFB-DBS rescues the depression-like phenotypes and selectively activates expression of dopamine receptors in brain regions distant from the target area of stimulation. Copyright © 2017. Published by Elsevier B.V.

Opioid activation of Toll-Like receptor 4 contributes to drug reinforcement

PubMed Central

Hutchinson, M.R.; Northcutt, A.L.; Hiranita, T.; Wang, X.; Lewis, S.; Thomas, J.; van Steeg, K.; Kopajtic, T.A.; Loram, L.; Sfregola, C.; Galer, E.; Miles, N.E.; Bland, S.T.; Amat, J.; Rozeske, R.R.; Maslanik, T.; Chapman, T.; Strand, K.; Fleshner, M.; Bachtell, R.K.; Somogyi, A.A.; Yin, H.; Katz, J.L.; Rice, K.C.; Maier, S.F.; Watkins, L.R.

2012-01-01

Opioid action was thought to exert reinforcing effects solely via the initial agonism of opioid receptors. Here we present evidence for an additional novel contributor to opioid reward: the innate immune pattern-recognition receptor, Toll-like receptor 4 (TLR4), and its MyD88-dependent signaling. Blockade of TLR4/MD2 by administration of the non-opioid, unnatural isomer of naloxone, (+)-naloxone (rats), or two independent genetic knockouts of MyD88-TLR4-dependent signaling (mice), suppressed opioid-induced conditioned place preference. (+)-Naloxone also reduced opioid (remifentanil) self-administration (rats), another commonly used behavioral measure of drug reward. Moreover, pharmacological blockade of morphine-TLR4/MD2 activity potently reduced morphine-induced elevations of extracellular dopamine in rat nucleus accumbens, a region critical for opioid reinforcement. Importantly, opioid-TLR4 actions are not a unidirectional influence on opioid pharmacodynamics, since TLR4 −/− mice had reduced oxycodone-induced p38 and JNK phosphorylation, whilst displaying potentiated analgesia. Similar to our recent reports of morphine-TLR4/MD2 binding, here we provide a combination of in silico and biophysical data to support (+)-naloxone and remifentanil binding to TLR4/MD2. Collectively, these data indicate that the actions of opioids at classical opioid receptors, together with their newly identified TLR4/MD2 actions, affect the mesolimbic dopamine system which amplifies opioid-induced elevations in extracellular dopamine levels and therefore possibly explaining altered opioid reward behaviors. Thus, the discovery of TLR4/MD2 recognition of opioids as foreign xenobiotic substances adds to the existing hypothesized neuronal reinforcement mechanisms, identifies a new drug target in TLR4/MD2 for the treatment of addictions, and provides further evidence supporting a role for central proinflammatory immune signaling in drug reward. PMID:22895704

Basal ganglia circuit loops, dopamine and motivation: A review and enquiry

PubMed Central

Ikemoto, Satoshi; Yang, Chen; Tan, Aaron

2015-01-01

Dopamine neurons located in the midbrain play a role in motivation that regulates approach behavior (approach motivation). In addition, activation and inactivation of dopamine neurons regulate mood and induce reward and aversion, respectively. Accumulating evidence suggests that such motivational role of dopamine neurons is not limited to those located in the ventral tegmental area, but also in the substantia nigra. The present paper reviews previous rodent work concerning dopamine’s role in approach motivation and the connectivity of dopamine neurons, and proposes two working models: One concerns the relationship between extracellular dopamine concentration and approach motivation. High, moderate and low concentrations of extracellular dopamine induce euphoric, seeking and aversive states, respectively. The other concerns circuit loops involving the cerebral cortex, basal ganglia, thalamus, epithalamus, and midbrain through which dopaminergic activity alters approach motivation. These models should help to generate hypothesis-driven research and provide insights for understanding altered states associated with drugs of abuse and affective disorders. PMID:25907747

Phasic Stimulation of Midbrain Dopamine Neuron Activity Reduces Salt Consumption

PubMed Central

Sandhu, Eleanor C.; Fernando, Anushka B. P.; Tossell, Kyoko; Kokkinou, Michelle; Glegola, Justyna; Howes, Oliver D.

2018-01-01

Abstract Salt intake is an essential dietary requirement, but excessive consumption is implicated in hypertension and associated conditions. Little is known about the neural circuit mechanisms that control motivation to consume salt, although the midbrain dopamine system, which plays a key role in other reward-related behaviors, has been implicated. We, therefore, examined the effects on salt consumption of either optogenetic excitation or chemogenetic inhibition of ventral tegmental area (VTA) dopamine neurons in male mice. Strikingly, optogenetic excitation of dopamine neurons decreased salt intake in a rapid and reversible manner, despite a strong salt appetite. Importantly, optogenetic excitation was not aversive, did not induce hyperactivity, and did not alter salt concentration preferences in a need-free state. In addition, we found that chemogenetic inhibition of dopamine neurons had no effect on salt intake. Lastly, optogenetic excitation of dopamine neurons reduced consumption of sucrose following an overnight fast, suggesting a more general role of VTA dopamine neuron excitation in organizing motivated behaviors. PMID:29766048

Estradiol, dopamine and motivation.

PubMed

Yoest, Katie E; Cummings, Jennifer A; Becker, Jill B

2014-01-01

The gonadal hormone estradiol modulates mesolimbic dopamine systems in the female rat. This modulatory effect is thought to be responsible for the observed effects of estradiol on motivated behaviors. Dopamine acting in the nucleus accumbens is thought to be important for the attribution of incentive motivational properties to cues that predict reward delivery, while dopamine in the striatum is associated with the expression of repetitive or stereotyped behaviors. Elevated concentrations of estradiol are associated with increased motivation for sex or cues associated with access to a mate, while simultaneously attenuating motivation for food. This shift in motivational salience is important for adaptive choice behavior in the natural environment. Additionally, estradiol's adaptive effects on motivation can be maladaptive when increasing motivation for non-natural reinforcers, such as drugs of abuse. Here we discuss the effect of estradiol on mesotelencephalic dopamine transmission and subsequent effects on motivated behaviors.

Effect of yohimbine on reinstatement of operant responding in rats is dependent on cue contingency but not food reward history.

PubMed

Chen, Yu-Wei; Fiscella, Kimberly A; Bacharach, Samuel Z; Tanda, Gianluigi; Shaham, Yavin; Calu, Donna J

2015-07-01

Yohimbine is an alpha-2 adrenoceptor antagonist that has been used in numerous studies as a pharmacological stressor in rodents, monkeys and humans. Recently, yohimbine has become the most common stress manipulation in studies on reinstatement of drug and food seeking. However, the wide range of conditions under which yohimbine promotes reward seeking is significantly greater than that of stressors like intermittent footshock. Here, we addressed two fundamental questions regarding yohimbine's effect on reinstatement of reward seeking: (1) whether the drug's effect on operant responding is dependent on previous reward history or cue contingency, and (2) whether yohimbine is aversive or rewarding under conditions typically used in reinstatement studies. We also used in vivo microdialysis to determine yohimbine's effect on dopamine levels in nucleus accumbens (NAc) and medial prefrontal cortex (mPFC). We found that the magnitude of yohimbine-induced (0.5, 1.0, 2.0 mg/kg) operant responding during the reinstatement tests was critically dependent on the contingency between lever pressing and discrete tone-light cue delivery but not the previous history with food reward during training. We also found that yohimbine (2 mg/kg) did not cause conditioned place aversion. Finally, we found that yohimbine modestly increased dopamine levels in mPFC but not NAc. Results suggest that yohimbine's effects on operant responding in reinstatement studies are likely independent of the history of contingent self-administration of food or drug rewards and may not be related to the commonly assumed stress-like effects of yohimbine. Published 2014. This article is a U.S. Government work and is in the public domain in the USA.

Diet-Induced Obesity and Diet-Resistant rats: differences in the rewarding and anorectic effects of D-amphetamine

PubMed Central

Valenza, Marta; Steardo, Luca; Cottone, Pietro; Sabino, Valentina

2015-01-01

Rationale Obesity is a leading public health problem worldwide. Multiple lines of evidence associate deficits in the brain reward circuit with obesity. Objective Whether alterations in brain reward sensitivity precede or are a consequence of obesity is unknown. This study aimed to investigate both innate and obesity-induced differences in the sensitivity to the effects of an indirect dopaminergic agonist. Methods Rats genetically prone to diet-induced obesity (DIO) and their counterpart diet-resistant (DR) were fed a chow diet and their response to D-amphetamine on intracranial self-stimulation and food intake were assessed. The same variables were then evaluated after exposing the rats to a high-fat diet, after DIO rats selectively developed obesity. Finally, gene expression levels of dopamine receptor 1 and 2 as well as tyrosine hydroxylase were measured in reward-related brain regions. Results In a pre-obesity state, DIO rats showed innate decreased sensitivity to the reward-enhancing and anorectic effects of D-amphetamine, as compared to DR rats. In a diet-induced obese state, the insensitivity to the potentiating effects of D-amphetamine on ICSS threshold persisted and became more marked in DIO rats, while the anorectic effects were comparable between genotypes. Finally, innate and obesity-induced differences in the gene expression of dopamine receptors were observed. Conclusions Our results demonstrate that brain reward deficits antedate the development of obesity and worsen after obesity is fully developed, suggesting that these alterations represent vulnerability factors for its development. Moreover, our data suggests that the reward-enhancing and anorectic effects of D-amphetamine are dissociable in the context of obesity. PMID:26047964

Effect of Levodopa on Reward and Impulsivity in a Rat Model of Parkinson’s Disease

PubMed Central

Carvalho, Miguel M.; Campos, Filipa L.; Marques, Mariana; Soares-Cunha, Carina; Kokras, Nikolaos; Dalla, Christina; Leite-Almeida, Hugo; Sousa, Nuno; Salgado, António J.

2017-01-01

The use of dopamine replacement therapies (DRT) in the treatment of Parkinson’s disease (PD) can lead to the development of dopamine dysregulation syndrome (DDS) and impulse control disorders (ICD), behavioral disturbances characterized by compulsive DRT self-medication and development of impulsive behaviors. However, the mechanisms behind these disturbances are poorly understood. In animal models of PD, the assessment of the rewarding properties of levodopa (LD), one of the most common drugs used in PD, has produced conflicting results, and its ability to promote increased impulsivity is still understudied. Moreover, it is unclear whether acute and chronic LD therapy differently affects reward and impulsivity. In this study we aimed at assessing, in an animal model of PD with bilateral mesostriatal and mesocorticolimbic degeneration, the behavioral effects of LD therapy regarding reward and impulsivity. Animals with either sham or 6-hydroxydopamine (6-OHDA)-induced bilateral lesions in the substantia nigra pars compacta (SNc) and ventral tegmental area (VTA) were exposed to acute and chronic LD treatment. We used the conditioned place preference (CPP) paradigm to evaluate the rewarding effects of LD, whereas impulsive behavior was measured with the variable delay-to-signal (VDS) task. Correlation analyses between behavioral measurements of reward or impulsivity and lesion extent in SNc/VTA were performed to pinpoint possible anatomical links of LD-induced behavioral changes. We show that LD, particularly when administered chronically, caused the development of impulsive-like behaviors in 6-OHDA-lesioned animals in the VDS. However, neither acute or chronic LD administration had rewarding effects in 6-OHDA-lesioned animals in the CPP. Our results show that in a bilateral rat model of PD, LD leads to the development of impulsive behaviors, strengthening the association between DRT and DDS/ICD in PD. PMID:28848409

Activation of VTA GABA neurons disrupts reward consumption

PubMed Central

van Zessen, Ruud; Phillips, Jana L.; Budygin, Evgeny A.; Stuber, Garret D.

2012-01-01

The activity of Ventral Tegmental Area (VTA) dopamine (DA) neurons promotes behavioral responses to rewards and environmental stimuli that predict them. VTA GABA inputs synapse directly onto DA neurons and may regulate DA neuronal activity to alter reward-related behaviors, however, the functional consequences of selective activation of VTA GABA neurons remains unknown. Here, we show that in vivo optogenetic activation of VTA GABA neurons disrupts reward consummatory behavior, but not conditioned anticipatory behavior in response to reward-predictive cues. In addition, direct activation of VTA GABA projections to the nucleus accumbens (NAc) resulted in detectable GABA release, but did not alter reward consumption. Furthermore, optogenetic stimulation of VTA GABA neurons directly suppressed the activity and excitability of neighboring DA neurons, as well as the release of DA in the NAc, suggesting that the dynamic interplay between VTA DA and GABA neurons can control the initiation and termination of reward-related behaviors. PMID:22445345

Hemispheric Asymmetries in Striatal Reward Responses Relate to Approach-Avoidance Learning and Encoding of Positive-Negative Prediction Errors in Dopaminergic Midbrain Regions.

PubMed

Aberg, Kristoffer Carl; Doell, Kimberly C; Schwartz, Sophie

2015-10-28

Some individuals are better at learning about rewarding situations, whereas others are inclined to avoid punishments (i.e., enhanced approach or avoidance learning, respectively). In reinforcement learning, action values are increased when outcomes are better than predicted (positive prediction errors [PEs]) and decreased for worse than predicted outcomes (negative PEs). Because actions with high and low values are approached and avoided, respectively, individual differences in the neural encoding of PEs may influence the balance between approach-avoidance learning. Recent correlational approaches also indicate that biases in approach-avoidance learning involve hemispheric asymmetries in dopamine function. However, the computational and neural mechanisms underpinning such learning biases remain unknown. Here we assessed hemispheric reward asymmetry in striatal activity in 34 human participants who performed a task involving rewards and punishments. We show that the relative difference in reward response between hemispheres relates to individual biases in approach-avoidance learning. Moreover, using a computational modeling approach, we demonstrate that better encoding of positive (vs negative) PEs in dopaminergic midbrain regions is associated with better approach (vs avoidance) learning, specifically in participants with larger reward responses in the left (vs right) ventral striatum. Thus, individual dispositions or traits may be determined by neural processes acting to constrain learning about specific aspects of the world. Copyright © 2015 the authors 0270-6474/15/3514491-10$15.00/0.

Reward, motivation, and emotion systems associated with early-stage intense romantic love.

PubMed

Aron, Arthur; Fisher, Helen; Mashek, Debra J; Strong, Greg; Li, Haifang; Brown, Lucy L

2005-07-01

Early-stage romantic love can induce euphoria, is a cross-cultural phenomenon, and is possibly a developed form of a mammalian drive to pursue preferred mates. It has an important influence on social behaviors that have reproductive and genetic consequences. To determine which reward and motivation systems may be involved, we used functional magnetic resonance imaging and studied 10 women and 7 men who were intensely "in love" from 1 to 17 mo. Participants alternately viewed a photograph of their beloved and a photograph of a familiar individual, interspersed with a distraction-attention task. Group activation specific to the beloved under the two control conditions occurred in dopamine-rich areas associated with mammalian reward and motivation, namely the right ventral tegmental area and the right postero-dorsal body and medial caudate nucleus. Activation in the left ventral tegmental area was correlated with facial attractiveness scores. Activation in the right anteromedial caudate was correlated with questionnaire scores that quantified intensity of romantic passion. In the left insula-putamen-globus pallidus, activation correlated with trait affect intensity. The results suggest that romantic love uses subcortical reward and motivation systems to focus on a specific individual, that limbic cortical regions process individual emotion factors, and that there is localization heterogeneity for reward functions in the human brain.

The dark side of dopaminergic therapies in Parkinson's disease: shedding light on aberrant salience.

PubMed

Poletti, Michele

2017-03-07

Psychotic subjects and patients with Parkinson's disease (PD) "on" dopaminergic drugs, especially on dopamine agonists, present a hyperdopaminergic state that interferes with learning processing. These clinical populations present with distinct alterations of learning that share an increased potential motivational significance of stimuli: psychotic subjects may attribute salience to neutral stimuli, while medicated PD patients may overvalue rewards. Herein is discussed the speculative hypothesis that the hyperdopaminergic state induced by dopaminergic treatments, especially with dopamine agonists, may also facilitate the attribution of salience to neutral stimuli in PD patients, altering the physiological attribution of salience. Preliminary empirical evidence is in agreement with this speculative hypothesis, which needs further empirical investigation. The clinical implications of this hypothesis are discussed in relation to behavioral addictions, psychosis proneness, and enhanced creativity in medicated PD patients.

Effort-related functions of nucleus accumbens dopamine and associated forebrain circuits.

PubMed

Salamone, J D; Correa, M; Farrar, A; Mingote, S M

2007-04-01

Over the last several years, it has become apparent that there are critical problems with the hypothesis that brain dopamine (DA) systems, particularly in the nucleus accumbens, directly mediate the rewarding or primary motivational characteristics of natural stimuli such as food. Hypotheses related to DA function are undergoing a substantial restructuring, such that the classic emphasis on hedonia and primary reward is giving way to diverse lines of research that focus on aspects of instrumental learning, reward prediction, incentive motivation, and behavioral activation. The present review discusses dopaminergic involvement in behavioral activation and, in particular, emphasizes the effort-related functions of nucleus accumbens DA and associated forebrain circuitry. The effects of accumbens DA depletions on food-seeking behavior are critically dependent upon the work requirements of the task. Lever pressing schedules that have minimal work requirements are largely unaffected by accumbens DA depletions, whereas reinforcement schedules that have high work (e.g., ratio) requirements are substantially impaired by accumbens DA depletions. Moreover, interference with accumbens DA transmission exerts a powerful influence over effort-related decision making. Rats with accumbens DA depletions reallocate their instrumental behavior away from food-reinforced tasks that have high response requirements, and instead, these rats select a less-effortful type of food-seeking behavior. Along with prefrontal cortex and the amygdala, nucleus accumbens is a component of the brain circuitry regulating effort-related functions. Studies of the brain systems regulating effort-based processes may have implications for understanding drug abuse, as well as energy-related disorders such as psychomotor slowing, fatigue, or anergia in depression.

Modelling individual differences in the form of Pavlovian conditioned approach responses: a dual learning systems approach with factored representations.

PubMed

Lesaint, Florian; Sigaud, Olivier; Flagel, Shelly B; Robinson, Terry E; Khamassi, Mehdi

2014-02-01

Reinforcement Learning has greatly influenced models of conditioning, providing powerful explanations of acquired behaviour and underlying physiological observations. However, in recent autoshaping experiments in rats, variation in the form of Pavlovian conditioned responses (CRs) and associated dopamine activity, have questioned the classical hypothesis that phasic dopamine activity corresponds to a reward prediction error-like signal arising from a classical Model-Free system, necessary for Pavlovian conditioning. Over the course of Pavlovian conditioning using food as the unconditioned stimulus (US), some rats (sign-trackers) come to approach and engage the conditioned stimulus (CS) itself - a lever - more and more avidly, whereas other rats (goal-trackers) learn to approach the location of food delivery upon CS presentation. Importantly, although both sign-trackers and goal-trackers learn the CS-US association equally well, only in sign-trackers does phasic dopamine activity show classical reward prediction error-like bursts. Furthermore, neither the acquisition nor the expression of a goal-tracking CR is dopamine-dependent. Here we present a computational model that can account for such individual variations. We show that a combination of a Model-Based system and a revised Model-Free system can account for the development of distinct CRs in rats. Moreover, we show that revising a classical Model-Free system to individually process stimuli by using factored representations can explain why classical dopaminergic patterns may be observed for some rats and not for others depending on the CR they develop. In addition, the model can account for other behavioural and pharmacological results obtained using the same, or similar, autoshaping procedures. Finally, the model makes it possible to draw a set of experimental predictions that may be verified in a modified experimental protocol. We suggest that further investigation of factored representations in computational neuroscience studies may be useful.

Modelling Individual Differences in the Form of Pavlovian Conditioned Approach Responses: A Dual Learning Systems Approach with Factored Representations

PubMed Central

Lesaint, Florian; Sigaud, Olivier; Flagel, Shelly B.; Robinson, Terry E.; Khamassi, Mehdi

2014-01-01

Reinforcement Learning has greatly influenced models of conditioning, providing powerful explanations of acquired behaviour and underlying physiological observations. However, in recent autoshaping experiments in rats, variation in the form of Pavlovian conditioned responses (CRs) and associated dopamine activity, have questioned the classical hypothesis that phasic dopamine activity corresponds to a reward prediction error-like signal arising from a classical Model-Free system, necessary for Pavlovian conditioning. Over the course of Pavlovian conditioning using food as the unconditioned stimulus (US), some rats (sign-trackers) come to approach and engage the conditioned stimulus (CS) itself – a lever – more and more avidly, whereas other rats (goal-trackers) learn to approach the location of food delivery upon CS presentation. Importantly, although both sign-trackers and goal-trackers learn the CS-US association equally well, only in sign-trackers does phasic dopamine activity show classical reward prediction error-like bursts. Furthermore, neither the acquisition nor the expression of a goal-tracking CR is dopamine-dependent. Here we present a computational model that can account for such individual variations. We show that a combination of a Model-Based system and a revised Model-Free system can account for the development of distinct CRs in rats. Moreover, we show that revising a classical Model-Free system to individually process stimuli by using factored representations can explain why classical dopaminergic patterns may be observed for some rats and not for others depending on the CR they develop. In addition, the model can account for other behavioural and pharmacological results obtained using the same, or similar, autoshaping procedures. Finally, the model makes it possible to draw a set of experimental predictions that may be verified in a modified experimental protocol. We suggest that further investigation of factored representations in computational neuroscience studies may be useful. PMID:24550719

Modulation of risk/reward decision making by dopaminergic transmission within the basolateral amygdala.

PubMed

Larkin, Joshua D; Jenni, Nicole L; Floresco, Stan B

2016-01-01

Dopamine (DA) transmission within cortico-limbic-striatal circuitry is integral in modulating decisions involving reward uncertainty. The basolateral amygdala (BLA) also plays a role in these processes, yet how DA transmission within this nucleus regulates cost/benefit decision making is unknown. We investigated the contribution of DA transmission within the BLA to risk/reward decision making assessed with a probabilistic discounting task. Rats were well-trained to choose between a small/certain reward and a large/risky reward, with the probability of obtaining the larger reward decreasing (100-12.5 %) or increasing (12.5-100 %) over a session. We examined the effects of antagonizing BLA D1 (SCH 23390, 0.1-1 μg) or D2 (eticlopride, 0.1-1 μg) receptors, as well as intra-BLA infusions of agonists for D1 (SKF 81297, 0.1-1 μg) and D2 (quinpirole, 1-10 μg) receptors. We also assessed how DA receptor stimulation may induce differential effects related to baseline levels of risky choice. BLA D1 receptor antagonism reduced risky choice by decreasing reward sensitivity, whereas D2 antagonism did not affect overall choice patterns. Stimulation of BLA D1 receptors optimized decision making in a baseline-dependent manner: in risk-averse rats, infusions of a lower dose of SKF81297 increased risky choice when reward probabilities were high (50 %), whereas in risk-prone rats, this drug reduced risky choice when probabilities were low (12.5 %). Quinpirole reduced risky choice in risk-prone rats, enhancing lose-shift behavior. These data highlight previously uncharacterized roles for BLA DA D1 and D2 receptors in biasing choice during risk/reward decision making through mediation of reward/negative feedback sensitivity.

(-)-Stepholidine reduces cue-induced reinstatement of cocaine seeking and cocaine self-administration in rats.

PubMed

Manuszak, M; Harding, W; Gadhiya, S; Ranaldi, R

2018-05-31

Dopamine receptors are implicated in cocaine reward and seeking. We hypothesize that (-)-stepholidine, a dopamine D1/D2/D3 multi-receptor agent, would be effective in reducing cocaine reward and seeking in an animal model. We investigated the effects of (-)-stepholidine in cue-induced reinstatement of cocaine seeking and cocaine self-administration (reward). Cue-induced reinstatement experiment: Rats were trained to press a lever reinforced by cocaine (1 mg/kg/injection) for 15 consecutive daily sessions, after which the response was extinguished by withholding cocaine and cocaine-paired cues (light and pump activation). This was followed by a cue-induced reinstatement test where subjects were exposed to two cocaine cue presentations and presses on the active lever produced cues. Subjects were treated with one of four (-)-stepholidine doses prior to the reinstatement test. Cocaine self-administration (reward) experiment: Rats were trained to self-administer cocaine under a progressive ratio schedule of reinforcement. After stable breakpoints were established, rats were injected with four doses of (-)-stepholidine prior to testing; each dose was injected prior to a separate test session with no-treatment sessions intervening to re-establish break points. (-)-Stepholidine significantly reduced cue-induced reinstatement of cocaine seeking in a dose-related manner. Additionally, (-)-stepholidine significantly reduced break points for cocaine reward. (-)-Stepholidine did not significantly affect locomotor activity. (-)-Stepholidine reduces cue-induced reinstatement of cocaine seeking and cocaine reward, suggesting that it may be useful in treating relapse in cocaine addiction. Copyright © 2018 Elsevier B.V. All rights reserved.

A mechanistic hypothesis of the factors that enhance vulnerability to nicotine use in females

PubMed Central

O'Dell, Laura E.; Torres, Oscar V.

2013-01-01

Women are particularly more vulnerable to tobacco use than men. This review proposes a unifying hypothesis that females experience greater rewarding effects of nicotine and more intense stress produced by withdrawal than males. We also provide a neural framework whereby estrogen promotes greater rewarding effects of nicotine in females via enhanced dopamine release in the nucleus accumbens (NAcc). During withdrawal, we suggest that corticotropin-releasing factor (CRF) stress systems are sensitized and promote a greater suppression of dopamine release in the NAcc of females versus males. Taken together, females display enhanced nicotine reward via estrogen and amplified effects of withdrawal via stress systems. Although this framework focuses on sex differences in adult rats, it is also applied to adolescent females who display enhanced rewarding effects of nicotine, but reduced effects of withdrawal from this drug. Since females experience strong rewarding effects of nicotine, a clinical implication of our hypothesis is that specific strategies to prevent smoking initiation among females are critical. Also, anxiolytic medications may be more effective in females that experience intense stress during withdrawal. Furthermore, medications that target withdrawal should not be applied in a unilateral manner across age and sex, given that nicotine withdrawal is lower during adolescence. This review highlights key factors that promote nicotine use in females, and future studies on sex-dependent interactions of stress and reward systems are needed to test our mechanistic hypotheses. Future studies in this area will have important translational value toward reducing health disparities produced by nicotine use in females. PMID:23684991

The Functional DRD3 Ser9Gly Polymorphism (rs6280) Is Pleiotropic, Affecting Reward as Well as Movement

PubMed Central

Savitz, Jonathan; Hodgkinson, Colin A.; Martin-Soelch, Chantal; Shen, Pei-Hong; Szczepanik, Joanna; Nugent, Allison; Herscovitch, Peter; Grace, Anthony A.; Goldman, David; Drevets, Wayne C.

2013-01-01

Abnormalities of motivation and behavior in the context of reward are a fundamental component of addiction and mood disorders. Here we test the effect of a functional missense mutation in the dopamine 3 receptor (DRD3) gene (ser9gly, rs6280) on reward-associated dopamine (DA) release in the striatum. Twenty-six healthy controls (HCs) and 10 unmedicated subjects with major depressive disorder (MDD) completed two positron emission tomography (PET) scans with [11C]raclopride using the bolus plus constant infusion method. On one occasion subjects completed a sensorimotor task (control condition) and on another occasion subjects completed a gambling task (reward condition). A linear regression analysis controlling for age, sex, diagnosis, and self-reported anhedonia indicated that during receipt of unpredictable monetary reward the glycine allele was associated with a greater reduction in D2/3 receptor binding (i.e., increased reward-related DA release) in the middle (anterior) caudate (p<0.01) and the ventral striatum (p<0.05). The possible functional effect of the ser9gly polymorphism on DA release is consistent with previous work demonstrating that the glycine allele yields D3 autoreceptors that have a higher affinity for DA and display more robust intracellular signaling. Preclinical evidence indicates that chronic stress and aversive stimulation induce activation of the DA system, raising the possibility that the glycine allele, by virtue of its facilitatory effect on striatal DA release, increases susceptibility to hyperdopaminergic responses that have previously been associated with stress, addiction, and psychosis. PMID:23365649

Cocaine affects foraging behaviour and biogenic amine modulated behavioural reflexes in honey bees.

PubMed

Søvik, Eirik; Even, Naïla; Radford, Catherine W; Barron, Andrew B

2014-01-01

In humans and other mammals, drugs of abuse alter the function of biogenic amine pathways in the brain leading to the subjective experience of reward and euphoria. Biogenic amine pathways are involved in reward processing across diverse animal phyla, however whether cocaine acts on these neurochemical pathways to cause similar rewarding behavioural effects in animal phyla other than mammals is unclear. Previously, it has been shown that bees are more likely to dance (a signal of perceived reward) when returning from a sucrose feeder after cocaine treatment. Here we examined more broadly whether cocaine altered reward-related behaviour, and biogenic amine modulated behavioural responses in bees. Bees developed a preference for locations at which they received cocaine, and when foraging at low quality sucrose feeders increase their foraging rate in response to cocaine treatment. Cocaine also increased reflexive proboscis extension to sucrose, and sting extension to electric shock. Both of these simple reflexes are modulated by biogenic amines. This shows that systemic cocaine treatment alters behavioural responses that are modulated by biogenic amines in insects. Since insect reward responses involve both octopamine and dopamine signalling, we conclude that cocaine treatment altered diverse reward-related aspects of behaviour in bees. We discuss the implications of these results for understanding the ecology of cocaine as a plant defence compound. Our findings further validate the honey bee as a model system for understanding the behavioural impacts of cocaine, and potentially other drugs of abuse.

Coexistence of Reward and Unsupervised Learning During the Operant Conditioning of Neural Firing Rates

PubMed Central

Kerr, Robert R.; Grayden, David B.; Thomas, Doreen A.; Gilson, Matthieu; Burkitt, Anthony N.

2014-01-01

A fundamental goal of neuroscience is to understand how cognitive processes, such as operant conditioning, are performed by the brain. Typical and well studied examples of operant conditioning, in which the firing rates of individual cortical neurons in monkeys are increased using rewards, provide an opportunity for insight into this. Studies of reward-modulated spike-timing-dependent plasticity (RSTDP), and of other models such as R-max, have reproduced this learning behavior, but they have assumed that no unsupervised learning is present (i.e., no learning occurs without, or independent of, rewards). We show that these models cannot elicit firing rate reinforcement while exhibiting both reward learning and ongoing, stable unsupervised learning. To fix this issue, we propose a new RSTDP model of synaptic plasticity based upon the observed effects that dopamine has on long-term potentiation and depression (LTP and LTD). We show, both analytically and through simulations, that our new model can exhibit unsupervised learning and lead to firing rate reinforcement. This requires that the strengthening of LTP by the reward signal is greater than the strengthening of LTD and that the reinforced neuron exhibits irregular firing. We show the robustness of our findings to spike-timing correlations, to the synaptic weight dependence that is assumed, and to changes in the mean reward. We also consider our model in the differential reinforcement of two nearby neurons. Our model aligns more strongly with experimental studies than previous models and makes testable predictions for future experiments. PMID:24475240

PPARγ activation attenuates opioid consumption and modulates mesolimbic dopamine transmission.

PubMed

de Guglielmo, Giordano; Melis, Miriam; De Luca, Maria Antonietta; Kallupi, Marsida; Li, Hong Wu; Niswender, Kevin; Giordano, Antonio; Senzacqua, Martina; Somaini, Lorenzo; Cippitelli, Andrea; Gaitanaris, George; Demopulos, Gregory; Damadzic, Ruslan; Tapocik, Jenica; Heilig, Markus; Ciccocioppo, Roberto

2015-03-01

PPARγ is one of the three isoforms identified for the peroxisome proliferator-activated receptors (PPARs) and is the receptor for the thiazolidinedione class of anti-diabetic medications including pioglitazone. PPARγ has been long studied for its role in adipogenesis and glucose metabolism, but the discovery of the localization in ventral tegmental area (VTA) neurons opens new vistas for a potential role in the regulation of reward processing and motivated behavior in drug addiction. Here, we demonstrate that activation of PPARγ by pioglitazone reduces the motivation for heroin and attenuates its rewarding properties. These effects are associated with a marked reduction of heroin-induced increase in phosphorylation of DARPP-32 protein in the nucleus accumbens (NAc) and with a marked and selective reduction of acute heroin-induced elevation of extracellular dopamine (DA) levels in the NAc shell, as measured by in vivo microdialysis. Through ex vivo electrophysiology in acute midbrain slices, we also show that stimulation of PPARγ attenuates opioid-induced excitation of VTA DA neurons via reduction of presynaptic GABA release from the rostromedial tegmental nucleus (RMTg). Consistent with this finding, site-specific microinjection of pioglitazone into the RMTg but not into the VTA reduced heroin taking. Our data illustrate that activation of PPARγ may represent a new pharmacotherapeutic option for the treatment of opioid addiction.

Pro-dopamine regulator, KB220Z, attenuates hoarding and shopping behavior in a female, diagnosed with SUD and ADHD.

PubMed

McLaughlin, Thomas; Blum, Kenneth; Steinberg, Bruce; Modestino, Edward J; Fried, Lyle; Baron, David; Siwicki, David; Braverman, Eric R; Badgaiyan, Rajendra D

2018-03-01

Background Addictive-like behaviors (e.g., hoarding and shopping) may be the result of the cumulative effects of dopaminergic and other neurotransmitter genetic variants as well as elevated stress levels. We, therefore, propose that dopamine homeostasis may be the preferred goal in combating such challenging and unwanted behaviors, when simple dopaminergic activation through potent agonists may not provide any resolution. Case presentation C.J. is a 38-year-old, single, female, living with her mother. She has a history of substance use disorder as well as attention deficit hyperactivity disorder, inattentive type. She had been stable on buprenorphine/naloxone combination and amphetamine, dextroamphetamine mixed salts for many years when unexpectedly she lost her job for oversleeping and not calling into work. KB200z (a pro-dopamine compound) was added to her regimen for complaints of low drive and motivation. After taking this nutraceutical for 4 weeks, she noticed a marked improvement in her mental status and many behaviors. She noted that her shopping and hoarding addictions had appreciably decreased. Furthermore, her lifelong history of terrifying lucid dreams was eliminated. Finally, she felt more in control; her locus of control shifted from external to more internal. Discussion The hypothesis is that C.J.'s reported, behavioral, and psychological benefits resulted from the pro-dopamine-regulating effect of KB220Z across the brain reward system. Conclusions This effect, we surmise, could be the result of a new dopamine balance, across C.J.'s brain reward system. Dopamine homeostasis is an effect of KB220Z seen in both animal and human placebo-controlled fMRI experiments.

Obesity and addiction: neurobiological overlaps.

PubMed

Volkow, N D; Wang, G-J; Tomasi, D; Baler, R D

2013-01-01

Drug addiction and obesity appear to share several properties. Both can be defined as disorders in which the saliency of a specific type of reward (food or drug) becomes exaggerated relative to, and at the expense of others rewards. Both drugs and food have powerful reinforcing effects, which are in part mediated by abrupt dopamine increases in the brain reward centres. The abrupt dopamine increases, in vulnerable individuals, can override the brain's homeostatic control mechanisms. These parallels have generated interest in understanding the shared vulnerabilities between addiction and obesity. Predictably, they also engendered a heated debate. Specifically, brain imaging studies are beginning to uncover common features between these two conditions and delineate some of the overlapping brain circuits whose dysfunctions may underlie the observed deficits. The combined results suggest that both obese and drug-addicted individuals suffer from impairments in dopaminergic pathways that regulate neuronal systems associated not only with reward sensitivity and incentive motivation, but also with conditioning, self-control, stress reactivity and interoceptive awareness. In parallel, studies are also delineating differences between them that centre on the key role that peripheral signals involved with homeostatic control exert on food intake. Here, we focus on the shared neurobiological substrates of obesity and addiction. © 2012 The Authors. obesity reviews © 2012 International Association for the Study of Obesity.

An extended reinforcement learning model of basal ganglia to understand the contributions of serotonin and dopamine in risk-based decision making, reward prediction, and punishment learning

PubMed Central

Balasubramani, Pragathi P.; Chakravarthy, V. Srinivasa; Ravindran, Balaraman; Moustafa, Ahmed A.

2014-01-01

Although empirical and neural studies show that serotonin (5HT) plays many functional roles in the brain, prior computational models mostly focus on its role in behavioral inhibition. In this study, we present a model of risk based decision making in a modified Reinforcement Learning (RL)-framework. The model depicts the roles of dopamine (DA) and serotonin (5HT) in Basal Ganglia (BG). In this model, the DA signal is represented by the temporal difference error (δ), while the 5HT signal is represented by a parameter (α) that controls risk prediction error. This formulation that accommodates both 5HT and DA reconciles some of the diverse roles of 5HT particularly in connection with the BG system. We apply the model to different experimental paradigms used to study the role of 5HT: (1) Risk-sensitive decision making, where 5HT controls risk assessment, (2) Temporal reward prediction, where 5HT controls time-scale of reward prediction, and (3) Reward/Punishment sensitivity, in which the punishment prediction error depends on 5HT levels. Thus the proposed integrated RL model reconciles several existing theories of 5HT and DA in the BG. PMID:24795614

Reward-related genes and personality traits in alcohol-dependent individuals: a pilot case control study.

PubMed

Landgren, Sara; Berglund, Kristina; Jerlhag, Elisabet; Fahlke, Claudia; Balldin, Jan; Berggren, Ulf; Zetterberg, Henrik; Blennow, Kaj; Engel, Jörgen A

2011-01-01

Components of the brain reward system, i.e. the mesolimbic dopamine, laterodorsal cholinergic and ghrelin signaling systems, have been implicated in alcohol reward in preclinical studies. Genetic variants of these systems have previously been linked to alcohol dependence. Here, we genotyped 31 single nucleotide polymorphisms (SNPs): 1 SNP in the dopamine D₂ receptor (DRD2) gene, 20 SNPs in 5 different nicotinic acetylcholine receptor subunit (CHRN*) genes, and 10 SNPs in the genes encoding pro-ghrelin (GHRL) and its receptor (GHSR), in a pilot study of type 1 alcoholics (n = 84) and healthy controls (n = 32). These individuals were characterized using the Temperament and Character Inventory. None of the SNPs were associated with risk of alcohol dependence in this population. The GG genotype of SNP rs13261190 in the CHRNB3 was associated with increased novelty seeking, while SNPs of the ghrelin signaling system were associated with decreased self-directedness (AA of rs495225, GHSR) and alterations in self-transcendence (AA of both rs42451 and rs35680, GHRL). In conclusion, this pilot study suggests that reward-related genes are associated with altered personality scores in type 1 alcohol dependence, which warrants future studies of these associations in larger study samples. Copyright © 2011 S. Karger AG, Basel.

Psychogenic and neural visual-cue response in PD dopamine dysregulation syndrome.

PubMed

Loane, Clare; Wu, Kit; O'Sullivan, Sean S; Lawrence, Andrew D; Woodhead, Zoe; Lees, Andrew J; Piccini, Paola; Politis, Marios

2015-11-01

Dopamine dysregulation syndrome (DDS) in Parkinson's disease (PD) patients refers to the compulsive use of dopaminergic replacement therapy and has serious psycho-social consequences. Mechanisms underlying DDS are not clear although has been linked to dysfunctional brain reward networks. With fMRI, we investigate behavioral and neural response to drug-cues in six PD DDS patients and 12 PD control patients in both the ON and OFF medication state. Behavioral measures of liking, wanting and subjectively 'feeling ON medication' were also collected. Behaviorally, PD DDS patients feel less ON and want their drugs more at baseline compared to PD controls. Following drug-cue exposure, PD DDS patients feel significantly more ON medication, which correlates with significant increases in reward related regions. The results demonstrate that exposure to drug-cues increases the subjective feeling of being 'ON' medication which corresponds to dysfunctional activation in reward related regions in PD DDS patients. These findings should be extended in future studies. Visual stimuli being sufficient to elicit behavioral response through neuroadaptations could have direct implications to the management of addictive behavior. Copyright © 2015 Elsevier Ltd. All rights reserved.

Mood, food, and obesity

PubMed Central

Singh, Minati

2014-01-01

Food is a potent natural reward and food intake is a complex process. Reward and gratification associated with food consumption leads to dopamine (DA) production, which in turn activates reward and pleasure centers in the brain. An individual will repeatedly eat a particular food to experience this positive feeling of gratification. This type of repetitive behavior of food intake leads to the activation of brain reward pathways that eventually overrides other signals of satiety and hunger. Thus, a gratification habit through a favorable food leads to overeating and morbid obesity. Overeating and obesity stems from many biological factors engaging both central and peripheral systems in a bi-directional manner involving mood and emotions. Emotional eating and altered mood can also lead to altered food choice and intake leading to overeating and obesity. Research findings from human and animal studies support a two-way link between three concepts, mood, food, and obesity. The focus of this article is to provide an overview of complex nature of food intake where various biological factors link mood, food intake, and brain signaling that engages both peripheral and central nervous system signaling pathways in a bi-directional manner in obesity. PMID:25225489

Who, what, where, when (and maybe even why)? How the experience of sexual reward connects sexual desire, preference, and performance.

PubMed

Pfaus, James G; Kippin, Tod E; Coria-Avila, Genaro A; Gelez, Hélène; Afonso, Veronica M; Ismail, Nafissa; Parada, Mayte

2012-02-01

Although sexual behavior is controlled by hormonal and neurochemical actions in the brain, sexual experience induces a degree of plasticity that allows animals to form instrumental and Pavlovian associations that predict sexual outcomes, thereby directing the strength of sexual responding. This review describes how experience with sexual reward strengthens the development of sexual behavior and induces sexually-conditioned place and partner preferences in rats. In both male and female rats, early sexual experience with partners scented with a neutral or even noxious odor induces a preference for scented partners in subsequent choice tests. Those preferences can also be induced by injections of morphine or oxytocin paired with a male rat's first exposure to scented females, indicating that pharmacological activation of opioid or oxytocin receptors can "stand in" for the sexual reward-related neurochemical processes normally activated by sexual stimulation. Conversely, conditioned place or partner preferences can be blocked by the opioid receptor antagonist naloxone. A somatosensory cue (a rodent jacket) paired with sexual reward comes to elicit sexual arousal in male rats, such that paired rats with the jacket off show dramatic copulatory deficits. We propose that endogenous opioid activation forms the basis of sexual reward, which also sensitizes hypothalamic and mesolimbic dopamine systems in the presence of cues that predict sexual reward. Those systems act to focus attention on, and activate goal-directed behavior toward, reward-related stimuli. Thus, a critical period exists during an individual's early sexual experience that creates a "love map" or Gestalt of features, movements, feelings, and interpersonal interactions associated with sexual reward.

DAT genotype modulates striatal processing and long-term memory for items associated with reward and punishment☆

PubMed Central

Wittmann, Bianca C.; Tan, Geoffrey C.; Lisman, John E.; Dolan, Raymond J.; Düzel, Emrah

2013-01-01

Previous studies have shown that appetitive motivation enhances episodic memory formation via a network including the substantia nigra/ventral tegmental area (SN/VTA), striatum and hippocampus. This functional magnetic resonance imaging (fMRI) study now contrasted the impact of aversive and appetitive motivation on episodic long-term memory. Cue pictures predicted monetary reward or punishment in alternating experimental blocks. One day later, episodic memory for the cue pictures was tested. We also investigated how the neural processing of appetitive and aversive motivation and episodic memory were modulated by dopaminergic mechanisms. To that end, participants were selected on the basis of their genotype for a variable number of tandem repeat polymorphism of the dopamine transporter (DAT) gene. The resulting groups were carefully matched for the 5-HTTLPR polymorphism of the serotonin transporter gene. Recognition memory for cues from both motivational categories was enhanced in participants homozygous for the 10-repeat allele of the DAT, the functional effects of which are not known yet, but not in heterozygous subjects. In comparison with heterozygous participants, 10-repeat homozygous participants also showed increased striatal activity for anticipation of motivational outcomes compared to neutral outcomes. In a subsequent memory analysis, encoding activity in striatum and hippocampus was found to be higher for later recognized items in 10-repeat homozygotes compared to 9/10-repeat heterozygotes. These findings suggest that processing of appetitive and aversive motivation in the human striatum involve the dopaminergic system and that dopamine plays a role in memory for both types of motivational information. In accordance with animal studies, these data support the idea that encoding of motivational events depends on dopaminergic processes in the hippocampus. PMID:23911780

Excessive D1 Dopamine Receptor Activation in the Dorsal Striatum Promotes Autistic-Like Behaviors.

PubMed

Lee, Yunjin; Kim, Hannah; Kim, Ji-Eun; Park, Jin-Young; Choi, Juli; Lee, Jung-Eun; Lee, Eun-Hwa; Han, Pyung-Lim

2018-07-01

The dopamine system has been characterized in motor function, goal-directed behaviors, and rewards. Recent studies recognize various dopamine system genes as being associated with autism spectrum disorder (ASD). However, how dopamine system dysfunction induces ASD pathophysiology remains unknown. In the present study, we demonstrated that mice with increased dopamine functions in the dorsal striatum via the suppression of dopamine transporter expression in substantia nigra neurons or the optogenetic stimulation of the nigro-striatal circuitry exhibited sociability deficits and repetitive behaviors relevant to ASD pathology in animal models, while these behavioral changes were blocked by a D1 receptor antagonist. Pharmacological activation of D1 dopamine receptors in normal mice or the genetic knockout (KO) of D2 dopamine receptors also produced typical autistic-like behaviors. Moreover, the siRNA-mediated inhibition of D2 dopamine receptors in the dorsal striatum was sufficient to replicate autistic-like phenotypes in D2 KO mice. Intervention of D1 dopamine receptor functions or the signaling pathways-related D1 receptors in D2 KO mice produced anti-autistic effects. Together, our results indicate that increased dopamine function in the dorsal striatum promotes autistic-like behaviors and that the dorsal striatum is the neural correlate of ASD core symptoms.

Role of Dopamine Signaling in Drug Addiction.

PubMed

Chen, Wan; Nong, Zhihuan; Li, Yaoxuan; Huang, Jianping; Chen, Chunxia; Huang, Luying

2017-01-01

Addiction is a chronic, relapsing disease of the brain that includes drug-induced compulsive seeking behavior and consumption of drugs. Dopamine (DA) is considered to be critical in drug addiction due to reward mechanisms in the midbrain. In this article, we review the major animal models in addictive drug experiments in vivo and in vitro. We discuss the relevance of the structure and pharmacological function of DA receptors. To improve the understanding of the role of DA receptors in reward pathways, specific brain regions, including the Ventral tegmental area, Nucleus accumbens, Prefrontal cortex, and Habenula, are highlighted. These factors contribute to the development of novel therapeutic targets that act at DA receptors. In addiction, the development of neuroimaging method will increase our understanding of the mechanisms underlying drug addiction. Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.org.

Pilot clinical observations between food and drug seeking derived from fifty cases attending an eating disorder clinic.

PubMed

Beitscher-Campbell, Harriet; Blum, Kenneth; Febo, Marcelo; Madigan, Margaret A; Giordano, John; Badgaiyan, Rajendra D; Braverman, Eric R; Dushaj, Kristina; Li, Mona; Gold, Mark S

2016-09-01

Background The reward deficiency syndrome hypothesis posits that genes are responsible for reward dependence and related behaviors. There is evidence that both bulimia and anorexia nervosa, especially in women, have been linked to a lifetime history of substance use disorder (SUD). There are difficulties in accepting food as an addiction similar to drugs; however, increasingly neuroimaging studies favor such an assertion. Case presentations We are reporting the evidence of comorbidity of eating disorders with SUD found within these case presentations. We show 50 case reports derived from two independent treatment centers in Florida that suggest the commonality between food and drug addictions. In an attempt to provide data from this cohort, many participants did not adequately respond to our questionnaire. Discussion We propose that dopamine agonist therapy may be of common benefit. Failure in the past may reside in too powerful D2 agonist activity leading to D2 receptor downregulation, while the new methodology may cause a reduction of "dopamine resistance" by inducing "dopamine homeostasis." While this is not a definitive study, it does provide some additional clinical evidence that these two addictions are not mutually exclusive. Conclusion Certainly, it is our position that there is an overlap between food- and drug-seeking behavior. We propose that the studies focused on an effort to produce natural activation of dopaminergic reward circuitry as a type of common therapy may certainly be reasonable. Additional research is warranted.

Addiction: beyond dopamine reward circuitry.

PubMed

Volkow, Nora D; Wang, Gene-Jack; Fowler, Joanna S; Tomasi, Dardo; Telang, Frank

2011-09-13

Dopamine (DA) is considered crucial for the rewarding effects of drugs of abuse, but its role in addiction is much less clear. This review focuses on studies that used PET to characterize the brain DA system in addicted subjects. These studies have corroborated in humans the relevance of drug-induced fast DA increases in striatum [including nucleus accumbens (NAc)] in their rewarding effects but have unexpectedly shown that in addicted subjects, drug-induced DA increases (as well as their subjective reinforcing effects) are markedly blunted compared with controls. In contrast, addicted subjects show significant DA increases in striatum in response to drug-conditioned cues that are associated with self-reports of drug craving and appear to be of a greater magnitude than the DA responses to the drug. We postulate that the discrepancy between the expectation for the drug effects (conditioned responses) and the blunted pharmacological effects maintains drug taking in an attempt to achieve the expected reward. Also, whether tested during early or protracted withdrawal, addicted subjects show lower levels of D2 receptors in striatum (including NAc), which are associated with decreases in baseline activity in frontal brain regions implicated in salience attribution (orbitofrontal cortex) and inhibitory control (anterior cingulate gyrus), whose disruption results in compulsivity and impulsivity. These results point to an imbalance between dopaminergic circuits that underlie reward and conditioning and those that underlie executive function (emotional control and decision making), which we postulate contributes to the compulsive drug use and loss of control in addiction.

Brain reactivity to alcohol and cannabis marketing during sobriety and intoxication.

PubMed

de Sousa Fernandes Perna, Elizabeth B; Theunissen, Eef L; Kuypers, Kim P C; Evers, Elisabeth A; Stiers, Peter; Toennes, Stefan W; Witteman, Jurriaan; van Dalen, Wim; Ramaekers, Johannes G

2017-05-01

Drugs of abuse stimulate striatal dopamine release and activate reward pathways. This study examined the impact of alcohol and cannabis marketing on the reward circuit in alcohol and cannabis users while sober and intoxicated. It was predicted that alcohol and cannabis marketing would increase striatal activation when sober and that reward sensitivity would be less during alcohol and cannabis intoxication. Heavy alcohol (n = 20) and regular cannabis users (n = 21) participated in a mixed factorial study involving administration of alcohol and placebo in the alcohol group and cannabis and placebo in the cannabis group. Non-drug users (n = 20) served as between group reference. Brain activation after exposure to alcohol and cannabis marketing movies was measured using functional magnetic resonance imaging and compared between groups while sober and compared with placebo while intoxicated. Implicit alcohol and cannabis cognitions were assessed by means of a single-category implicit association test. Alcohol and cannabis marketing significantly increased striatal BOLD activation across all groups while sober. Striatal activation however decreased during intoxication with alcohol and cannabis. Implicit associations with cannabis marketing cues were significantly more positive in alcohol and cannabis users as compared with non-drug using controls. Public advertising of alcohol or cannabis use elicits striatal activation in the brain's reward circuit. Reduction of marketing would reduce brain exposure to reward cues that motivate substance use. Conversely, elevated dopamine levels protect against the reinforcing potential of marketing. © 2016 Society for the Study of Addiction.

Influence of reward motivation on human declarative memory.

PubMed

Miendlarzewska, Ewa A; Bavelier, Daphne; Schwartz, Sophie

2016-02-01

Motivational relevance can prioritize information for memory encoding and consolidation based on reward value. In this review, we pinpoint the possible psychological and neural mechanisms by which reward promotes learning, from guiding attention to enhancing memory consolidation. We then discuss how reward value can spill-over from one conditioned stimulus to a non-conditioned stimulus. Such generalization can occur across perceptually similar items or through more complex relations, such as associative or logical inferences. Existing evidence suggests that the neurotransmitter dopamine boosts the formation of declarative memory for rewarded information and may also control the generalization of reward values. In particular, temporally-correlated activity in the hippocampus and in regions of the dopaminergic circuit may mediate value-based decisions and facilitate cross-item integration. Given the importance of generalization in learning, our review points to the need to study not only how reward affects later memory but how learned reward values may generalize to related representations and ultimately alter memory structure. Copyright © 2015 Elsevier Ltd. All rights reserved.

Gene Expression Profiling with Cre-Conditional Pseudorabies Virus Reveals a Subset of Midbrain Neurons That Participate in Reward Circuitry

PubMed Central

Pomeranz, Lisa E.; Ekstrand, Mats I.; Latcha, Kaamashri N.; Smith, Gregory A.; Enquist, Lynn W.

2017-01-01

The mesolimbic dopamine pathway receives inputs from numerous regions of the brain as part of a neural system that detects rewarding stimuli and coordinates a behavioral response. The capacity to simultaneously map and molecularly define the components of this complex multisynaptic circuit would thus advance our understanding of the determinants of motivated behavior. To accomplish this, we have constructed pseudorabies virus (PRV) strains in which viral propagation and fluorophore expression are activated only after exposure to Cre recombinase. Once activated in Cre-expressing neurons, the virus serially labels chains of presynaptic neurons. Dual injection of GFP and mCherry tracing viruses simultaneously illuminates nigrostriatal and mesolimbic circuitry and shows no overlap, demonstrating that PRV transmission is confined to synaptically connected neurons. To molecularly profile mesolimbic dopamine neurons and their presynaptic inputs, we injected Cre-conditional GFP virus into the NAc of (anti-GFP) nanobody-L10 transgenic mice and immunoprecipitated translating ribosomes from neurons infected after retrograde tracing. Analysis of purified RNA revealed an enrichment of transcripts expressed in neurons of the dorsal raphe nuclei and lateral hypothalamus that project to the mesolimbic dopamine circuit. These studies identify important inputs to the mesolimbic dopamine pathway and further show that PRV circuit-directed translating ribosome affinity purification can be broadly applied to identify molecularly defined neurons comprising complex, multisynaptic circuits. SIGNIFICANCE STATEMENT The mesolimbic dopamine circuit integrates signals from key brain regions to detect and respond to rewarding stimuli. To further define this complex multisynaptic circuit, we constructed a panel of Cre recombinase-activated pseudorabies viruses (PRVs) that enabled retrograde tracing of neural inputs that terminate on Cre-expressing neurons. Using these viruses and Retro-TRAP (translating ribosome affinity purification), a previously reported molecular profiling method, we developed a novel technique that provides anatomic as well as molecular information about the neural components of polysynaptic circuits. We refer to this new method as PRV-Circuit-TRAP (PRV circuit-directed TRAP). Using it, we have identified major projections to the mesolimbic dopamine circuit from the lateral hypothalamus and dorsal raphe nucleus and defined a discrete subset of transcripts expressed in these projecting neurons, which will allow further characterization of this important pathway. Moreover, the method we report is general and can be applied to the study of other neural circuits. PMID:28283558

Selectivity in Postencoding Connectivity with High-Level Visual Cortex Is Associated with Reward-Motivated Memory

PubMed Central

Murty, Vishnu P.; Tompary, Alexa; Adcock, R. Alison

2017-01-01

Reward motivation has been demonstrated to enhance declarative memory by facilitating systems-level consolidation. Although high-reward information is often intermixed with lower reward information during an experience, memory for high value information is prioritized. How is this selectivity achieved? One possibility is that postencoding consolidation processes bias memory strengthening to those representations associated with higher reward. To test this hypothesis, we investigated the influence of differential reward motivation on the selectivity of postencoding markers of systems-level memory consolidation. Human participants encoded intermixed, trial-unique memoranda that were associated with either high or low-value during fMRI acquisition. Encoding was interleaved with periods of rest, allowing us to investigate experience-dependent changes in connectivity as they related to later memory. Behaviorally, we found that reward motivation enhanced 24 h associative memory. Analysis of patterns of postencoding connectivity showed that, even though learning trials were intermixed, there was significantly greater connectivity with regions of high-level, category-selective visual cortex associated with high-reward trials. Specifically, increased connectivity of category-selective visual cortex with both the VTA and the anterior hippocampus predicted associative memory for high- but not low-reward memories. Critically, these results were independent of encoding-related connectivity and univariate activity measures. Thus, these findings support a model by which the selective stabilization of memories for salient events is supported by postencoding interactions with sensory cortex associated with reward. SIGNIFICANCE STATEMENT Reward motivation is thought to promote memory by supporting memory consolidation. Yet, little is known as to how brain selects relevant information for subsequent consolidation based on reward. We show that experience-dependent changes in connectivity of both the anterior hippocampus and the VTA with high-level visual cortex selectively predicts memory for high-reward memoranda at a 24 h delay. These findings provide evidence for a novel mechanism guiding the consolidation of memories for valuable events, namely, postencoding interactions between neural systems supporting mesolimbic dopamine activation, episodic memory, and perception. PMID:28100737

AgRP neurons regulate development of dopamine neuronal plasticity and nonfood-associated behaviors

PubMed Central

Dietrich, Marcelo O; Bober, Jeremy; Ferreira, Jozélia G; Tellez, Luis A; Mineur, Yann S; Souza, Diogo O; Gao, Xiao-Bing; Picciotto, Marina R; Araújo, Ivan; Liu, Zhong-Wu; Horvath, Tamas L

2012-01-01

It is not known whether behaviors unrelated to feeding are affected by hypothalamic regulators of hunger. We found that impairment of Agouti-related protein (AgRP) circuitry by either Sirt1 knockdown in AgRP-expressing neurons or early postnatal ablation of these neurons increased exploratory behavior and enhanced responses to cocaine. In AgRP circuit–impaired mice, ventral tegmental dopamine neurons exhibited enhanced spike timing–dependent long-term potentiation, altered amplitude of miniature postsynaptic currents and elevated dopamine in basal forebrain. Thus, AgRP neurons determine the set point of the reward circuitry and associated behaviors. PMID:22729177

Reward-centricity and attenuated aversions: An adolescent phenotype emerging from studies in laboratory animals

PubMed Central

Doremus-Fitzwater, Tamara L.; Spear, Linda P.

2016-01-01

Adolescence is an evolutionarily conserved developmental period, with neural circuits and behaviors contributing to the detection, procurement, and receipt of rewards bearing similarity across species. Studies with laboratory animals suggest that adolescence is typified by a “reward-centric” phenotype—an increased sensitivity to rewards relative to adults. In contrast, adolescent rodents are reportedly less sensitive to the aversive properties of many drugs and naturally aversive stimuli. Alterations within the mesocorticolimbic dopamine and endocannabinoid systems likely contribute to an adolescent reward-sensitive, yet aversion-resistant, phenotype. Although early hypotheses postulated that developmental changes in dopaminergic circuitry would result in a “reward deficiency” syndrome, evidence now suggests the opposite: that adolescents are uniquely poised to seek out hedonic stimuli, experience greater “pleasure” from rewards, and consume rewarding stimuli in excess. Future studies that more clearly define the role of specific brain regions and neurotransmitter systems in the expression of behaviors toward reward- and aversive-related cues and stimuli are necessary to more fully understand an adolescent-proclivity for and vulnerability to rewards and drugs of potential abuse. PMID:27524639

Reward-centricity and attenuated aversions: An adolescent phenotype emerging from studies in laboratory animals.

PubMed

Doremus-Fitzwater, Tamara L; Spear, Linda P

2016-11-01

Adolescence is an evolutionarily conserved developmental period, with neural circuits and behaviors contributing to the detection, procurement, and receipt of rewards bearing similarity across species. Studies with laboratory animals suggest that adolescence is typified by a "reward-centric" phenotype-an increased sensitivity to rewards relative to adults. In contrast, adolescent rodents are reportedly less sensitive to the aversive properties of many drugs and naturally aversive stimuli. Alterations within the mesocorticolimbic dopamine and endocannabinoid systems likely contribute to an adolescent reward-sensitive, yet aversion-resistant, phenotype. Although early hypotheses postulated that developmental changes in dopaminergic circuitry would result in a "reward deficiency" syndrome, evidence now suggests the opposite: that adolescents are uniquely poised to seek out hedonic stimuli, experience greater "pleasure" from rewards, and consume rewarding stimuli in excess. Future studies that more clearly define the role of specific brain regions and neurotransmitter systems in the expression of behaviors toward reward- and aversive-related cues and stimuli are necessary to more fully understand an adolescent-proclivity for and vulnerability to rewards and drugs of potential abuse. Copyright © 2016 Elsevier Ltd. All rights reserved.

Sexual Experience in Female Rodents: Cellular Mechanisms and Functional Consequences

PubMed Central

Meisel, Robert L.; Mullins, Amanda J.

2007-01-01

The neurobiology of female sexual behavior has largely focused on mechanisms of hormone action on nerve cells and how these effects translate into the display of copulatory motor patterns. Of equal importance, though less studied, are some of the consequences of engaging in sexual behavior, including the rewarding properties of sexual interactions and how sexual experience alters copulatory efficiency. This review summarizes the effects of sexual experience on reward processes and copulation in female Syrian hamsters. Neural correlates of these sexual interactions include long-term cellular changes in dopamine transmission and postsynaptic signaling pathways related to neuronal plasticity (e.g., dendritic spine formation). Taken together, these studies suggest that sexual experience enhances the reinforcing properties of sexual behavior, which has the coincident outcome of increasing copulatory efficiency in a way that can increase reproductive success. PMID:16978593

Tamping Ramping: Algorithmic, Implementational, and Computational Explanations of Phasic Dopamine Signals in the Accumbens

PubMed Central

Lloyd, Kevin; Dayan, Peter

2015-01-01

Substantial evidence suggests that the phasic activity of dopamine neurons represents reinforcement learning’s temporal difference prediction error. However, recent reports of ramp-like increases in dopamine concentration in the striatum when animals are about to act, or are about to reach rewards, appear to pose a challenge to established thinking. This is because the implied activity is persistently predictable by preceding stimuli, and so cannot arise as this sort of prediction error. Here, we explore three possible accounts of such ramping signals: (a) the resolution of uncertainty about the timing of action; (b) the direct influence of dopamine over mechanisms associated with making choices; and (c) a new model of discounted vigour. Collectively, these suggest that dopamine ramps may be explained, with only minor disturbance, by standard theoretical ideas, though urgent questions remain regarding their proximal cause. We suggest experimental approaches to disentangling which of the proposed mechanisms are responsible for dopamine ramps. PMID:26699940

HIV-1 TAT protein enhances sensitization to methamphetamine by affecting dopaminergic function.

PubMed

Kesby, James P; Najera, Julia A; Romoli, Benedetto; Fang, Yiding; Basova, Liana; Birmingham, Amanda; Marcondes, Maria Cecilia G; Dulcis, Davide; Semenova, Svetlana

2017-10-01

Methamphetamine abuse is common among humans with immunodeficiency virus (HIV). The HIV-1 regulatory protein TAT induces dysfunction of mesolimbic dopaminergic systems which may result in impaired reward processes and contribute to methamphetamine abuse. These studies investigated the impact of TAT expression on methamphetamine-induced locomotor sensitization, underlying changes in dopamine function and adenosine receptors in mesolimbic brain areas and neuroinflammation (microgliosis). Transgenic mice with doxycycline-induced TAT protein expression in the brain were tested for locomotor activity in response to repeated methamphetamine injections and methamphetamine challenge after a 7-day abstinence period. Dopamine function in the nucleus accumbens (Acb) was determined using high performance liquid chromatography. Expression of dopamine and/or adenosine A receptors (ADORA) in the Acb and caudate putamen (CPu) was assessed using RT-PCR and immunohistochemistry analyses. Microarrays with pathway analyses assessed dopamine and adenosine signaling in the CPu. Activity-dependent neurotransmitter switching of a reserve pool of non-dopaminergic neurons to a dopaminergic phenotype in the ventral tegmental area (VTA) was determined by immunohistochemistry and quantified with stereology. TAT expression enhanced methamphetamine-induced sensitization. TAT expression alone decreased striatal dopamine (D1, D2, D4, D5) and ADORA1A receptor expression, while increasing ADORA2A receptors expression. Moreover, TAT expression combined with methamphetamine exposure was associated with increased adenosine A receptors (ADORA1A) expression and increased recruitment of dopamine neurons in the VTA. TAT expression and methamphetamine exposure induced microglia activation with the largest effect after combined exposure. Our findings suggest that dopamine-adenosine receptor interactions and reserve pool neuronal recruitment may represent potential targets to develop new treatments for methamphetamine abuse in individuals with HIV. Copyright © 2017 Elsevier Inc. All rights reserved.

Contrasting Roles of Dopamine and Noradrenaline in the Motivational Properties of Social Play Behavior in Rats.

PubMed

Achterberg, E J Marijke; van Kerkhof, Linda W M; Servadio, Michela; van Swieten, Maaike M H; Houwing, Danielle J; Aalderink, Mandy; Driel, Nina V; Trezza, Viviana; Vanderschuren, Louk J M J

2016-02-01

Social play behavior, abundant in the young of most mammalian species, is thought to be important for social and cognitive development. Social play is highly rewarding, and as such, the expression of social play depends on its pleasurable and motivational properties. Since the motivational properties of social play have only sporadically been investigated, we developed a setup in which rats responded for social play under a progressive ratio schedule of reinforcement. Dopaminergic neurotransmission plays a key role in incentive motivational processes, and both dopamine and noradrenaline have been implicated in the modulation of social play behavior. Therefore, we investigated the role of dopamine and noradrenaline in the motivation for social play. Treatment with the psychostimulant drugs methylphenidate and cocaine increased responding for social play, but suppressed its expression during reinforced play periods. The dopamine reuptake inhibitor GBR-12909 increased responding for social play, but did not affect its expression, whereas the noradrenaline reuptake inhibitor atomoxetine decreased responding for social play as well as its expression. The effects of methylphenidate and cocaine on responding for social play, but not their play-suppressant effects, were blocked by pretreatment with the dopamine receptor antagonist α-flupenthixol. In contrast, pretreatment with the α2-adrenoceptor antagonist RX821002 prevented the play-suppressant effect of methylphenidate, but left its effect on responding for social play unaltered. In sum, the present study introduces a novel method to study the incentive motivational properties of social play behavior in rats. Using this paradigm, we demonstrate dissociable roles for dopamine and noradrenaline in social play behavior: dopamine stimulates the motivation for social play, whereas noradrenaline negatively modulates the motivation for social play behavior and its expression.

The Risky Business of Dopamine Agonists in Parkinson Disease and Impulse Control Disorders

PubMed Central

Claassen, Daniel O.; van den Wildenberg, Wery P.M.; Ridderinkhof, K. Richard; Jessup, Charles K.; Harrison, Madaline B.; Wooten, G. Frederick; Wylie, Scott A.

2011-01-01

Risk-taking behavior is characterized by pursuit of reward in spite of potential negative consequences. Dopamine neurotransmission along the mesocorticolimbic pathway is a potential modulator of risk behavior. In patients with Parkinson's Disease (PD), impulse control disorder (ICD) can result from dopaminergic medication use, particularly Dopamine Agonists (DAA). Behaviors associated with ICD include hypersexuality as well as compulsive gambling, shopping, and eating, and are potentially linked to alterations to risk processing. Using the Balloon Analogue Risk task, we assessed the role of agonist therapy on risk-taking behavior in PD patients with (n=22) and without (n=19) active ICD symptoms. Patients performed the task both ‘on’ and ‘off’ DAA. DAA increased risk-taking in PD patients with active ICD symptoms, but did not affect risk behavior of PD controls. DAA dose was also important in explaining risk behavior. Both groups similarly reduced their risk-taking in high compared to low risk conditions and following the occurrence of a negative consequence, suggesting that ICD patients do not necessarily differ in their ability to process and adjust to some aspects of negative consequences. Our findings suggest dopaminergic augmentation of risk-taking behavior as a potential contributing mechanism for the emergence of ICD in PD patients. PMID:21604834

Muscarinic M4 Receptors on Cholinergic and Dopamine D1 Receptor-Expressing Neurons Have Opposing Functionality for Positive Reinforcement and Influence Impulsivity.

PubMed

Klawonn, Anna M; Wilhelms, Daniel B; Lindström, Sarah H; Singh, Anand Kumar; Jaarola, Maarit; Wess, Jürgen; Fritz, Michael; Engblom, David

2018-01-01

The neurotransmitter acetylcholine has been implicated in reward learning and drug addiction. However, the roles of the various cholinergic receptor subtypes on different neuron populations remain elusive. Here we study the function of muscarinic M4 receptors (M4Rs) in dopamine D1 receptor (D1R) expressing neurons and cholinergic neurons (expressing choline acetyltransferase; ChAT), during various reward-enforced behaviors and in a "waiting"-impulsivity test. We applied cell-type-specific gene deletions targeting M4Rs in D1RCre or ChATCre mice. Mice lacking M4Rs in D1R-neurons displayed greater cocaine seeking and drug-primed reinstatement than their littermate controls in a Pavlovian conditioned place preference (CPP) paradigm. Furthermore, the M4R-D1RCre mice initiated significantly more premature responses (PRs) in the 5-choice-serial-reaction-time-task (5CSRTT) than their littermate controls, indicating impaired waiting impulse control. In contrast, mice lacking M4Rs in cholinergic neurons did not acquire cocaine Pavlovian conditioning. The M4R-ChATCre mice were also unable to learn positive reinforcement to either natural reward or cocaine in an operant runway paradigm. Immediate early gene (IEG) expression ( cFos and FosB ) induced by repeated cocaine injections was significantly increased in the forebrain of M4R-D1RCre mice, whereas it remained normal in the M4R-ChATCre mice. Our study illustrates that muscarinic M4Rs on specific neural populations, either cholinergic or D1R-expressing, are pivotal for learning processes related to both natural reward and drugs of abuse, with opposing functionality. Furthermore, we found that neurons expressing both M4Rs and D1Rs are important for signaling impulse control.

The agranular and granular insula differentially contribute to gambling-like behavior on a rat slot machine task: effects of inactivation and local infusion of a dopamine D4 agonist on reward expectancy.

PubMed

Cocker, P J; Lin, M Y; Barrus, M M; Le Foll, B; Winstanley, C A

2016-09-01

Rats, like humans, are susceptible to the reinforcing effects of reward-related stimuli presented within a compound stimulus array, putatively analogous to the so-called near-miss effect. We have previously demonstrated using a rodent slot machine task (rSMT) that the reward expectancy these stimuli elicit is critically mediated by the dopamine D4 receptor. D4 receptors are principally located in prefrontal regions activated during slot machine play in humans, such as the insular cortex. The insula has recently attracted considerable interest as it appears to play a crucial role in substance and behavioral addictions. However, the insula is a heterogeneous area, and the relative contributions of subregions to addictive behaviors are unclear. Male Long Evans rats were trained to perform the rSMT, and then bilateral cannula targeting either the granular or agranular insula were implanted. The effects of inactivation and local administration of a D4 agonist were investigated. Temporary inactivation of the agranular, but not the granular insula impaired performance on the rSMT. In contrast, local infusion of the D4 agonist PD168077 into the agranular insula had no effect on task performance, but when administered into the granular insula, it improved animals' ability to differentiate winning from non-winning trials. The agranular insula may therefore modulate decision making when conflicting stimuli are present, potentially due to its role in generating a cohesive emotional percept based on both externally and internally generated signals, whereas the granular insular is not critical for this process. Nevertheless, D4 receptors within the granular insula may amplify the incentive salience of aversive environmental stimuli. These data provide insight into the neurobiological mechanism underpinning maladaptive reward expectancy during gambling and provide further evidence that D4 receptors represent a potential target for developing pharmacotherapies for problem gambling.

The left hemisphere learns what is right: Hemispatial reward learning depends on reinforcement learning processes in the contralateral hemisphere.

PubMed

Aberg, Kristoffer Carl; Doell, Kimberly Crystal; Schwartz, Sophie

2016-08-01

Orienting biases refer to consistent, trait-like direction of attention or locomotion toward one side of space. Recent studies suggest that such hemispatial biases may determine how well people memorize information presented in the left or right hemifield. Moreover, lesion studies indicate that learning rewarded stimuli in one hemispace depends on the integrity of the contralateral striatum. However, the exact neural and computational mechanisms underlying the influence of individual orienting biases on reward learning remain unclear. Because reward-based behavioural adaptation depends on the dopaminergic system and prediction error (PE) encoding in the ventral striatum, we hypothesized that hemispheric asymmetries in dopamine (DA) function may determine individual spatial biases in reward learning. To test this prediction, we acquired fMRI in 33 healthy human participants while they performed a lateralized reward task. Learning differences between hemispaces were assessed by presenting stimuli, assigned to different reward probabilities, to the left or right of central fixation, i.e. presented in the left or right visual hemifield. Hemispheric differences in DA function were estimated through differential fMRI responses to positive vs. negative feedback in the left vs. right ventral striatum, and a computational approach was used to identify the neural correlates of PEs. Our results show that spatial biases favoring reward learning in the right (vs. left) hemifield were associated with increased reward responses in the left hemisphere and relatively better neural encoding of PEs for stimuli presented in the right (vs. left) hemifield. These findings demonstrate that trait-like spatial biases implicate hemisphere-specific learning mechanisms, with individual differences between hemispheres contributing to reinforcing spatial biases. Copyright © 2016 Elsevier Ltd. All rights reserved.

The partial dopamine D2 receptor agonist aripiprazole is associated with weight gain in adolescent anorexia nervosa.

PubMed

Frank, Guido K W; Shott, Megan E; Hagman, Jennifer O; Schiel, Marissa A; DeGuzman, Marisa C; Rossi, Brogan

2017-04-01

Finding medication to support treatment of anorexia nervosa has been difficult. Neuroscience-based approaches may help in this effort. Recent brain imaging studies in adults and adolescents with anorexia nervosa suggest that dopamine-related reward circuits are hypersensitive and could provide a treatment target. Here, we present a retrospective chart review of 106 adolescents with anorexia nervosa some of whom were treated with the dopamine D2 receptor partial agonist aripiprazole during treatment in a specialized eating disorder program. The results show that aripiprazole treatment was associated with greater increase in body mass index (BMI) during treatment. The use of dopamine receptor agonists may support treatment success in anorexia nervosa and should be further investigated. © 2017 Wiley Periodicals, Inc.

Dopamine antagonism decreases willingness to expend physical, but not cognitive, effort: a comparison of two rodent cost/benefit decision-making tasks.

PubMed

Hosking, Jay G; Floresco, Stan B; Winstanley, Catharine A

2015-03-01

Successful decision making often requires weighing a given option's costs against its associated benefits, an ability that appears perturbed in virtually every severe mental illness. Animal models of such cost/benefit decision making overwhelmingly implicate mesolimbic dopamine in our willingness to exert effort for a larger reward. Until recently, however, animal models have invariably manipulated the degree of physical effort, whereas human studies of effort have primarily relied on cognitive costs. Dopamine's relationship to cognitive effort has not been directly examined, nor has the relationship between individuals' willingness to expend mental versus physical effort. It is therefore unclear whether willingness to work hard in one domain corresponds to willingness in the other. Here we utilize a rat cognitive effort task (rCET), wherein animals can choose to allocate greater visuospatial attention for a greater reward, and a previously established physical effort-discounting task (EDT) to examine dopaminergic and noradrenergic contributions to effort. The dopamine antagonists eticlopride and SCH23390 each decreased willingness to exert physical effort on the EDT; these drugs had no effect on willingness to exert mental effort for the rCET. Preference for the high effort option correlated across the two tasks, although this effect was transient. These results suggest that dopamine is only minimally involved in cost/benefit decision making with cognitive effort costs. The constructs of mental and physical effort may therefore comprise overlapping, but distinct, circuitry, and therapeutic interventions that prove efficacious in one effort domain may not be beneficial in another.

Decoding the Dopamine Signal in Macaque Prefrontal Cortex: A Simulation Study Using the Cx3Dp Simulator

PubMed Central

Spühler, Isabelle Ayumi; Hauri, Andreas

2013-01-01

Dopamine transmission in the prefrontal cortex plays an important role in reward based learning, working memory and attention. Dopamine is thought to be released non-synaptically into the extracellular space and to reach distant receptors through diffusion. This simulation study examines how the dopamine signal might be decoded by the recipient neuron. The simulation was based on parameters from the literature and on our own quantified, structural data from macaque prefrontal area 10. The change in extracellular dopamine concentration was estimated at different distances from release sites and related to the affinity of the dopamine receptors. Due to the sparse and random distribution of release sites, a transient heterogeneous pattern of dopamine concentration emerges. Our simulation predicts, however, that at any point in the simulation volume there is sufficient dopamine to bind and activate high-affinity dopamine receptors. We propose that dopamine is broadcast to its distant receptors and any change from the local baseline concentration might be decoded by a transient change in the binding probability of dopamine receptors. Dopamine could thus provide a graduated ‘teaching’ signal to reinforce concurrently active synapses and cell assemblies. In conditions of highly reduced or highly elevated dopamine levels the simulations predict that relative changes in the dopamine signal can no longer be decoded, which might explain why cognitive deficits are observed in patients with Parkinson’s disease, or induced through drugs blocking dopamine reuptake. PMID:23951205

Dynorphin/Kappa Opioid Receptor Signaling in Preclinical Models of Alcohol, Drug, and Food Addiction.

PubMed

Karkhanis, Anushree; Holleran, Katherine M; Jones, Sara R

2017-01-01

The dynorphin/kappa opioid receptor (KOR) system is implicated in the "dark side" of addiction, in which stress exacerbates maladaptive responses to drug and alcohol exposure. For example, acute stress and acute ethanol exposure result in an elevation in dynorphin, the KOR endogenous ligand. Activation of KORs results in modulation of several neurotransmitters; however, this chapter will focus on its regulatory effects on dopamine in mesolimbic areas. Specifically, KOR activation has an inhibitory effect on dopamine release, thereby influencing reward processing. Repeated stimulation of KORs, for example, via chronic drug and/or stress exposure, results in increased function of the dynorphin/KOR system. This augmentation in KOR function shifts the homeostatic balance in favor of an overall reduction in dopamine signaling via either by reducing dopamine release or by increasing dopamine transporter function. This chapter examines the effects of chronic ethanol exposure on KOR function and the downstream effects on dopamine transmission. Additionally, the impact of chronic cocaine exposure and its effects on KOR function will be explored. Further, KORs may also be involved in driving excessive consumption of food, contributing to the risk of developing obesity. While some studies have shown that KOR agonists reduce drug intake, other studies have shown that antagonists reduce addiction-like behaviors, demonstrating therapeutic potential. For example, KOR inhibition reduces ethanol intake in dependent animals, motivation to self-administer cocaine in chronic stress-exposed animals, and food consumption in obese animals. This chapter will delve into the mechanisms by which modulation of the dynorphin/KOR system may be therapeutic. © 2017 Elsevier Inc. All rights reserved.

Neurobiological correlates of social functioning in autism.

PubMed

Neuhaus, Emily; Beauchaine, Theodore P; Bernier, Raphael

2010-08-01

Although autism is defined by deficits in three areas of functioning (social, communicative, and behavioral), impairments in social interest and restricted behavioral repertoires are central to the disorder. As a result, a detailed understanding of the neurobiological systems subserving social behavior may have implications for prevention, early identification, and intervention for affected families. In this paper, we review a number of potential neurobiological mechanisms--across several levels of analysis--that subserve normative social functioning. These include neural networks, neurotransmitters, and hormone systems. After describing the typical functioning of each system, we review available empirical findings specific to autism. Among the most promising potential mechanisms of social behavioral deficits in autism are those involving neural networks including the amygdala, the mesocorticolimbic dopamine system, and the oxytocin system. Particularly compelling are explanatory models that integrate mechanisms across biological systems, such as those linking dopamine and oxytocin with brain regions critical to reward processing. Copyright 2010 Elsevier Ltd. All rights reserved.

A common neural circuit mechanism for internally guided and externally reinforced forms of motor learning.

PubMed

Hisey, Erin; Kearney, Matthew Gene; Mooney, Richard

2018-04-01

The complex skills underlying verbal and musical expression can be learned without external punishment or reward, indicating their learning is internally guided. The neural mechanisms that mediate internally guided learning are poorly understood, but a circuit comprising dopamine-releasing neurons in the midbrain ventral tegmental area (VTA) and their targets in the basal ganglia are important to externally reinforced learning. Juvenile zebra finches copy a tutor song in a process that is internally guided and, in adulthood, can learn to modify the fundamental frequency (pitch) of a target syllable in response to external reinforcement with white noise. Here we combined intersectional genetic ablation of VTA neurons, reversible blockade of dopamine receptors in the basal ganglia, and singing-triggered optogenetic stimulation of VTA terminals to establish that a common VTA-basal ganglia circuit enables internally guided song copying and externally reinforced syllable pitch learning.

Acute stress-induced cortisol elevations mediate reward system activity during subconscious processing of sexual stimuli.

PubMed

Oei, Nicole Y L; Both, Stephanie; van Heemst, Diana; van der Grond, Jeroen

2014-01-01

Stress is thought to alter motivational processes by increasing dopamine (DA) secretion in the brain's "reward system", and its key region, the nucleus accumbens (NAcc). However, stress studies using functional magnetic resonance imaging (fMRI), mainly found evidence for stress-induced decreases in NAcc responsiveness toward reward cues. Results from both animal and human PET studies indicate that the stress hormone cortisol may be crucial in the interaction between stress and dopaminergic actions. In the present study we therefore investigated whether cortisol mediated the effect of stress on DA-related responses to -subliminal-presentation of reward cues using the Trier Social Stress Test (TSST), which is known to reliably enhance cortisol levels. Young healthy males (n = 37) were randomly assigned to the TSST or control condition. After stress induction, brain activation was assessed using fMRI during a backward-masking paradigm in which potentially rewarding (sexual), emotionally negative and neutral stimuli were presented subliminally, masked by pictures of inanimate objects. A region of interest analysis showed that stress decreased activation in the NAcc in response to masked sexual cues (voxel-corrected, p<05). Furthermore, with mediation analysis it was found that high cortisol levels were related to stronger NAcc activation, showing that cortisol acted as a suppressor variable in the negative relation between stress and NAcc activation. The present findings indicate that cortisol is crucially involved in the relation between stress and the responsiveness of the reward system. Although generally stress decreases activation in the NAcc in response to rewarding stimuli, high stress-induced cortisol levels suppress this relation, and are associated with stronger NAcc activation. Individuals with a high cortisol response to stress might on one hand be protected against reductions in reward sensitivity, which has been linked to anhedonia and depression, but they may ultimately be more vulnerable to increased reward sensitivity, and addictions. Future studies investigating effects of stress on reward sensitivity should take into account the severity of the stressor and the individual cortisol response to stress. Copyright © 2013 Elsevier Ltd. All rights reserved.