dopamine and wanting


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(Updated 3/25/04)

Noam Chomsky
A Review of B. F. Skinner's Verbal Behavior
Language, 35, No. 1 (1959), 26-58.
"From this sample, it can be seen that the notion of reinforcement has totally lost whatever objective meaning it may ever have had. Running through these examples, we see that a person can be reinforced though he emits no response at all, and that the reinforcing stimulus need not impinge on the reinforced person or need not even exist (it is sufficient that it be imagined or hoped for). When we read that a person plays what music he likes (165), says what he likes (165), thinks what he likes (438-39), reads what books he likes (163), etc., BECAUSE he finds it reinforcing to do so, or that we write books or inform others of facts BECAUSE we are reinforced by what we hope will be the ultimate behavior of reader or listener, we can only conclude that the term reinforcement has a purely ritual function. The phrase "X is reinforced by Y (stimulus, state of affairs, event, etc.)" is being used as a cover term for "X wants Y," "X likes Y," "X wishes that Y were the case," etc. Invoking the term reinforcement has no explanatory force, and any idea that this paraphrase introduces any new clarity or objectivity into the description of wishing, liking, etc., is a serious delusion. The only effect is to obscure the important differences among the notions being paraphrased." [Full Text]

Berridge KC, Robinson TE.
What is the role of dopamine in reward: hedonic impact, reward learning, or incentive salience?
Brain Res Brain Res Rev. 1998 Dec;28(3):309-69.
"What roles do mesolimbic and neostriatal dopamine systems play in reward? Do they mediate the hedonic impact of rewarding stimuli? Do they mediate hedonic reward learning and associative prediction? Our review of the literature, together with results of a new study of residual reward capacity after dopamine depletion, indicates the answer to both questions is 'no'. Rather, dopamine systems may mediate the incentive salience of rewards, modulating their motivational value in a manner separable from hedonia and reward learning. In a study of the consequences of dopamine loss, rats were depleted of dopamine in the nucleus accumbens and neostriatum by up to 99% using 6-hydroxydopamine. In a series of experiments, we applied the 'taste reactivity' measure of affective reactions (gapes, etc.) to assess the capacity of dopamine-depleted rats for: 1) normal affect (hedonic and aversive reactions), 2) modulation of hedonic affect by associative learning (taste aversion conditioning), and 3) hedonic enhancement of affect by non-dopaminergic pharmacological manipulation of palatability (benzodiazepine administration). We found normal hedonic reaction patterns to sucrose vs. quinine, normal learning of new hedonic stimulus values (a change in palatability based on predictive relations), and normal pharmacological hedonic enhancement of palatability. We discuss these results in the context of hypotheses and data concerning the role of dopamine in reward. We review neurochemical, electrophysiological, and other behavioral evidence. We conclude that dopamine systems are not needed either to mediate the hedonic pleasure of reinforcers or to mediate predictive associations involved in hedonic reward learning. We conclude instead that dopamine may be more important to incentive salience attributions to the neural representations of reward-related stimuli. Incentive salience, we suggest, is a distinct component of motivation and reward. In other words, dopamine systems are necessary for 'wanting' incentives, but not for 'liking' them or for learning new 'likes' and 'dislikes'." [Abstract]

Ahn, Soyon, Phillips, Anthony G.
Dopaminergic Correlates of Sensory-Specific Satiety in the Medial Prefrontal Cortex and Nucleus Accumbens of the Rat
J. Neurosci. 1999 19: 29RC-
"Changes in dopamine (DA) efflux in the medial prefrontal cortex and nucleus accumbens of rats were monitored using in vivo microdialysis during sensory-specific satiety experiments. Rats consumed significant amounts of a palatable food during an initial meal but ate little when the same food was available as a second meal. In contrast, rats given a different palatable food ate a significant quantity during the second meal. DA efflux in both brain regions reflected this difference in food intake, indicating that DA activity is influenced by changes in the deprivation state of animals and sensory incentive properties of food. Given the proposed role of DA in motivated behaviors, these findings suggest that DA efflux may signal the relative incentive salience of foods and thus is a determinant of the pattern of food consumption observed in sensory-specific satiety."
[Full Text]

Volkow ND, Wang GJ, Fowler JS, Telang F, Maynard L, Logan J, Gatley SJ, Pappas N, Wong C, Vaska P, Zhu W, Swanson JM.
Evidence that methylphenidate enhances the saliency of a mathematical task by increasing dopamine in the human brain.
Am J Psychiatry. 2004 Jul;161(7):1173-80.
"OBJECTIVE: Methylphenidate is the most commonly prescribed drug for attention deficit hyperactivity disorder (ADHD), yet its therapeutic mechanisms are poorly understood. The objective of this study was to assess if methylphenidate, by increasing dopamine (neurotransmitter involved in motivation) in brain, would enhance the saliency of an academic task, making it more interesting. METHOD: Healthy subjects (N=16) underwent positron emission tomography with [(11)C]raclopride (dopamine D(2) receptor radioligand that competes with endogenous dopamine for binding) to assess the effects of oral methylphenidate (20 mg) on extracellular dopamine in the striatum. The authors compared the effects of methylphenidate during an academic task (solving mathematical problems with monetary reinforcement) and a neutral task (passively viewing cards with no remuneration). In parallel, the effects of methylphenidate on the interest that the academic task elicited were also evaluated. RESULTS: Methylphenidate, when coupled with the mathematical task, significantly increased extracellular dopamine, but this did not occur when coupled with the neutral task. The mathematical task did not increase dopamine when coupled with placebo. Subjective reports about interest and motivation in the mathematical task were greater with methylphenidate than with placebo and were associated with dopamine increases. CONCLUSIONS: The significant association between methylphenidate-induced dopamine increases and the interest and motivation for the task confirms the prediction that methylphenidate enhances the saliency of an event by increasing dopamine. The enhanced interest for the task could increase attention and improve performance and could be one of the mechanisms underlying methylphenidate's therapeutic effects. These findings support educational strategies that make schoolwork more interesting as nonpharmacological interventions to treat ADHD." [Abstract]

Leyton M, Boileau I, Benkelfat C, Diksic M, Baker G, Dagher A.
Amphetamine-induced increases in extracellular dopamine, drug wanting, and novelty seeking: a PET/[11C]raclopride study in healthy men.
Neuropsychopharmacology. 2002 Dec;27(6):1027-35.
"Eight healthy men underwent two positron emission tomography (PET) [11C]raclopride scans, one following placebo, the second following d-amphetamine (0.30 mg/kg, p.o.). PET data were analyzed using: (1) brain parametric maps to statistically generate regions of significant change; and (2) a priori identified regions of interest (ROI) manually drawn on each individual's co-registered magnetic resonance (MR) images. Compared with placebo, d-amphetamine decreased [11C]raclopride binding potential (BP) with significant effects in ventral but not dorsal striatum. Change in BP in the statistically generated cluster correlated with self-reported drug-induced 'drug wanting' (r = 0.83, p =.01) and the personality trait of Novelty Seeking-Exploratory Excitability (r = 0.79, p =.02). The same associations were seen in the manually drawn ROI in ventral striatum but not in dorsal putamen or caudate. Changes in extracellular dopamine (DA) did not correlate with mood. Mesolimbic DA might mediate interest in obtaining reward rather than reward, per se. Individual differences in amphetamine-induced DA release might be related to predispositions to drug and novelty seeking." [Abstract]

de la Fuente-Fernandez R, Phillips AG, Zamburlini M, Sossi V, Calne DB, Ruth TJ, Stoessl AJ.
Dopamine release in human ventral striatum and expectation of reward.
Behav Brain Res. 2002 Nov 15;136(2):359-63.
"Using the ability of [11C]raclopride to compete with dopamine for D(2)/D(3) receptors, we investigated by positron emission tomography the effect of placebo (saline) injection on dopamine release in the ventral striatum of patients with Parkinson's disease. We found evidence for placebo-induced dopamine release of similar magnitude to that reported in healthy volunteers after amphetamine administration. However, in contrast to the dorsal striatum, there were no differences in [11C]raclopride binding potential changes between patients who experienced the reward (those who reported placebo-induced clinical benefit) and those who did not. We conclude that the release of dopamine in the ventral striatum (nucleus accumbens) is related to the expectation of reward and not to the reward itself. These observations have potential implications for the treatment of drug addiction." [Abstract]

Schmidt K, Nolte-Zenker B, Patzer J, Bauer M, Schmidt LG, Heinz A.
Psychopathological correlates of reduced dopamine receptor sensitivity in depression, schizophrenia, and opiate and alcohol dependence.
Pharmacopsychiatry. 2001 Mar;34(2):66-72.
"A dysfunction of central dopaminergic neurotransmission has been found in various neuropsychiatric diseases, and may be associated with a common psychopathological correlate. One hypothesis suggests that dopaminergic stimulation of the brain reward system reinforces behavior because it is experienced as pleasurable, and that dopaminergic dysfunction leads to anhedonia, the inability to experience pleasure. An alternative hypothesis assumes that dopaminergic stimulation does not promote pleasure or "liking" of a reward but rather mediates "wanting" of a reward, and suggests that dopaminergic dysfunction is associated with a failure to be motivated by stimuli that indicate reward. We measured negative symptoms, psychomotor slowing and dopamine receptor sensitivity in twelve drug-free patients with major depression, seventeen alcohol-dependent and sixteen opiate-dependent patients, ten schizophrenics with neuroleptic medication, and ten healthy controls. The sensitivity of central dopamine receptors was assessed with the growth hormone response to apomorphine application. Psychomotor slowing was measured in a reaction-time test and anhedonia and other negative symptoms were assessed with self-rating scales and the Scale for the Assessment of Negative Symptoms. Patients with major depression, alcohol dependence and neuroleptic medication displayed a reduced sensitivity of central dopamine receptors compared to control subjects. Anhedonia was not a common correlate of dopamine receptor dysfunction. Instead, affective flattening was associated with both dopamine receptor sensitivity and psychomotor slowing. Our findings thus do not support the anhedonia hypothesis of central dopaminergic dysfunction. Rather, affective flattening may result from the lack of an emotional response towards reward-indicating stimuli. These findings indicate that patients with dopaminergic dysfunction are not unable to experience pleasure, but may fail to be motivated by environmental stimuli to seek reward." [Abstract]

Salamone JD, Correa M.
Motivational views of reinforcement: implications for understanding the behavioral functions of nucleus accumbens dopamine.
Behav Brain Res. 2002 Dec 2;137(1-2):3-25.
"Although the Skinnerian 'Empirical Law of Effect' does not directly consider the fundamental properties of stimuli that enable them to act as reinforcers, such considerations are critical for determining if nucleus accumbens dopamine systems mediate reinforcement processes. Researchers who have attempted to identify the critical characteristics of reinforcing stimuli or activities have generally arrived at an emphasis upon motivational factors. A thorough review of the behavioral literature indicates that, across several different investigators offering a multitude of theoretical approaches, motivation is seen by many as being fundamental to the process of reinforcement. The reinforcer has been described as a goal, a commodity, an incentive, or a stimulus that is being approached, self-administered, attained or preserved. Reinforcers also have been described as activities that are preferred, deprived or in some way being regulated. It is evident that this 'motivational' or 'regulatory' view of reinforcement has had enormous influence over the hypothesis that DA directly mediates 'reward' or 'reinforcement' processes. Indeed, proponents of the DA/reward hypothesis regularly cite motivational theorists and employ their language. Nevertheless, considerable evidence indicates that low/moderate doses of DA antagonists, and depletions of DA in nucleus accumbens, can suppress instrumental responding for food while, at the same time, these conditions leave fundamental aspects of reinforcement (i.e. primary or unconditioned reinforcement; primary motivation or primary incentive properties of natural reinforcers) intact. Several complex features of the literature on dopaminergic involvement in reinforcement are examined below, and it is argued that the assertions that DA mediates 'reward' or 'reinforcement' are inaccurate and grossly oversimplified. Thus, it appears as though it is no longer tenable to assert that drugs of abuse are simply turning on the brain's natural 'reward system'. In relation to the hypothesis that DA systems are involved in 'wanting', but not 'liking', it is suggested in the present review that 'wanting' has both directional aspects (e.g. appetite to consume food) and activational aspects (e.g. activation for initiating and sustaining instrumental actions; tendency to work for food). The present paper reviews findings in support of the hypothesis that low doses of DA antagonists and accumbens DA depletions do not impair appetite to consume food, but do impair activational aspects of motivation. This suggestion is consistent with the studies showing that low doses of DA antagonists and accumbens DA depletions alter the relative allocation of instrumental responses, making the animals less likely to engage in instrumental responses that have a high degree of work-related response costs. In addition, this observation is consistent with studies demonstrating that accumbens DA depletions make rats highly sensitive to ratio requirements on operant schedules. Although accumbens DA is not seen as directly mediating appetite to consume food, principles of behavioral economics indicate that accumbens DA could be involved in the elasticity of demand for food in terms of the tendency to pay work-related response costs. Future research must focus upon how specific aspects of task requirements (i.e. ratio requirements, intermittence of reinforcement, temporal features of response requirements, dependence upon conditioned stimuli) interact with the effects of accumbens DA depletions, and which particular factors determine sensitivity to the effects of DA antagonism or depletion." [Abstract]

Robinson TE, Berridge KC.
The psychology and neurobiology of addiction: an incentive-sensitization view.
Addiction. 2000 Aug;95 Suppl 2:S91-117.
"The question of addiction specifically concerns (1), the process by which drug-taking behavior, in certain individuals, evolves into compulsive patterns of drug-seeking and drug-taking behavior that take place at the expense of most other activities and (2), the inability to cease drug-taking; the problem of relapse. In this paper current biopsychological views of addiction are critically evaluated in light of the "incentive-sensitization theory of addiction", which we first proposed in 1993, and new developments in research are incorporated. We argue that traditional negative reinforcement, positive reinforcement, and hedonic accounts of addiction are neither necessary nor sufficient to account for compulsive patterns of drug-seeking and drug-taking behavior. Four major tenets of the incentive-sensitization view are discussed. These are: (1) Potentially addictive drugs share the ability to produce long-lasting adaptations in neural systems. (2) The brain systems that are changed include those normally involved in the process of incentive motivation and reward. (3) The critical neuroadaptations for addiction render these brain reward systems hypersensitive ("sensitized") to drugs and drug-associated stimuli. (4) The brain systems that are sensitized do not mediate the pleasurable or euphoric effects of drugs (drug "liking"), but instead they mediate a subcomponent of reward we have termed incentive salience (drug "wanting"). We also discuss the role that mesolimbic dopamine systems play in reward, evidence that neural sensitization happens in humans, and the implications of incentive-sensitization for the development of therapies in the treatment of addiction." [Abstract]

Berridge KC.
Pleasures of the brain.
Brain Cogn. 2003 Jun;52(1):106-28.
"How does the brain cause positive affective reactions to sensory pleasure? An answer to pleasure causation requires knowing not only which brain systems are activated by pleasant stimuli, but also which systems actually cause their positive affective properties. This paper focuses on brain causation of behavioral positive affective reactions to pleasant sensations, such as sweet tastes. Its goal is to understand how brain systems generate 'liking,' the core process that underlies sensory pleasure and causes positive affective reactions. Evidence suggests activity in a subcortical network involving portions of the nucleus accumbens shell, ventral pallidum, and brainstem causes 'liking' and positive affective reactions to sweet tastes. Lesions of ventral pallidum also impair normal sensory pleasure. Recent findings regarding this subcortical network's causation of core 'liking' reactions help clarify how the essence of a pleasure gloss gets added to mere sensation. The same subcortical 'liking' network, via connection to brain systems involved in explicit cognitive representations, may also in turn cause conscious experiences of sensory pleasure." [Abstract]

Reynolds, Sheila M., Berridge, Kent C.
Positive and Negative Motivation in Nucleus Accumbens Shell: Bivalent Rostrocaudal Gradients for GABA-Elicited Eating, Taste "Liking"/"Disliking" Reactions, Place Preference/Avoidance, and Fear
J. Neurosci. 2002 22: 7308-7320
"Microinjection of the GABAA agonist muscimol in the rostral medial accumbens shell in rats elicits appetitive eating behavior, but in the caudal shell instead elicits fearful defensive treading behavior. To further test the hypothesis that rostral shell muscimol microinjections produce positive motivational states, whereas caudal shell muscimol produces negative states, we measured behavioral place preference/avoidance conditioning and affective hedonic and aversive orofacial expressions of taste-elicited "liking" and "disliking" (gapes, etc.) in addition to fear and feeding behaviors. Farthest rostral muscimol microinjections (75 ng) caused increased eating behavior and also caused positive conditioned place preferences and increased positive hedonic reactions to the taste of sucrose. By contrast, caudal shell microinjections elicited negative defensive treading and caused robust negative conditioned place avoidance and negative aversive reactions to sucrose or quinine tastes. Intermediate rostral microinjections elicited effects of mixed positive/negative valence (positive appetitive eating behavior but negative place avoidance and negative taste reactions at mid-rostral sites, and sometimes positive eating simultaneously with fearful defensive treading more caudally). These results indicate that GABAergic neurotransmission in local microcircuits in nucleus accumbens mediates motivated/affective behavior that is bivalently organized along rostrocaudal gradients."

Volkow ND, Wang GJ, Maynard L, Jayne M, Fowler JS, Zhu W, Logan J, Gatley SJ, Ding YS, Wong C, Pappas N.
Brain dopamine is associated with eating behaviors in humans.
Int J Eat Disord. 2003 Mar;33(2):136-42.
"OBJECTIVE: Eating behavior in humans is influenced by variables other than just hunger-satiety including cognitive restraint, emotional distress, and sensitivity to food stimuli. We investigate the role of dopamine (DA), a neurotransmitter involved with food motivation, in these variables. METHODS: We used the Dutch Eating Behavior Questionnaire (DEBQ) to measure Restraint, Emotionality, and Externality in 10 subjects. We correlated DEBQ scores with brain DA levels. Positron emission tomography and [(11)C]raclopride uptake were used to measure baseline D(2) receptors (neutral stimulation) and to assess changes in extracellular DA to food stimulation (display of food). RESULTS: Restraint was correlated with DA changes with food stimulation (higher restraint, greater responsivity), emotionality was negatively correlated with baseline D(2) receptors (higher emotionality, lower D(2) receptors), whereas externality was not. These correlations were significant in the dorsal but not in the ventral striatum. DISCUSSION: These results provide evidence that DA in the dorsal striatum is involved with the restraint and emotionality components regulating eating behavior and that these two dimensions reflect different neurobiologic processes." [Abstract]

Goto, Yukiori, O'Donnell, Patricio
Synchronous Activity in the Hippocampus and Nucleus Accumbens In Vivo
J. Neurosci. 2001 21: 131-
"The hippocampus is one of the brain regions involved in cognitive functions, including learning and memory. Extensive studies have unveiled how information is processed within this system. However, the mechanisms by which hippocampal activity is translated into action remain unsolved. One important target of hippocampal projections is the nucleus accumbens, which has been described as the motivation-to-action interface. Previous experiments indicate that these projections can control information processing in this region by setting neurons into a depolarized state. Here, we report that membrane potential transitions in nucleus accumbens neurons are correlated with electrical activity in the ventral hippocampus, suggesting that hippocampal neural activity can determine ensembles of active accumbens neurons." [Full Text]

Drevets WC, Gautier C, Price JC, Kupfer DJ, Kinahan PE, Grace AA, Price JL, Mathis CA.
Amphetamine-induced dopamine release in human ventral striatum correlates with euphoria.
Biol Psychiatry. 2001 Jan 15;49(2):81-96.
"BACKGROUND: Studies in experimental animals have implicated the mesolimbic dopaminergic projections into the ventral striatum in the neural processes underlying behavioral reinforcement and motivated behavior; however, understanding the relationship between subjective emotional experience and ventral striatal dopamine (DA) release has awaited human studies. Using positron emission tomography (PET), we correlated the change in endogenous dopamine concentrations following dextroamphetamine (AMPH) administration with the associated hedonic response in human subjects and compared the strength of this correlation across striatal subregions. METHODS: We obtained PET measures of [(11)C]raclopride specific binding to DA D2/D3 receptors before and after AMPH injection (0.3 mg/kg IV) in seven healthy subjects. The change in [(11)C]raclopride binding potential (DeltaBP) induced by AMPH pretreatment and the correlation between DeltaBP and the euphoric response to AMPH were compared between the anteroventral striatum (AVS; comprised of accumbens area, ventromedial caudate, and anteroventral putamen) and the dorsal caudate (DCA) using an MRI-based region of interest analysis of the PET data. RESULTS: The mean DeltaBP was greater in the AVS than in the DCA (p <.05). The AMPH-induced changes in euphoria analog scale scores correlated inversely with DeltaBP in the AVS (r = -.95; p <.001), but not in the DCA (r =.30, ns). Post hoc assessments showed that changes in tension-anxiety ratings correlated positively with DeltaBP in the AVS (r =.80; p [uncorrected] <.05) and that similar relationships may exist between DeltaBP and emotion ratings in the ventral putamen (as were found in the AVS). CONCLUSIONS: The preferential sensitivity of the ventral striatum to the DA releasing effects of AMPH previously demonstrated in experimental animals extends to humans. The magnitude of ventral striatal DA release correlates positively with the hedonic response to AMPH." [Abstract]

Michel Barrot, Jocelien D. A. Olivier, Linda I. Perrotti, Ralph J. DiLeone, Olivier Berton, Amelia J. Eisch, Soren Impey, Daniel R. Storm, Rachael L. Neve, Jerry C. Yin, Venetia Zachariou, and Eric J. Nestler
CREB activity in the nucleus accumbens shell controls gating of behavioral responses to emotional stimuli
PNAS 99: 11435-11440; published online before print as 10.1073/pnas.172091899
"The transcription factor cAMP response element (CRE)-binding protein (CREB) has been shown to regulate neural plasticity. Drugs of abuse activate CREB in the nucleus accumbens, an important part of the brain's reward pathways, and local manipulations of CREB activity have been shown to affect cocaine reward, suggesting an active role of CREB in adaptive processes that follow exposure to drugs of abuse. Using CRE-LacZ reporter mice, we show that not only rewarding stimuli such as morphine, but also aversive stimuli such as stress, activate CRE-mediated transcription in the nucleus accumbens shell. Using viral-mediated gene transfer to locally alter the activity of CREB, we show that this manipulation affects morphine reward, as well as the preference for sucrose, a more natural reward. We then show that local changes in CREB activity induce a more general syndrome, by altering reactions to anxiogenic, aversive, and nociceptive stimuli as well. Increased CREB activity in the nucleus accumbens shell decreases an animal's responses to each of these stimuli, whereas decreased CREB activity induces an opposite phenotype. These results show that environmental stimuli regulate CRE-mediated transcription within the nucleus accumbens shell, and that changes in CREB activity within this brain area subsequently alter gating between emotional stimuli and their behavioral responses. This control appears to be independent of the intrinsic appetitive or aversive value of the stimulus. The potential relevance of these data to addiction and mood disorders is discussed." [Full Text]

Helen Phillips
The pleasure seekers
New Scientist, 11 October 2003
"At first glance, the "reward centre" idea seems hard to fault. The self-stimulation experiments, beginning with rats in the 1950s and followed by the human experiments in the 1960s, seemed perfectly clear. Modern brain-imaging studies have confirmed that the centre works overtime whenever you're enjoying something, whether it's sex or chocolate, drugs or music. And chemical analysis shows that, whatever your pleasure, dopamine fuels the circuit. "Dopamine was the pleasure transmitter," says Berridge. "The evidence seemed so strong. If you shut down dopamine signalling by giving a drug that blocks dopamine receptors, you dilute the reward value of everything." So why did he and others begin to question the status quo?

Berridge reckons that his doubts began to creep in around the late 1980s, with a few surprise results. He'd found that he could watch rats' facial expressions to judge their reactions to certain tastes. Believe it or not, rats actually look pleased when given sweet things to taste, and produce the rat equivalent of a disgusted look in response to bitterness. The assumption was that these expressions were of pleasure or displeasure, mediated by the reward centre. The surprise came when Berridge blocked the dopamine signal with drugs. In theory, with dopamine knocked out there was now no way for the rats to sense the reward value of the sweetness, so he was expecting not to see any "pleased" expressions. But the rats seemed just as expressive as ever.

Putting it down to experimental error, Berridge tried a more foolproof test. He used rats in which dopamine-producing cells had been wiped out with a neurotoxin. It was already known that these animals simply stopped eating. "They would voluntarily starve to death if the experimenter didn't intervene and feed them," says Berridge. Researchers had always thought that the rats' lack of dopamine meant they didn't like food. But when Berridge force-fed them with sweet and bitter liquids, their facial reactions were normal. "They still showed the proper positive face to sugar and the proper negative face to quinine," he says. "It looked like their reaction to pleasure was normal even though their dopamine was gone."

What was going on? The experiments prompted Berridge to look back at Heath's brain electrode results. He was struck this time by what feelings the subjects reported. They all said they felt good, and always pleaded for more when the controls were taken away. But was it pleasure? The reports mentioned feelings of alertness, warmth and goodwill, arousal, a desire to masturbate, or to drink even though they weren't thirsty. It sounded more like desire than pleasure. This fitted perfectly with Berridge's rats. Even with no activity in the reward area, they seemed to "like" the taste of sweet food. They just didn't "want" it. Could the dopamine system be a desire circuit that mediates our feelings of wanting something, rather than a pleasure centre that supplies our feelings of liking?

Although it was Berridge who drew attention to the distinction between wanting and liking, he is by no means the only researcher to realise that "pleasure" is not quite the right term to attach to activity in the dopamine system. If people are given drugs that block or stimulate dopamine release, it doesn't alter how much they report liking certain tastes. What that suggests is that the dopamine system itself doesn't produce feelings of pleasure, says Panksepp. "The dopamine system is about motivation and seeking. It gives a generalised desire or urge, an eagerness to engage with the world."

Studies of drug addiction add weight to the idea that the dopamine system is not about pleasure but desire. Addicts always end up needing more of their drug to keep the pleasure level steady. But they never say they develop a greater "liking" for any drug - they just "want" it more and more. ..." [Full Text]

Pecina S, Cagniard B, Berridge KC, Aldridge JW, Zhuang X.
Hyperdopaminergic mutant mice have higher "wanting" but not "liking" for sweet rewards.
J Neurosci. 2003 Oct 15;23(28):9395-402.
"What is the role of dopamine in natural rewards? A genetic mutant approach was taken to examine the consequences of elevated synaptic dopamine on (1) spontaneous food and water intake, (2) incentive motivation and learning to obtain a palatable sweet reward in a runway task, and (3) affective "liking" reactions elicited by the taste of sucrose. A dopamine transporter (DAT) knockdown mutation that preserves only 10% of normal DAT, and therefore causes mutant mice to have 70% elevated levels of synaptic dopamine, was used to identify dopamine effects on food intake and reward. We found that hyperdopaminergic DAT knockdown mutant mice have higher food and water intake. In a runway task, they demonstrated enhanced acquisition and greater incentive performance for a sweet reward. Hyperdopaminergic mutant mice leave the start box more quickly than wild-type mice, require fewer trials to learn, pause less often in the runway, resist distractions better, and proceed more directly to the goal. Those observations suggest that hyperdopaminergic mutant mice attribute greater incentive salience ("wanting") to a sweet reward in the runway test. But sucrose taste fails to elicit higher orofacial "liking" reactions from mutant mice in an affective taste reactivity test. These results indicate that chronically elevated extracellular dopamine facilitates "wanting" and learning of an incentive motivation task for a sweet reward, but elevated dopamine does not increase "liking" reactions to the hedonic impact of sweet tastes." [Abstract]

Zhang M, Balmadrid C, Kelley AE.
Nucleus accumbens opioid, GABaergic, and dopaminergic modulation of palatable food motivation: contrasting effects revealed by a progressive ratio study in the rat.
Behav Neurosci. 2003 Apr;117(2):202-11.
"The current studies were designed to evaluate whether incentive motivation for palatable food is altered after manipulations of opioid, GABAergic, and dopaminergic transmission within the nucleus accumbens. A progressive ratio schedule was used to measure lever-pressing for sugar pellets after microinfusion of drugs into the nucleus accumbens in non-food-deprived rats. The mu opioid agonist D-Ala2, NMe-Phe4, Glyo15-enkephalin and the indirect dopamine agonist amphetamine induced a marked increase in break point and correct lever-presses; the GABA(A) agonist muscimol did not affect breakpoint or lever-presses. The data suggest that opioid, dopaminergic, and GABAergic systems within the accumbens differentially modulate food-seeking behavior through mechanisms related to hedonic evaluation of food, incentive salience, and control of motor feeding circuits, respectively." [Abstract]

Berridge KC.
Food reward: brain substrates of wanting and liking.
Neurosci Biobehav Rev. 1996;20(1):1-25.
"What are the neutral substrates of food reward? Are reward and pleasure identical? Can taste pleasure be assessed in animals? Is reward necessarily conscious? These questions have re-emerged in recent years, and there is now sufficient evidence to prompt re-examination of many preconceptions concerning reward and its relation to brain systems. This paper reviews evidence from many sources regarding both the psychological structure of food reward and the neutral systems that mediate it. Special attention is paid to recent evidence from "tasty reactivity" studies of affective reactions to food. I argue that this evidence suggests the following surprising possibilities regarding the functional components and brain substrates of food reward. (1) Reward contains distinguishable psychological or functional components--"liking" (pleasure/palatability) and "wanting" (appetite/incentive motivation). These can be manipulated and measured separately. (2) Liking and wanting have separable neutral substrates. Mediation of liking related to food reward involves neurotransmitter systems such as opioid and GABA/benzodiazepine systems, and anatomical structures such as ventral pallidum and brainstem primary gustatory relays. Mediation of wanting related to food reward involves mesotelencephalic dopamine systems, and divisions of nucleus accumbens and amygdala. Both liking and wanting arise from vastly distributed neutral systems, but the two systems are separable. (3) Neutral processing of food reward is not confined to the limbic forebrain. Aspects of food reward begin to be processed in the brainstem. A neutral manipulation can enhance reward or produce aversion but no single lesion or transection is likely abolish all properties of food reward. (4) Both wanting and liking can exist without subjective awareness. Conscious experience can distort or blur the underlying reward process that gave rise to it. Subjective reports may contain false assessments of underlying processes, or even fail at all to register important reward processes. The core processes of liking and wanting that constitute reward are distinct from the subjective report or conscious awareness of those processes." [Abstract]

Kelley AE, Bakshi VP, Haber SN, Steininger TL, Will MJ, Zhang M.
Opioid modulation of taste hedonics within the ventral striatum.
Physiol Behav. 2002 Jul;76(3):365-77.
"There is a long-standing interest in the role of endogenous opioid peptides in feeding behavior and, in particular, in the modulation of food reward and palatability. Since drugs such as heroin, morphine, alcohol, and cannabinoids, interact with this system, there may be important common neural substrates between food and drug reward with regard to the brain's opioid systems. In this paper, we review the proposed functional role of opioid neurotransmission and mu opiate receptors within the nucleus accumbens and surrounding ventral striatum. Opioid compounds, particularly those selective for the mu receptor, induce a potent increase in food intake, sucrose, salt, saccharin, and ethanol intake. We have explored this phenomenon with regard to macronutrient selection, regional specificity, role of output structures, Fos mapping, analysis of motivational state, and enkephalin gene expression. We hypothesize that opioid-mediated mechanisms within ventral striatal medium spiny neurons mediate the affective or hedonic response to food ('liking' or food 'pleasure'). A further refinement of this hypothesis is that activation of ventral striatal opioids specifically encodes positive affect induced by tasty and/or calorically dense foods (such as sugar and fat), and promotes behaviors associated with this enhanced palatability. It is proposed that this brain mechanism was beneficial in evolutionary development for ensuring the consumption of relatively scarce, high-energy food sources. However, in modern times, with unlimited supplies of high-calorie food, it has contributed to the present epidemic of obesity." [Abstract]

Pecina S, Berridge KC.
Opioid site in nucleus accumbens shell mediates eating and hedonic 'liking' for food: map based on microinjection Fos plumes.
Brain Res. 2000 Apr 28;863(1-2):71-86.
"Microinjection of opioid agonists, such as morphine, into the nucleus accumbens shell produces increases in eating behavior (i.e. 'wanting' for food). This study (1) reports direct evidence that activation of accumbens opioid receptors in rats also augments food 'liking', or the hedonic impact of taste, and (2) identified a neural site that definitely contains receptors capable of increasing food intake. Morphine microinjections (0.5 microgram) into accumbens shell, which caused rats to increase eating, were found also to cause selective increases in positive hedonic patterns of behavioral affective reaction elicited by oral sucrose, using the 'taste reactivity' test of hedonic palatability. This positive shift indicated that morphine microinjections enhanced the hedonic impact of food palatability. The accumbens site mediating morphine-induced increases in food 'wanting' and 'liking' was identified using a novel method based on local expression of Fos induced directly by drug microinjections. The plume-shaped region of drug-induced increase in Fos immunoreactivity immediately surrounding a morphine microinjection site (Fos plume) was objectively mapped. A point-sampling procedure was used to measure the shape and size of 'positive' plumes of Fos expression triggered by microinjections of morphine at locations that caused increases in eating behavior. This revealed a functionally 'positive' neural region, containing receptors directly activated by behaviorally-effective drug microinjections. A subtraction mapping procedure was then used to eliminate all surrounding regions containing any 'negative' Fos plumes that failed to increase food intake. The subtraction produced a conservative map of the positive site, by eliminating regions that gave mixed effects, and leaving only a positive region that must contain receptors capable of mediating increases in food intake. The resulting mapped 'opioid eating site' was contained primarily within the medial caudal subregion of the nucleus accumbens shell, and did not substantially penetrate either into the accumbens core or into other subregions of the shell. Several other structures outside the nucleus accumbens (such as rostral ventral pallidum), immediately medial and adjacent to the shell, also appeared to be included in the functional site. Opioid receptors within this site thus are capable of mediating morphine-induced increases in eating, in part by enhancing the hedonic reward properties of food." [Abstract]

Wyvell, Cindy L., Berridge, Kent C.
Intra-Accumbens Amphetamine Increases the Conditioned Incentive Salience of Sucrose Reward: Enhancement of Reward "Wanting" without Enhanced "Liking" or Response Reinforcement
J. Neurosci. 2000 20: 8122-8130
"Amphetamine microinjection into the nucleus accumbens shell enhanced the ability of a Pavlovian reward cue to trigger increased instrumental performance for sucrose reward in a pure conditioned incentive paradigm. Rats were first trained to press one of two levers to obtain sucrose pellets. They were separately conditioned to associate a Pavlovian cue (30 sec light) with free sucrose pellets. On test days, the rats received bilateral microinjection of intra-accumbens vehicle or amphetamine (0.0, 2.0, 10.0, or 20.0 microgram/0.5 microliter), and lever pressing was tested in the absence of any reinforcement contingency, while the Pavlovian cue alone was freely presented at intervals throughout the session. Amphetamine microinjection selectively potentiated the cue-elicited increase in sucrose-associated lever pressing, although instrumental responding was not reinforced by either sucrose or the cue during the test. Intra-accumbens amphetamine can therefore potentiate cue-triggered incentive motivation for reward in the absence of primary or secondary reinforcement. Using the taste reactivity measure of hedonic impact, it was shown that intra-accumbens amphetamine failed to increase positive hedonic reaction patterns elicited by sucrose (i.e., sucrose "liking") at doses that effectively increase sucrose "wanting." We conclude that nucleus accumbens dopamine specifically mediates the ability of reward cues to trigger "wanting" (incentive salience) for their associated rewards, independent of both hedonic impact and response reinforcement." [Full Text]

Kelley, Ann E., Berridge, Kent C.
The Neuroscience of Natural Rewards: Relevance to Addictive Drugs
J. Neurosci. 2002 22: 3306-3311 [Full Text]

Wolf, Marina E.
Addiction: Making the Connection Between Behavioral Changes and Neuronal Plasticity in Specific Pathways
Mol. Interv. 2002 2: 146-157
"There is an emerging consensus that drug addiction is a form of maladaptive learning. Drugs of abuse usurp the neuronal circuitry involved in motivation and reward, leading to aberrant engagement of learning processes. As a result, drug-associated cues can trigger craving and compulsive drug-seeking behavior, and voluntary control over drug use is lost. Abused drugs can also modulate long-term potentiation (LTP) and long-term depression (LTD) in neuronal circuits associated with the addiction process, suggesting a way for the behavioral consequences of drug-taking to become reinforced by learning mechanisms. This review will assess progress in correlating these effects on LTP and LTD with behavioral changes in animal models of addiction, particularly behavioral sensitization." [Full Text]

El-Ghundi M, O'Dowd BF, Erclik M, George SR.
Attenuation of sucrose reinforcement in dopamine D1 receptor deficient mice.
Eur J Neurosci. 2003 Feb;17(4):851-62.
"Dopaminergic systems are thought to mediate the rewarding and reinforcing effects of palatable food. However, the relative contribution of different dopamine receptor subtypes is not clear. We used dopamine D1 receptor deficient mice (D1 -/-) and their wild-type and heterozygous littermates to study the role of the D1 receptor in palatable food reinforced behaviour using operant responding and free access paradigms. Non-deprived mice were trained to press a lever for sucrose pellets under three schedules of reinforcement including fixed ratios (FR-1 and FR-4) and a progressive ratio (PR). Responding on one lever was reinforced by the delivery of a sucrose pellet or solution while responding on a second lever had no programmed consequences. Initially, D1 mutant mice took longer to learn to discriminate between the two levers and had significantly lower operant responding for sucrose pellets and solution than wild-type and heterozygous mice under all schedules of reinforcement. Food deprivation enhanced responding on the active lever in all mice although it remained significantly lower in D1 -/- mice than in control mice. Following extinction of sucrose reinforcement and reversal of the levers, D1 -/- mice showed deficits in extinguishing and reversing previously learned responses. Home cage intake and preference of sucrose pellets and solutions when given under free-choice access paradigms were similar among the groups. These results suggest that the dopamine D1 receptor plays a role in the motivation to work for reward (palatable food) but not in reward perception and is critical in learning new but relevant information and discontinuing previously learned responses." [Abstract]

Robinson TE, Kolb B.
Alterations in the morphology of dendrites and dendritic spines in the nucleus accumbens and prefrontal cortex following repeated treatment with amphetamine or cocaine.
Eur J Neurosci 1999 May;11(5):1598-604
"Repeated treatment with psychostimulant drugs produces changes in brain and behaviour that far outlast their initial neuropharmacological actions. The nature of persistent drug-induced neurobehavioural adaptations is of interest because they are thought to contribute to the development of dependence and addiction, and other forms of psychopathology, e.g. amphetamine psychosis. There are many reports that psychostimulants produce biochemical adaptations in brain monoamine systems, especially dopamine systems. The purpose of the present study was to determine if they might also alter the morphology of neurons in brain regions that receive monoaminergic innervation. Rats were given repeated injections of either amphetamine or cocaine, or, to control for general motor activity, allowed access to a running wheel. They were then left undisturbed for 24-25 days before their brains were processed for Golgi-Cox staining. Treatment with either amphetamine or cocaine (but not wheel running experience) increased the number of dendritic branches and the density of dendritic spines on medium spiny neurons in the shell of the nucleus accumbens, and on apical dendrites of layer V pyramidal cells in the prefrontal cortex. Cocaine also increased dendritic branching and spine density on the basilar dendrites of pyramidal cells. In addition, both drugs doubled the incidence of branched spines on medium spiny neurons. It is suggested that some of the persistent neurobehavioural consequences of repeated exposure to psychostimulant drugs may be due to their ability to reorganize patterns of synaptic connectivity in the nucleus accumbens and prefrontal cortex." [Abstract]

Cho J, Duke D, Manzino L, Sonsalla PK, West MO.
Dopamine depletion causes fragmented clustering of neurons in the sensorimotor striatum: evidence of lasting reorganization of corticostriatal input.
J Comp Neurol. 2002 Oct 7;452(1):24-37.
"Firing during sensorimotor exam was used to categorize single neurons in the lateral striatum of awake, unrestrained rats. Five rats received unilateral injection of 6-hydroxydopamine (6-OHDA) into the medial forebrain bundle to deplete striatal dopamine (DA; >98% depletion, postmortem assay). Three months after treatment, rats exhibited exaggerated rotational behavior induced by L-dihydroxyphenylalanine (L-DOPA) and contralateral sensory neglect. Electrode track "depth profiles" on the DA-depleted side showed fragmented clustering of neurons related to sensorimotor activity of single body parts (SBP neurons). Clusters were smaller than normal, and more SBP neurons were observed in isolation, outside of clusters. More body parts were represented per unit volume. No recovery in these measures was observed up to one year post lesion. Overall distributions of neurons related to different body parts were not altered. The fragmentation of SBP clusters after DA depletion indicates that a percentage of striatal SBP neurons switched responsiveness from one body part to one or more different body parts. Because the specific firing that characterizes striatal SBP neurons is mediated by corticostriatal inputs (Liles and Updyke [1985] Brain Res. 339:245-255), the data indicate that DA depletion resulted in a reorganization of corticostriatal connections, perhaps via unmasking or sprouting of connections to adjacent clusters of striatal neurons. After reorganization, sensory activity in a localized body part activates striatal neurons that have switched to that body part. In turn, switched signals sent from basal ganglia to premotor and motor neurons, which likely retain their original connections, would create mismatches in these normally precise topographic connections. Switched signals could partially explain parkinsonian deficits in motor functions involving somatosensory guidance and their intractability to L-DOPA therapy-particularly if the switching involves sprouting." [Abstract]

Rotzinger S, Bush DE, Vaccarino FJ.
Cholecystokinin modulation of mesolimbic dopamine function: regulation of motivated behaviour.
Pharmacol Toxicol. 2002 Dec;91(6):404-13.
This article reviews evidence and presents a hypothesis regarding the effects of stress on motivated behaviour, and in particular the observation that stress can have both motivationally inhibitory and motivationally facilitatory effects. This issue will be addressed with regard to psychostimulant self-administration, and the role that the neurobiological mechanisms underlying motivated behaviour are thought to be involved in the evolution of addictions. Evidence from animal studies shows that stress and stress-related hormones such as corticosterone can facilitate mesolimbic dopamine function and the behavioural effects of psychostimulants, particularly at lower levels of stress. Conversely, higher levels of stress can inhibit motivated behaviour, and evidence is presented that this may occur in part through the effects of the neuropeptide cholecystokinin (CCK), acting through CCK-B receptors in the nucleus accumbens. Individual differences in endogenous CCK and dopamine systems are hypothesized to be important modulators of individual differences in motivated behaviour. [Abstract]




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Recent Dopamine/Wanting Research

1) Saunders BT, Robinson TE
The role of dopamine in the accumbens core in the expression of Pavlovian-conditioned responses.
Eur J Neurosci. 2012 Jul 11;
The role of dopamine in reward is a topic of debate. For example, some have argued that phasic dopamine signaling provides a prediction-error signal necessary for stimulus-reward learning, whereas others have hypothesized that dopamine is not necessary for learning per se, but for attributing incentive motivational value ('incentive salience') to reward cues. These psychological processes are difficult to tease apart, because they tend to change together. To disentangle them we took advantage of natural individual variation in the extent to which reward cues are attributed with incentive salience, and asked whether dopamine (specifically in the core of the nucleus accumbens) is necessary for the expression of two forms of Pavlovian-conditioned approach behavior - one in which the cue acquires powerful motivational properties (sign-tracking) and another closely related one in which it does not (goal-tracking). After acquisition of these conditioned responses (CRs), intra-accumbens injection of the dopamine receptor antagonist flupenthixol markedly impaired the expression of a sign-tracking CR, but not a goal-tracking CR. Furthermore, dopamine antagonism did not produce a gradual extinction-like decline in behavior, but maximally impaired expression of a sign-tracking CR on the very first trial, indicating the effect was not due to new learning (i.e. it occurred in the absence of new prediction-error computations). The data support the view that dopamine in the accumbens core is not necessary for learning stimulus-reward associations, but for attributing incentive salience to reward cues, transforming predictive conditional stimuli into incentive stimuli with powerful motivational properties. [PubMed Citation] [Order full text from Infotrieve]

2) Overduin J, Figlewicz DP, Bennett-Jay JL, Kittleson S, Cummings DE
Ghrelin Increases the Motivation to Eat but Does Not Alter Food Palatability.
Am J Physiol Regul Integr Comp Physiol. 2012 Jun 6;
Homeostatic eating cannot explain overconsumption of food and pathologic weight gain. A more likely factor promoting excessive eating is food reward and its representation in the central nervous system (CNS). The anorectic hormones leptin and insulin reduce food reward and inhibit related CNS reward pathways. Conversely, the orexigenic gastrointestinal hormone ghrelin activates both homeostatic and reward-related neurocircuits. The current studies were conducted to identify in rats the effects of intracerebroventricular (ICV) ghrelin infusions on two distinct aspects of food reward: hedonic valuation (i.e., "liking") and the motivation to self-administer (i.e., "wanting") food. To assess hedonic valuation of liquid food, lick motor patterns were recorded using lickometry. Although ghrelin administration increased energy intake, it did not alter the avidity of licking (initial lick rates or lick-cluster size). Several positive-control conditions ruled out lick-rate ceiling effects. Similarly, when the liquid diet was hedonically devaluated with quinine supplementation, ghrelin failed to reverse the associated reduction of energy intake and avidity of licking. The effects of ghrelin on rats' motivation to eat were assessed using bar-pressing to self-administer food in a progressive-ratio paradigm. Ghrelin markedly increased motivation to eat, to levels comparable to or greater than those seen following 24 hours of food deprivation. Pre-treatment with the dopamine D1 receptor antagonist SCH-23390 eliminated ghrelin-induced increases in bar pressing, without compromising generalized licking motor control, indicating a role for D1 signaling in ghrelin's motivational feeding effects. These results indicate that ghrelin increases the motivation to eat via D1 receptor-dependent mechanisms, without affecting perceived food palatability. [PubMed Citation] [Order full text from Infotrieve]

3) Becker S, Gandhi W, Schweinhardt P
Cerebral interactions of pain and reward and their relevance for chronic pain.
Neurosci Lett. 2012 Jun 29;520(2):182-7.
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. [PubMed Citation] [Order full text from Infotrieve]

4) Oei NY, Rombouts SA, Soeter RP, van Gerven JM, Both S
Dopamine modulates reward system activity during subconscious processing of sexual stimuli.
Neuropsychopharmacology. 2012 Jun;37(7):1729-37.
Dopaminergic medication influences conscious processing of rewarding stimuli, and is associated with impulsive-compulsive behaviors, such as hypersexuality. Previous studies have shown that subconscious subliminal presentation of sexual stimuli activates brain areas known to be part of the 'reward system'. In this study, it was hypothesized that dopamine modulates activation in key areas of the reward system, such as the nucleus accumbens, during subconscious processing of sexual stimuli. Young healthy males (n=53) were randomly assigned to two experimental groups or a control group, and were administered a dopamine antagonist (haloperidol), a dopamine agonist (levodopa), or placebo. Brain activation was assessed during a backward-masking task with subliminally presented sexual stimuli. Results showed that levodopa significantly enhanced the activation in the nucleus accumbens and dorsal anterior cingulate when subliminal sexual stimuli were shown, whereas haloperidol decreased activations in those areas. Dopamine thus enhances activations in regions thought to regulate 'wanting' in response to potentially rewarding sexual stimuli that are not consciously perceived. This running start of the reward system might explain the pull of rewards in individuals with compulsive reward-seeking behaviors such as hypersexuality and patients who receive dopaminergic medication. [PubMed Citation] [Order full text from Infotrieve]

5) Boileau I, Payer D, Houle S, Behzadi A, Rusjan PM, Tong J, Wilkins D, Selby P, George TP, Zack M, Furukawa Y, McCluskey T, Wilson AA, Kish SJ
Higher binding of the dopamine D3 receptor-preferring ligand [11C]-(+)-propyl-hexahydro-naphtho-oxazin in methamphetamine polydrug users: a positron emission tomography study.
J Neurosci. 2012 Jan 25;32(4):1353-9.
Positron emission tomography (PET) findings suggesting lower D2-type dopamine receptors and dopamine concentration in brains of stimulant users have prompted speculation that increasing dopamine signaling might help in drug treatment. However, this strategy needs to consider the possibility, based on animal and postmortem human data, that dopaminergic activity at the related D3 receptor might, in contrast, be elevated and thereby contribute to drug-taking behavior. We tested the hypothesis that D3 receptor binding is above normal in methamphetamine (MA) polydrug users, using PET and the D3-preferring ligand [11C]-(+)-propyl-hexahydro-naphtho-oxazin ([11C]-(+)-PHNO). Sixteen control subjects and 16 polydrug users reporting MA as their primary drug of abuse underwent PET scanning after [11C]-(+)-PHNO. Compared with control subjects, drug users had higher [11C]-(+)-PHNO binding in the D3-rich midbrain substantia nigra (SN; +46%; p<0.02) and in the globus pallidus (+9%; p=0.06) and ventral pallidum (+11%; p=0.1), whereas binding was slightly lower in the D2-rich dorsal striatum (approximately -4%, NS; -12% in heavy users, p=0.01) and related to drug-use severity. The [11C]-(+)-PHNO binding ratio in D3-rich SN versus D2-rich dorsal striatum was 55% higher in MA users (p=0.004), with heavy but not moderate users having ratios significantly different from controls. [11C]-(+)-PHNO binding in SN was related to self-reported "drug wanting." We conclude that the dopamine D3 receptor, unlike the D2 receptor, might be upregulated in brains of MA polydrug users, although lower dopamine levels in MA users could have contributed to the finding. Pharmacological studies are needed to establish whether normalization of D3 receptor function could reduce vulnerability to relapse in stimulant abuse. [PubMed Citation] [Order full text from Infotrieve]

6) Blum K, Gardner E, Oscar-Berman M, Gold M
"Liking" and "wanting" linked to Reward Deficiency Syndrome (RDS): hypothesizing differential responsivity in brain reward circuitry.
Curr Pharm Des. 2012;18(1):113-8.
In an attempt to resolve controversy regarding the causal contributions of mesolimbic dopamine (DA) systems to reward, we evaluate the three main competing explanatory categories: "liking,"learning," and "wanting" [1]. That is, DA may mediate (a) the hedonic impact of reward (liking), (b) learned predictions about rewarding effects (learning), or (c) the pursuit of rewards by attributing incentive salience to reward-related stimuli (wanting). We evaluate these hypotheses, especially as they relate to the Reward Deficiency Syndrome (RDS), and we find that the incentive salience or "wanting" hypothesis of DA function is supported by a majority of the evidence. Neuroimaging studies have shown that drugs of abuse, palatable foods, and anticipated behaviors such as sex and gaming affect brain regions involving reward circuitry, and may not be unidirectional. Drugs of abuse enhance DA signaling and sensitize mesolimbic mechanisms that evolved to attribute incentive salience to rewards. Addictive drugs have in common that they are voluntarily selfadministered, they enhance (directly or indirectly) dopaminergic synaptic function in the nucleus accumbens (NAC), and they stimulate the functioning of brain reward circuitry (producing the "high" that drug users seek). Although originally believed simply to encode the set point of hedonic tone, these circuits now are believed to be functionally more complex, also encoding attention, reward expectancy, disconfirmation of reward expectancy, and incentive motivation. Elevated stress levels, together with polymorphisms of dopaminergic genes and other neurotransmitter genetic variants, may have a cumulative effect on vulnerability to addiction. The RDS model of etiology holds very well for a variety of chemical and behavioral addictions. [PubMed Citation] [Order full text from Infotrieve]

7) Smith KS, Berridge KC, Aldridge JW
Disentangling pleasure from incentive salience and learning signals in brain reward circuitry.
Proc Natl Acad Sci U S A. 2011 Jul 5;108(27):E255-64.
Multiple signals for reward-hedonic impact, motivation, and learned associative prediction-are funneled through brain mesocorticolimbic circuits involving the nucleus accumbens and ventral pallidum. Here, we show how the hedonic "liking" and motivation "wanting" signals for a sweet reward are distinctly modulated and tracked in this circuit separately from signals for Pavlovian predictions (learning). Animals first learned to associate a fixed sequence of Pavlovian cues with sucrose reward. Subsequent intraaccumbens microinjections of an opioid-stimulating drug increased the hedonic liking impact of sucrose in behavior and firing signals of ventral pallidum neurons, and likewise, they increased incentive salience signals in firing to the reward-proximal incentive cue (but did not alter firing signals to the learned prediction value of a reward-distal cue). Microinjection of a dopamine-stimulating drug instead enhanced only the motivation component but did not alter hedonic impact or learned prediction signals. Different dedicated neuronal subpopulations in the ventral pallidum tracked signal enhancements for hedonic impact vs. incentive salience, and a faster firing pattern also distinguished incentive signals from slower hedonic signals, even for a third overlapping population. These results reveal separate neural representations of wanting, liking, and prediction components of the same reward within the nucleus accumbens to ventral pallidum segment of mesocorticolimbic circuitry. [PubMed Citation] [Order full text from Infotrieve]

8) Cunningham KA, Fox RG, Anastasio NC, Bubar MJ, Stutz SJ, Moeller FG, Gilbertson SR, Rosenzweig-Lipson S
Selective serotonin 5-HT(2C) receptor activation suppresses the reinforcing efficacy of cocaine and sucrose but differentially affects the incentive-salience value of cocaine- vs. sucrose-associated cues.
Neuropharmacology. 2011 Sep;61(3):513-23.
Serotonin (5-HT) controls affective and motivational aspects of palatable food and drug reward and the 5-HT(2C) receptor (5-HT(2C)R) has emerged as a key regulator in this regard. We have evaluated the efficacy of a selective 5-HT(2C)R agonist, WAY 163909, in cocaine and sucrose self-administration and reinstatement assays employing parallel experimental designs in free-fed rats. WAY 163909 dose-dependently reduced the reinforcing efficacy of cocaine (ID(50) = 1.19 mg/kg) and sucrose (ID(50) = 0.7 mg/kg) as well as reinstatement (ID(50) = 0.5 mg/kg) elicited by exposure to cocaine-associated contextual cues, but not sucrose-associated contextual cues. The ID(50) of WAY 163909 predicted to decrease the reinforcing efficacy of cocaine or sucrose as well as reinstatement upon exposure to cocaine-associated cues was ?5-12-fold lower than that predicted to suppress horizontal ambulation (ID(50) = 5.89 mg/kg) and ?2-5-fold lower than that predicted to suppress vertical activity (ID(50) = 2.3 mg/kg). Thus, selective stimulation of the 5-HT(2C)R decreases the reinforcing efficacy of cocaine and sucrose in freely-fed rats, but differentially alters the incentive-salience value of cocaine- vs. sucrose-associated cues at doses that do not impair locomotor activity. Future research is needed to tease apart the precise contribution of 5-HT(2C)R neurocircuitry in reward and motivation and the learning and memory processes that carry the encoding for associations between environmental cues and consumption of rewarding stimuli. A more complete preclinical evaluation of these questions will ultimately allow educated proof-of-concept trials to test the efficacy of selective 5-HT(2C)R agonists as adjunctive therapy in chronic health maladies including obesity, eating disorders and drug addiction. [PubMed Citation] [Order full text from Infotrieve]

9) Gradin VB, Kumar P, Waiter G, Ahearn T, Stickle C, Milders M, Reid I, Hall J, Steele JD
Expected value and prediction error abnormalities in depression and schizophrenia.
Brain. 2011 Jun;134(Pt 6):1751-64.
The dopamine system has been linked to anhedonia in depression and both the positive and negative symptoms of schizophrenia, but it remains unclear how dopamine dysfunction could mechanistically relate to observed symptoms. There is considerable evidence that phasic dopamine signals encode prediction error (differences between expected and actual outcomes), with reinforcement learning theories being based on prediction error-mediated learning of associations. It has been hypothesized that abnormal encoding of neural prediction error signals could underlie anhedonia in depression and negative symptoms in schizophrenia by disrupting learning and blunting the salience of rewarding events, and contribute to psychotic symptoms by promoting aberrant perceptions and the formation of delusions. To test this, we used model based functional magnetic resonance imaging and an instrumental reward-learning task to investigate the neural correlates of prediction errors and expected-reward values in patients with depression (n=15), patients with schizophrenia (n=14) and healthy controls (n=17). Both patient groups exhibited abnormalities in neural prediction errors, but the spatial pattern of abnormality differed, with the degree of abnormality correlating with syndrome severity. Specifically, reduced prediction errors in the striatum and midbrain were found in depression, with the extent of signal reduction in the bilateral caudate, nucleus accumbens and midbrain correlating with increased anhedonia severity. In schizophrenia, reduced prediction error signals were observed in the caudate, thalamus, insula and amygdala-hippocampal complex, with a trend for reduced prediction errors in the midbrain, and the degree of blunting in the encoding of prediction errors in the insula, amygdala-hippocampal complex and midbrain correlating with increased severity of psychotic symptoms. Schizophrenia was also associated with disruption in the encoding of expected-reward values in the bilateral amygdala-hippocampal complex and parahippocampal gyrus, with the degree of disruption correlating with psychotic symptom severity. Neural signal abnormalities did not correlate with negative symptom severity in schizophrenia. These findings support the suggestion that a disruption in the encoding of prediction error signals contributes to anhedonia symptoms in depression. In schizophrenia, the findings support the postulate of an abnormality in error-dependent updating of inferences and beliefs driving psychotic symptoms. Phasic dopamine abnormalities in depression and schizophrenia are suggested by our observation of prediction error abnormalities in dopamine-rich brain areas, given the evidence for dopamine encoding prediction errors. The findings are consistent with proposals that psychiatric syndromes reflect different disorders of neural valuation and incentive salience formation, which helps bridge the gap between biological and phenomenological levels of understanding. [PubMed Citation] [Order full text from Infotrieve]

10) Kurti AN, Matell MS
Nucleus accumbens dopamine modulates response rate but not response timing in an interval timing task.
Behav Neurosci. 2011 Apr;125(2):215-25.
While previous work has demonstrated that systemic dopamine manipulations can modulate temporal perception by altering the speed of internal clock processes, the neural site of this modulation remains unclear. Based on recent research suggesting that changes in incentive salience can alter the perception of time, as well as work showing that nucleus accumbens (NAc) shell dopamine (DA) levels modulate the incentive salience of discriminative stimuli that predict instrumental outcomes, we assessed whether microinjections of DA agents into the NAc shell would impact temporal perception. Rats were trained on either a 10-s or 30-s temporal production procedure and received intra-NAc shell microinfusions of sulpiride, amphetamine, and saline. Results showed that NAc DA modulations had no effect on response timing, but intra-NAc shell sulpiride microinfusions significantly decreased response rates relative to saline and amphetamine. Our findings therefore suggest that neither NAc shell DA levels, nor the resultant changes in incentive salience signaled by this structure, impact temporal control. [PubMed Citation] [Order full text from Infotrieve]

11) Dickson SL, Egecioglu E, Landgren S, Skibicka KP, Engel JA, Jerlhag E
The role of the central ghrelin system in reward from food and chemical drugs.
Mol Cell Endocrinol. 2011 Jun 20;340(1):80-7.
Here we review recent advances that identify a role for the central ghrelin signalling system in reward from both natural rewards (such as food) and artificial rewards (that include alcohol and drugs of abuse). Whereas ghrelin emerged as a stomach-derived hormone involved in energy balance, hunger and meal initiation via hypothalamic circuits, it now seems clear that it also has a role in motivated reward-driven behaviours via activation of the so-called "cholinergic-dopaminergic reward link". This reward link comprises a dopamine projection from the ventral tegmental area (VTA) to the nucleus accumbens together with a cholinergic input, arising primarily from the laterodorsal tegmental area. Ghrelin administration into the VTA or LDTg activates the "cholinergic-dopaminergic" reward link, suggesting that ghrelin may increase the incentive value of motivated behaviours such as reward-seeking behaviour ("wanting" or "incentive motivation"). Further, direct injection of ghrelin into the brain ventricles or into the VTA increases the consumption of rewarding foods as well as alcohol in mice and rats. Studies in rodents show beneficial effects of ghrelin receptor (GHS-R1A) antagonists to suppress the intake of palatable food, to reduce preference for caloric foods, to suppress food reward and motivated behaviour for food. They have also been shown to reduce alcohol consumption, suppress reward induced by alcohol, cocaine and amphetamine. Furthermore, variations in the GHS-R1A and pro-ghrelin genes have been associated with high alcohol consumption, smoking and increased weight gain in alcohol dependent individuals as well as with bulimia nervosa and obesity. Thus, the central ghrelin signalling system interfaces neurobiological circuits involved in reward from food as well as chemical drugs; agents that directly or indirectly suppress this system emerge as potential candidate drugs for suppressing problematic over-eating that leads to obesity as well as for the treatment of substance use disorder. [PubMed Citation] [Order full text from Infotrieve]

12) Egecioglu E, Skibicka KP, Hansson C, Alvarez-Crespo M, Friberg PA, Jerlhag E, Engel JA, Dickson SL
Hedonic and incentive signals for body weight control.
Rev Endocr Metab Disord. 2011 Sep;12(3):141-51.
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. [PubMed Citation] [Order full text from Infotrieve]

13) Jerlhag E, Engel JA
Ghrelin receptor antagonism attenuates nicotine-induced locomotor stimulation, accumbal dopamine release and conditioned place preference in mice.
Drug Alcohol Depend. 2011 Sep 1;117(2-3):126-31.
[PubMed Citation] [Order full text from Infotrieve]

14) Flagel SB, Clark JJ, Robinson TE, Mayo L, Czuj A, Willuhn I, Akers CA, Clinton SM, Phillips PE, Akil H
A selective role for dopamine in stimulus-reward learning.
Nature. 2011 Jan 6;469(7328):53-7.
Individuals make choices and prioritize goals using complex processes that assign value to rewards and associated stimuli. During Pavlovian learning, previously neutral stimuli that predict rewards can acquire motivational properties, becoming attractive and desirable incentive stimuli. However, whether a cue acts solely as a predictor of reward, or also serves as an incentive stimulus, differs between individuals. Thus, individuals vary in the degree to which cues bias choice and potentially promote maladaptive behaviour. Here we use rats that differ in the incentive motivational properties they attribute to food cues to probe the role of the neurotransmitter dopamine in stimulus-reward learning. We show that intact dopamine transmission is not required for all forms of learning in which reward cues become effective predictors. Rather, dopamine acts selectively in a form of stimulus-reward learning in which incentive salience is assigned to reward cues. In individuals with a propensity for this form of learning, reward cues come to powerfully motivate and control behaviour. This work provides insight into the neurobiology of a form of stimulus-reward learning that confers increased susceptibility to disorders of impulse control. [PubMed Citation] [Order full text from Infotrieve]

15) George O, Koob GF
Individual differences in prefrontal cortex function and the transition from drug use to drug dependence.
Neurosci Biobehav Rev. 2010 Nov;35(2):232-47.
Several neuropsychological hypotheses have been formulated to explain the transition to addiction, including hedonic allostasis, incentive salience, and the development of habits. A key feature of addiction that remains to be explored is the important individual variability observed in the propensity to self-administer drugs, the sensitivity to drug-associated cues, the severity of the withdrawal state, and the ability to quit. In this review, we suggest that the concept of self-regulation, combined with the concept of modularity of cognitive function, may aid in the understanding of the neural basis of individual differences in the vulnerability to drugs and the transition to addiction. The thesis of this review is that drug addiction involves a failure of the different subcomponents of the executive systems controlling key cognitive modules that process reward, pain, stress, emotion, habits, and decision-making. A subhypothesis is that the different patterns of drug addiction and individual differences in the transition to addiction may emerge from differential vulnerability in one or more of the subcomponents. [PubMed Citation] [Order full text from Infotrieve]

16) Evans AH, Lawrence AD, Cresswell SA, Katzenschlager R, Lees AJ
Compulsive use of dopaminergic drug therapy in Parkinson's disease: reward and anti-reward.
Mov Disord. 2010 May 15;25(7):867-76.
A few Parkinson patients develop a disabling pattern of compulsive dopaminergic drug use ("dopamine dysregulation syndrome"-DDS). DDS patients commonly identify aversive dysphoric "OFF" mood-states as a primary motivation to compulsively use their drugs. We compared motoric, affective, non-motor symptoms and incentive arousal after overnight medication withdrawal and after levodopa in DDS and control PD patients. Twenty DDS patients were matched to 20 control PD patients for age, gender, and disease duration and underwent a standard levodopa challenge. Somatic symptomatology, positive and negative affective states, drug effects, reward responsivity, motor disability, and dyskinesias were tested in the "OFF"-state after overnight withdrawal of medications, and then after a challenge with a standard dose of levodopa, after a full "ON"-state was achieved. In the "OFF"-state, DDS patients reported lower positive affect, and more motor and non-motor disability. In the "ON"-state, DDS patients had higher expressions of drug "wanting," reward responsivity, and dyskinesias. Positive and negative affect, non-motor symptomatology, and motor disability were comparable. These findings suggest that affective, motivational, and motoric disturbances in PD are associated with the transition to compulsive drug use in individuals who inappropriately overuse their dopaminergic medication. [PubMed Citation] [Order full text from Infotrieve]

17) Heinz A, Schlagenhauf F
Dopaminergic dysfunction in schizophrenia: salience attribution revisited.
Schizophr Bull. 2010 May;36(3):472-85.
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. [PubMed Citation] [Order full text from Infotrieve]

18) Opland DM, Leinninger GM, Myers MG
Modulation of the mesolimbic dopamine system by leptin.
Brain Res. 2010 Sep 2;1350:65-70.
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. [PubMed Citation] [Order full text from Infotrieve]

19) Berridge KC, Ho CY, Richard JM, DiFeliceantonio AG
The tempted brain eats: pleasure and desire circuits in obesity and eating disorders.
Brain Res. 2010 Sep 2;1350:43-64.
What we eat, when and how much, all are influenced by brain reward mechanisms that generate "liking" and "wanting" for foods. As a corollary, dysfunction in reward circuits might contribute to the recent rise of obesity and eating disorders. Here we assess brain mechanisms known to generate "liking" and "wanting" for foods and evaluate their interaction with regulatory mechanisms of hunger and satiety, relevant to clinical issues. "Liking" mechanisms include hedonic circuits that connect together cubic-millimeter hotspots in forebrain limbic structures such as nucleus accumbens and ventral pallidum (where opioid/endocannabinoid/orexin signals can amplify sensory pleasure). "Wanting" mechanisms include larger opioid networks in nucleus accumbens, striatum, and amygdala that extend beyond the hedonic hotspots, as well as mesolimbic dopamine systems, and corticolimbic glutamate signals that interact with those systems. We focus on ways in which these brain reward circuits might participate in obesity or in eating disorders. [PubMed Citation] [Order full text from Infotrieve]

20) Prasad P, Ambekar A, Vaswani M
Dopamine D2 receptor polymorphisms and susceptibility to alcohol dependence in Indian males: a preliminary study.
BMC Med Genet. 2010;11:24.
[PubMed Citation] [Order full text from Infotrieve]