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Books by Tony Ward (Author of Theories of Sexual Offending)

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Transmission begins with an action potential that arrives to the terminal, inducing synaptic vesicle fusion and release of DA. After reuptake, the transmitter can be repackaged into synaptic vesicles or may be degraded by the enzyme monoamine oxidase, resulting in the DA metabolite homovanillic acid. Neurotransmission within the mesolimbic pathway begins with an action potential that is generated in VTA neurons, resulting in the presynaptic release of DA.

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Five distinct DA receptors D 1 to D 5 can mediate neurotransmission, and are coupled positively to activation of adenylyl cyclase D 1 and D 5 receptors or negatively to inhibition of adenylyl cyclase D 2 , D 3 , D 4. Given its anatomical organization, the NAc is considered a limbic—motor interface [ 68 ] translating information about rewards into appropriate behavioral responses to obtain these rewards. For example, DA modulates the sensitivity of MSNs to excitatory glutamatergic projections from pre-frontal and limbic regions, and thereby modulates firing activity of NAc neurons [ 35 , 69 ].

Although the precise causal link between DA release and NAc cell firing is unclear, D 1 and D 2 receptors are generally considered to exert opposite effects at the cellular level, with D 1 -like receptor-expressing cells responding to DA with excitatory increases in firing activity, and D 2 -like receptor-expressing cells responding with decreased firing activity. However, in the context of DA release in the brain, a cooperative interplay between NAc neurons that encode reward information probably occurs.

Furthermore, transmission of DA to the NAc occurs with the same temporal resolution as NAc neuron-patterned cell firing, and this DA release and firing are coincident during goal-directed actions in rodents [ 71 ]. In addition, the frequency of firing activity of VTA neurons may be a key component in modulating the mesolimbic reward pathway and encoding reward information. Studies using channel rhodopsin to precisely control VTA neuron firing activity suggest that phasic, but not tonic, activation of VTA neurons is sufficient to drive behavioral conditioning to rewards and elicit DA transients [ 72 ], and thus indicates the likely importance of the frequency of VTA neuron firing activity.

Disruption of molecular, cellular, or circuitry mechanisms that are essential for the reward system may, in theory, result in aberrant reward-system function. Although a primary or even common molecular mechanism for dysregulating the reward system has yet to be identified, we briefly consider in the following section some of the potential molecules and mechanisms that may underlie abnormal reward processing.

Because the major neurotransmitter mediating mesolimbic transmission is DA, alterations in the synthesis, release, or reuptake of DA may result in an abnormally functioning reward system. Amphetamines and cocaine mediate their effects in the mesolimbic pathway by increasing the release of DA. Cocaine and amphetamines, both of which directly interact with the DAT, exert their effects, at least in part, by blocking in the case of cocaine or reversing the direction of in the case of amphetamine this transporter, resulting in increased synaptic DA [ 73 ].

Increased DA-transporter expression has also been shown in post-mortem analyses of brain tissue from human subjects addicted to cocaine [ 75 ]. Such studies indicate that alterations in DAT expression or function can result in an altered reward system in response to drugs of abuse. Similarly, alteration in the expression or regulation of DA receptors would also be expected to dysregulate reward-system functions. Altered DA receptor function could involve increased or decreased receptor expression or signaling responsiveness to DA thereby altering the reward system.

For example, the DA hypothesis of schizophrenia suggests that excess mesolimbic DA levels may be pro-psychotic, and involve alterations in the activity of striatal D 2 receptors, which are the major site of action for typical antipsychotic medications [ 76 ]. There is clear evidence of dysregulated striatal DA function in schizophrenia [ 77 ], and a meta-analysis of multiple studies indicated a significant increase in striatal D 2 receptors in patients with schizophrenia who were not on medication [ 78 ].

Studies have also suggested an increased affinity of D 2 receptors for DA in schizophrenia, which may produce D 2 receptor supersensitivity in the NAc, contributing to psychosis [ 79 ]. In an interesting animal model correlate to these studies, transient overexpression of D 2 receptors in the striatum of mice resulted in deficits in prefrontal working memory, resembling some of the features of human schizophrenia [ 80 ].

Studies such as these indicate that alterations in DA receptor expression or function can result in a dysfunctional reward system. Molecules that are activated downstream of DA receptor signaling in the NAc also play important roles in mediating reward responses and changes in their function may also dysregulate the reward system. These molecules include the heterotrimeric G proteins activated by DA receptors and also the adenylyl cyclases.

Interestingly, genetic knockout of adenylyl cyclase type 5 in mice prevents the reward response to opioids such as morphine [ 81 ]. Phosphorylated DARPP, by inhibiting PP-1, acts in a combined manner with other protein kinases to increase the level of phosphorylation of various downstream effector proteins, and modulation of protein phosphorylation by DA is thought to play an important role in drug reward.

DARPP may thereby influence the long-term neuronal adaptations associated with natural rewards or with rewards from drugs of abuse [ 83 , 84 ]. Support for this concept is provided in genetic models in mice lacking the DARPP gene, which results in decreased responses to cocaine in conditioned place preference behaviors [ 85 ]. Activation of CREB seems to produce similar behavioral responses to rewarding stimuli: CREB is also induced in the NAc by natural rewards such as sucrose , and similarly reduces an animal's sensitivity to the rewarding effects of sucrose [ 89 ].

Finally, although the molecules highlighted here are clearly involved in DA mesolimbic transmission and reward responses, this represents only a brief overview and readers are encouraged to see other recent reviews of this topic [ 86 , 91 - 93 ]. Animal models, particularly those using rodents, have provided key mechanistic insights that have elucidated the neurobiology of the brain reward system.

Although animal models cannot recapitulate the entire spectrum of phenotypes apparent in clinical presentations of illness, they provide powerful approaches for experimental studies using various environmental, genetic, pharmacological, and biological manipulations. With regard to studying behavior, a high degree of experimental control can be achieved by precisely controlling the animal's life experiences, environment, diet, and history of drug exposure, enabling inferences to be made concerning the causality of effects seen in experimental studies.

However, for complex psychiatric disorders with largely unknown genetic etiologies, environmental insults, specific pathologies, or biomarkers, the building of animal models with high construct validity has not yet been possible [ 94 ]. With this limitation in mind, an alternative strategy has been to develop mouse genetic models for example, knockout or transgenic mice of psychiatric disorders with relevant behavioral phenotypes face validity that are responsive to pharmacotherapies that are clinically effective predictive validity.

Books by Tony Ward (Author of Theories of Sexual Offending)

Primary rewards are vital to gene propagation, and thus responses to such stimuli have been shaped by evolution to elicit approach-oriented behaviors. These stimuli include food and sexual behavior given that sustenance and procreation are crucial for the survival of a species [ 95 , 96 ] , and social interactions with conspecifics [ 39 , 97 ]. Nonclinical human neuroimaging studies indicate that the mesolimbic DA response to primary rewards may operate similarly in humans in response to more abstract, or secondary, rewards such as monetary incentives [ 98 - ].

Thus, most clinical studies investigating responses to rewards have used monetary incentives as a proxy for primary rewards, because money is adaptable to the research environment, may be parametrically scaled, may be won or lost, and may be delivered at precise intervals. It should be noted that few of the preclinical and clinical studies reviewed here involve longitudinal data collection, and it is difficult to make any inferences about the developmental nature of reward-processing systems in the disorders reviewed. In this regard, although our goal is to propose a possible common framework for conceptualizing a range of seemingly disparate phenotypes and possibly to ultimately identify novel biological markers and influence nosological classification, inferences about etiology must be appropriately cautious in the context of largely cross-sectional data.

Perhaps the greatest convergence of empirical evidence supporting reward-network dysfunction in psychiatry emanates from research on substance-use disorders [ ]. The month prevalence estimates for substance-use and abuse disorder are about 3. Contemporary theories addressing the pathophysiology of substance-use disorders highlight altered motivational states, cognitive control, inhibitory function, and decision-making, mediated in large part by dysfunctional output of mesolimbic and mesocortical brain systems [ - ]. The rewarding effects of drugs of abuse derive in large part from the sizeable increases in extracellular DA in limbic regions, and in the NAc in particular, during drug use [ , ].

In addition, drug-induced increases in striatal DA have been linked with subjective feelings of euphoria [ , ]. The firing of DA cells that accompanies drug use encodes a number of reward properties, including reward expectancy [ ], reward learning [ ], and the consolidation of contextual memories [ ]. All of these processes are believed to contribute to the intense motivation to attain drugs of abuse [ ]. To better understand the neurobiology of drug abuse and addiction in humans, several animal models have been developed to investigate different aspects of drug addiction [ , ].

Among these, the models that incorporate self-administration of drugs are thought to best capture the human condition because animals voluntarily seek drugs and because drugs that are self-administered by animals correspond well with those that have abuse potential in humans. From mechanistic neurobiological and behavioral studies in rodents, it has become clear that the mesolimbic pathway is a key component for the rewarding effect of drugs of abuse, and is essential for behaviors related to drug reward, salience, and motivation [ ].

For example, using rodent models, researchers have determined that nearly all psychoactive drugs of abuse for example, cocaine, amphetamines, alcohol, opiates, cannabinoids, nicotine induce alterations in the transmission of DA within the mesolimbic pathway, with most of these drugs increasing extracellular concentrations of DA [ ]. Studies using an in vivo microdialysis technique, which measures minute changes in brain neurotransmitter levels in the behaving animal, have shown that drugs of abuse can increase tonic DA concentrations in the NAc.

In addition, studies using fast-scanning cyclic voltammetry, which can detect the level of DA release in the intact brain on a timescale of seconds, have shown an increased frequency of spontaneous phasic DA signals in the NAc in response to cannabinoids and nicotine in awake, behaving animals [ , ], and also temporally distinct DA signals in response to cocaine [ ]. Dopamine neurotransmission is strongly implicated in the reinforcement of self-administering drugs or electrical stimulation in animals. The seminal animal research by Olds and Milner [ 54 ] provided the initial foundation for our modern understanding of brain-reward mechanisms.

In those pioneering studies, rats were given the ability to self-administer electrical stimulation to various brain regions including the mesolimbic pathway. The rats persistently and repeatedly chose to stimulate the VTA mesolimbic DA pathway but not other brain areas , often to the exclusion of other behaviors. Behavioral studies in rodents also indicate that DA is essential for the self-administration of drugs of abuse for which the mesolimbic pathway has been identified as a crucial substrate [ , ].

In the typical drug self-administration procedure, animals obtain a drug by performing a simple behavior such as pressing a lever , and animals will readily self-administer the same drugs that are abused by humans [ ]. The importance of mesolimbic DA transmission to drug self-administration is supported by pharmacological and lesion studies. Direct DA receptor agonists can mimic the effects of substances of abuse, and these agonists are self-administered both systemically and locally into the NAc in rats and monkeys [ - ].

By contrast, DA receptor antagonists administered systemically increase the rate of operant responding for cocaine in animals [ - ]. In addition, lesion or inactivation of the mesolimbic DA system in the VTA [ , ] or in the NAc [ - ] decreases cocaine, amphetamine, heroin, and nicotine self-administration in rats. These findings indicate the crucial importance of the mesolimbic DA system in drug-taking. There is a confluence of clinical evidence that substance-use disorders are characterized by relative hyperactivation of mesolimbic regions in response to drug cues that is, increased reward motivation.

Wexler and colleagues [ ] presented cocaine-addicted subjects with videotapes containing cocaine-associated cues, and reported relatively increased anterior cingulate cortex ACC activation during the presentation of the cocaine cues, despite decreased overall frontal lobe activation. The non-dependent group showed relatively increased mesocorticolimbic reactivity to stimuli predicting monetary reward compared with stimuli predicting cigarette rewards, and subsequently spent relatively more effort to obtain money relative to cigarettes. By contrast, the nicotine-dependent group showed equivalent responses to both categories of reward cues, and anticipatory mesocorticolimbic activation predicted subsequent motivation to obtain both rewards, suggesting an imbalance in reward motivation in response to drug-predicting cues relative to monetary cues in those with nicotine dependence.

Myrick and colleagues [ ] reported that activation in the NAc, anterior cingulate, and left orbitofrontal cortex in response to alcohol images predicted cravings in alcoholics. Oberlin and colleagues [ ] reported that the magnitude of striatal activation to alcohol cues the odors of the preferred alcohol drink in heavy drinkers was modulated by antisocial trait density.

Finally, Filbey and colleagues [ ] showed that regular marijuana users who abstained from use for 72 hours were characterized by relatively increased reward-circuitry activity, including the VTA, thalamus, ACC, insula, and amygdala, in response to tactile marijuana cues. These studies reflect the overall pattern of data in a range of substance-abuse disorders, which shows relatively increased mesolimbic activation in response to drug cues, accompanied by increased states of reward motivation in response to these cues [ ].

In contrast to the hyperactive responses of reward circuitry to drug-related cues, there is evidence that substance-use disorders are alternatively characterized by a reduced motivation for non-drug rewards [ ]. For example, Asensio and collegues [ ] reported hypoactivation of the dorsal and ventral striatum and the dorsomedial pre-frontal cortex when cocaine addicts viewed pleasant images not linked to substance cues.

Gilman and Hommer [ ] reported subjective hypoarousal to normative positive images in alcohol-dependent participants. Andrews and colleagues [ ] reported decreased NAc activation to monetary-reward outcome that predicted family history of alcoholism. In a study using multi-modal psychophysiological measurements, Lubman and colleagues [ ] reported decreased arousal ratings and physiological measures of reward motivation to pleasant pictures relative to drug-cue images in opiate-dependent participants.

Luo and colleagues [ ] found relatively decreased right ventral striatal activation during the anticipation of delayed relative to immediate monetary rewards in cigarette smokers that is, decreased reward motivation for delayed monetary rewards. However, Jia et al. Attenuated motivation for non-drug rewards has also been reported in younger populations at risk for substance abuse. Schneider and colleagues [ ] found that adolescents with risky substance- use patterns had reduced striatal activity relative to low-risk adolescents during monetary-reward motivation [ 17 ][ Similarly, Peters and colleagues [ ] reported reduced ventral striatal responses during the anticipation of food reward in adolescent smokers.

Notably, Andrews and colleagues [ ] found this effect in family members of those with substance abuse, suggesting that this pattern may be evident even in the absence of the direct effects of repeated drug use on the brain. Overall, these studies highlight that the effects of altered mesolimbic function in substance-use disorders may be characterized not only by increased reward motivation for substance-related stimuli, but also by decreased reward motivation for natural rewards but there are exceptions [ ] , which may lead to increased drug-seeking behaviors.

Molecular-imaging studies of substance-use disorders have focused on imaging the D 2 post-synaptic receptor [ , ]. There are multiple lines of evidence that cocaine dependence is associated with a decrease in D 2 receptor binding [ - ], a pattern that seems to persist after disease remission [ ]. Decreases in D 2 receptor binding have also been found in heroin addiction [ ], alcohol dependence [ , ], methamphetamine abuse [ , ], prompting a number of researchers to posit that low D 2 receptor availability may serve as a biomarker for substance abuse, potentially reflecting an altered sensitivity to various rewards [ - ].

Future research that combines molecular and functional imaging approaches will be necessary to elucidate the causes and consequences of altered reward processing in substance-use disorders in at-risk individuals [ ]. A number of agents that modulate functional output of DA systems are effective first-line treatments for substance-use disorders [ ].

Modafinil is a non-amphetamine stimulant with DA and glutamatergic effects, and with moderate effectiveness for the treatment of cocaine dependence [ ] and possibly methamphetamine dependence [ ]. Bupropion is a DA and norepinephrine reuptake inhibitor that is an effective treatment to promote smoking cessation [ ]. Dextroamphetamine causes release of DA as well as norepinephrine and serotonin and is an effective treatment for amphetamine abuse [ ]. Finally, risperidone, a D 2 -receptor antagonist, has shown promise for the treatment of methamphetamine abuse [ ], and aripiprizole, a partial D 2 agonist is a promising treatment for amphetamine abuse [ ].

Unipolar major depressive disorder MDD is associated with significant psychosocial and medical morbidity and mortality [ - ], and has an estimated lifetime prevalence of Anhedonia, the decreased response to pleasurable stimuli, is a defining symptom of the disorder to the extent that MDD may be diagnosed even in the absence of depressed mood if anhedonia and other secondary symptoms are present [ 1 ]. Anhedonia is also a central feature of a number of neurobiological theories of depression that posit that deficits in emotional and motivational responses to appetitive stimuli are core features of the disorder [ ], and the anhedonic endophenotype of MDD is perhaps the most well supported [ 10 ].

Because anhedonia is a defining symptom of affective disorders, animal models of hedonic deficits have been addressed in preclinical models of affective disorders. Chronic mild stress has been reported to induce an anhedonic-like state in rodents,that resembles the affective disorder phenotypes in humans [ ]. In particular, Willner and colleagues originally reported that chronic and sequential exposure of rats or mice to a mild stress regimen caused decreases in responsiveness to rewards [ , ], commonly reported as a decrease in the consumption of and preference for sucrose solutions, and a decrease in the rewarding properties of pharmacological and natural rewards in the place preference behavioral paradigm [ , - ].

The chronic stress paradigm is considered to have a greater etiological relevance and face validity in mimicking MDD than other animal models, and therefore has become one of the most widely used preclinical paradigms of affective disorders [ ]. Chronic mild stress causes significant reductions in absolute and relative sucrose intake in rats, that is associated with a decrease in striatal DA activity, and is reversed after chronic antidepressant administration with imipramine [ ]. Decreased DA release to the NAc has been shown to occur after exposure to chronic repeated or an unavoidable stress regimen in rats [ , , ], suggesting that stress significantly reduces mesolimbic DA transmission in rodent models.

Altered DA function may also be related to changes in D 1 receptors, which have been shown to alter functional output in the rat limbic system after chronic unpredictable stress [ ]. Therefore, stress-induced neurochemical changes, including decreased DA activity in the mesolimbic pathway, contributes to decreased natural reward sucrose -seeking in this animal model of affective disorders. Reward-system dysfunction in MDD is well established [ - ].

Behavioral studies have reliably found that individuals with MDD show a blunted response to a range of rewarding stimuli [ - ]. Reward learning has also been found to be impaired in MDD [ ], and this impairment is correlated with the severity of anhedonic symptoms [ ]. Additionally, the severity of MDD has been found to correlate strongly with the magnitude of the rewarding effects of administration of oral D-amphetamine, which increases DA availability [ ], and anhedonic symptoms in the general population predict rewarded effort-based decision-making [ ].

Functional neuroimaging studies in MDD have consistently indicated hypoactivation in reward-processing regions, including the dorsal and ventral striatum [ - ] and a host of other reward structures, including the medial prefrontal cortex [ , ], the pregenual and subgenual anterior cingulate, and the medial frontal gyrus [ , ]. Reduced mesolimbic activity in MDD has been found during reward anticipation and outcomes in both adults and children [ , - ] and during reward learning [ ].

For example, Smoski et al. In a follow-up study, Dichter and colleagues [ ] reported that when these same patients were treated with behavior-oriented psychotherapy designed to increase interactions with potentially rewarding situations, striatal regions showed increased functioning during reward anticipation, similar to results of Forbes et al. Finally, there is also evidence that reward-network function shows greater impairment in MDD while patients are processing pleasant images relative to monetary rewards [ ]. Altered reward-network responsivity may also be characteristic of individuals with a history of MDD but without significant current symptoms, suggesting that anhedonia may represent a trait marker of MDD vulnerability, independent of current MDD state [ , ].

Although studying patients with remitted depression is not sufficient to establish reward-processing deficit as a trait marker of depression, given that the effect of past illness and treatments on brain function may not be conclusively excluded, it is nevertheless a necessary initial step to identify this disease trait.

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It also has the advantage of mitigating the potential confounding effects of current mood state, illness severity, non-specific effects of chronic illness and stress, and effects of psychotropic medication usage [ , ]. Thus, examining linkages between brain function and a history of MDD holds the promise of ultimately aiding in the identification of trait-like endophenotypic vulnerability markers predictive of MDD onset before clinically impairing symptoms appear. Further converging evidence of the crucial role that reward-network functioning plays in MDD is found in literature documenting the remarkable consistency with which antidepressant response is predicted by pretreatment functioning of the ACC.

The ACC plays a central role in processing positively valenced emotions [ ] and other rewards [ ], and in coding value representations of anticipated rewards [ ], as shown in studies of sleep deprivation [ - ], psychopharmacological intervention [ - ], cognitive behavioral therapy [ , ] and a combined approach of therapy and psychopharmacological intervention [ ]. Given the linkages between anhedonia, unipolar MDD, and mesolimbic dysfunction, and the prevalence of anhedonia in a number of other Axis I disorders, including bipolar disorder, schizophrenia, and post-traumatic stress disorder, an area of neglected study is the direct comparison between MDD and these other conditions.

A notable exception is a study by Lawrence et al. Whereas the bipolar group was characterized by differential ventral striatal responses to nearly all emotion categories, the unipolar group was characterized by blunted response to happy but not sad stimuli, suggesting that diminished reward outcome to pleasant stimuli may uniquely characterize unipolar MDD relative to bipolar MDD.

Future three-group studies comparing MDD with other disorders characterized by anhedonia are needed to distinguish similarities and differences between these conditions with respect to processing reward stimuli. Molecular-imaging studies of unipolar depression have reported decreased monoamine signaling, which is consistent with functional brain-imaging data suggestive of altered reward processing [ ]. In addition to a substantial body of literature on positron emission tomography PET addressing serotonin 5-HT 2 receptor density in depression [ , ], DAT-binding potential has received considerable attention.

Dunlop and Nemeroff [ ] summarized the literature to date addressing molecular-imaging studies of DA signaling in MDD. These studies have indicated increased D 2 receptor binding in the basal ganglia [ ], striatum [ , ], and putamen [ ], whereas other studies have reported lower [ ] or no difference [ , , ] in striatal D 2 transporter binding potential. Mania has been conceptualized as a tendency to show heightened response to positive emotions and rewards [ ], along with excessive goal pursuit and unrealistically high expectancy of success. It has been suggested that these symptoms may reflect upregulation of the mesolimbic DA system in bipolar disorder [ ].

Behavioral studies of response to rewards in bipolar disorder indicate deficits in behavioral adaptation to changing reward contingencies [ ] and prolonged elevation of mood in response to monetary reward in euthymic patients with bipolar disorder [ ]. Reward motivation is also atypical in individuals with bipolar disorder, as shown by a self-report measure of reward responsivity [ ] and in eye-tracking studies of monetary gains and losses [ ].

Although functional MRI studies have identified prefrontal dysfunction in bipolar disorder and manic psychosis, evidence for abnormalities in reward-related neural network function in mania is scarce [ - ]. Although several studies have suggested alterations in the shape [ ], size [ , ] and function [ ] of the basal ganglia in bipolar disorder, there are only three published functional neuroimaging research studies addressing responses to rewards in bipolar disorder.

Lawrence and colleagues [ ] reported increased ventral striatal and ventral prefrontal cortical responses to mildly happy facial expressions in bipolar disorder. Finally, Jogia and colleagues [ ] reported relative ACC hyperactivation during reward processing in bipolar disorder. Molecular-imaging studies of striatal DAT availability in bipolar disorder generally suggest increased functional DA throughput but Suhara et al. Amsterdam and Newberg [ ] reported higher striatal DAT binding in the right posterior putamen and left caudate in a small number of patients with bipolar disorder; Chang and colleagues [ ] reported that unmedicated euthymic subjects with bipolar disorder had significantly relatively higher whole striatal DAT binding; and Anand and colleagues [ ] reported relatively lower DAT availability in the dorsal caudate nucleus DCN bilaterally.

There is also evidence that the presence of psychosis may moderate patterns of DA receptor binding. Specifically, striatal D 2 receptor signaling seems to be greater in psychotic patients with bipolar disorder [ , ], whereas no differences in D 2 availability were found between non-psychotic patients with bipolar disorder and controls [ , ].

Bupropion, a DA and norepinephrine reuptake inhibitor, is an effective antidepressant [ ] that seems to specifically increase feelings of positive affect [ ]. Particularly relevant in the present context are previous reports [ , , ] that although both DA and non-DA agents can be used to effectively treat mood disorders, DA agents generally have superior effects on symptoms of anhedonia, specifically when compared with non-DA agents [ 19 , - ]. Tremblay and colleagues [ ] reported that depressed patients had relatively greater increases in striatal and orbitofrontal cortex activation in response to emotional pictures after administration of dextroamphetamine a stimulant associated with increased DA release.

This highlights the crucial role that the selection of reward-relevant outcome measures will have for studies addressing the efficacy of DA agents in the treatment of mood disorders. Feeding is a complex process that involves a sensory response to the sight and smell of food, previous feeding experiences, satiety signals elicited by ingestion, and hormonal signals related to energy balance.

DA release in specific brain regions is associated with pleasurable and rewarding events, and the mesolimbic system is thought to reward positive aspects of feeding. Some of the most elegant and informative studies clarifying the involvement of DA in feeding and other neurobiological functions come from the studies of Palmiter and colleagues. Zhou and Palmiter [ ] developed a DA-deficient mouse by genetically deleting tyrosine hydroxylase, the key enzyme required for the synthesis of L-3,4-dihydroxyphenylalanine L-DOPA , the chemical precursor of catecholamines.

Moreover, restoration of tyrosine hydroxylase gene expression using gene therapy was able rescue the deficient feeding behavior in these DA-deficient mice [ ]. Using gene therapy to enable DA production within only the caudate putamen restored mouse feeding on regular chow diet, and also normal nest-building behavior, whereas restoration of DA production into the NAc only restored the exploratory behavior [ ]. A salient result from these animal studies is that DA transduction in the central or lateral regions of the caudate putamen was sufficient to permanently rescue mice from the starvation that would occur inevitably without daily L-DOPA injections.

However, restoration of DA into the NAc in these studies was not sufficient to rescue normal feeding behavior, but this may have been due to an inability to anatomically restore gene expression throughout the entire NAc [ ]. Taken together, the DA-deficient mouse studies indicate the essential requirement of DA for normal feeding behavior and survival.

In addition, there is extensive experimental evidence in animal contexts supporting a role for the mesolimbic reward pathway on appetitive and motivational behaviors [ , ]. Mesolimboic DA release is associated with most pleasurable or rewarding events, and food is one type of reward that is often used during the training of animals.

There is an increase in DA release measured in awake, behaving animals by microdialysis or by fastscanning cyclic voltammetry in the NAc in response to unexpected food rewards or stimuli that predict food rewards [ 72 , - ]. Moreover, drugs that enhance operant responding for such food rewards, such as amphetamine, are most effective when administered into the NAc, whereas DA receptor antagonists administered into the NAc block the stimulant effects [ 57 , ]. Pharmacological control of the output from the NAc shell can also have profound effects on food consumption [ , ], as does surgical or chemical lesion of the nigrostriatal or mesolimbic DA pathways.

These results suggest that DA release in the striatum is required to integrate relevant signals for sustained feeding [ , , ]. These studies emphasize the importance of DA transmission and the mesolimbic reward pathway for food consumption, feeding behavior, and food rewards in animal models. Bulimia nervosa BN is an eating disorder characterized by recurrent binge eating followed by compensatory behaviors.

There is high comorbidity between BN and substance abuse, and there is a considerable body of data suggesting that disturbed appetitive behaviors for food in BN may reflect a dysregulation of reward mechanisms that is common to both BN and substance-abuse disorders [ ]. Indeed, early hallmark preclinical studies by Hoebel and colleagues [ ] highlighted commonalities between BN and addiction disorders in terms of neurobiology, psychopharmacology, neurochemistry, and behavior [ ].

Binge eating has also been suggested to serve an emotion regulatory function, and thus has many qualities of reward-mediated behaviors [ ]. There has been a small handful of functional neuroimaging studies of response to rewards in BN, with a wide range of rewarding stimuli presented. It is important to note that functional brain imaging studies in eating disorders have the methodological challenge of confounds associated with nutritional imbalances in affected individuals. One way to overcome this is to focus on individuals who are recovered from these disorders at the time of scanning, but it is important to note that such an approach may minimize the extent of brain responsivity differences that would characterize individuals meeting current criteria for this disorder.

Several studies have reported reduced reward motivation for food rewards in eating disorders.

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Joos and colleagues [ ] found reduced activation of the ACC in individuals with concurrent BN during the presentation of visual food cues, and Bohon and Stice [ ] reported trends towards decreased right insular cortex activation to the anticipated receipt of chocolate milkshake solution and in the right posterior and dorsal insula in response to milkshake consumption in women with BN.

Other studies have found atypical responses during reward outcome for monetary and food rewards. Wagner and colleagues [ ] reported that women who had recovered from BN had equivalent DCN responses to monetary-reward outcomes, whereas CN responses in the control group were specifically linked to monetary gains relative to losses. Frank and colleagues [ ] reported decreased ACC reward outcome responses to the blinded administration of glucose in participants who had recovered from bulimia.

By contrast, Uher and colleagues [ ] reported increased activation of the ACC, orbitofrontal cortex, occipital cortex, and cerebellum in response to food rewards in patients with bulimia; however, they did find hypoactivity in the lateral prefrontal cortex in patients with BN when compared with controls. Several studies have included different patient groups relevant to eating disorders, allowing for identification of brain imaging patterns specific to different types of eating disorders.

Schienle and colleagues [ ] examined reward outcome by presenting food images to overweight and normal-weight controls, overweight individuals with binge-eating disorder, and normal-weight individuals with BN. These authors reported increased medial orbital frontal cortex activation in the binge-eating disordered group, and greater cingulate cortex and insula activation in the bulimic group, relative to all other groups. These studies compliment candidate genetic behavior investigations in BN that have reported altered allelic frequencies for the DAT gene [ ] and DA receptor genes [ , ] in individuals with bulimia.

Molecular-imaging data addressing striatal DA function in BN are lacking. Of the numerous trials of the effects of psychopharmacologic agents for the treatment of BN, none has been primarily a DA agent [ ]. AN is characterized by extremely low body weight, distorted body image, and fear of gaining weight, with an estimated prevalence of 0. Watson and colleagues [ ] outlined a framework delineating linkages between AN and reward-processing deficits. Their model stressed the highly social nature of eating, the overlapping reward circuitry of gustatory and social stimuli [ , ], and the tendency of individuals with AN to deprive themselves of pleasure.

Additionally, Zucker and colleagues [ ] described commonalities between AN and ASD in social and interpersonal impairments, suggesting that impaired social function and social motivation may be a novel framework to conceptualize core deficits of AN. Individuals with AN report a heightened response to both punishment and reward outcome, even in the absence of clinically significant symptoms of anxiety or depression [ ].

Fladung and colleagues [ ] assessed responses to images depicting a female body with underweight, normal-weight, and overweight canonical whole-body features. They reported higher ventral striatal activation during processing of underweight images compared with normal-weight images in women with acute AN, but the reverse pattern in the control group. Joos and colleagues [ ] also reported hyper-reactive reward-outcome responses in anorexia during the processing of food-reward images. A small handful of studies have directly compared reward responses in AN and bulimia.

Wagner and colleagues [ ] reported increased CN activation to monetary-reward outcomes in women recovered from anorexia, and relatively equivalent CN responses to monetary gains and losses a strongly similar pattern of results to that found by Wagner et al. Uher and colleagues [ ] also found similar brain-activation patterns in individuals with AN and bulimia, with both groups showing hyperactivation relative to controls in areas relevant to reward processing, including the ACC and the orbitofrontal cortex. However, other studies have emphasized brain-activation differences during reward outcome between anorexia and bulimia.

Brooks and colleagues [ ] found that in response to food-reward outcomes, individuals with anorexia had greater activation of the dorsolateral prefrontal cortex, the cerebellum, and the right pre-cuneus relative to controls. They also had greater activation of the caudate, superior temporal gyrus, right insula, and supplementary motor area, and greater deactivation in the parietal lobe and dorsal posterior cingulate cortex relative to those with bulimia. It should be noted that this study did not include a non-food-reward condition, a design feature that would be necessary to assess the functional integrity of brain-reward systems to different classes of rewards.

Interestingly, individuals at risk for an eating disorder that is, those with higher dietary restraint have enhanced anticipatory responses to food rewards in the orbitofrontal cortex and the dorsolateral prefrontal cortex [ ], suggesting that hyperactive functioning of anticipatory reward processing may be a risk factor for eating disorders. Psychopharmacologic treatments for AN have yielded only moderate success, and the majority of treatments are antidepressants that act primarily on non-DA systems [ ].

A small number of double-blind trials have evaluated the effects of antipsychotics, with essentially non-significant effects [ - ]. Anhedonia has been hypothesized to be a core feature of schizophrenia [ - ], and it has been suggested that individuals with high levels of social anhedonia are more likely to develop schizophrenia-spectrum disorders [ ], although the link between anhedonia and the so-called schizophrenia prodrome has not been firmly established [ ].

The centrality of incentive motivation deficits to schizophrenia is suggested by the long-standing hypotheses regarding the role of DA disturbances in the pathophysiology of the disorder [ - ]. The DA hypothesis of schizophrenia suggests that excess DA transmission may be pro-psychotic, and originally gained support from pharmacological evidence that drugs that decrease DA activity for example,, the phenothiazine neuroleptics are antipsychotic, whereas drugs that promote DA activity for example,, amphetamines are psychotomimetic [ 76 , ].

Current models of schizophrenia suggest that the disorder is due to both common and rare gene mutations, copy-number variations, and possibly epigenetic factors [ ], all of which can affect multiple brain neurotransmitter systems and multiple risk genes [ - ]. In rodent models, hyperlocomotive behaviors and disruptions in the pre-pulse inhibition PPI response a measure of sensorimotor gating are generally viewed as being psychotomimetic, as both hyperlocomotion and disrupted PPI can be normalized and attenuated by antipsychotic medications [ ].

However, no current behavioral paradigms truly capture the positive symptoms of schizophrenia such as hallucinations and delusions. There have been numerous reports of PPI deficits in patients with schizophrenia [ , ]; however, exactly which endophenotype in schizophrenia is manifested as disrupted PPI remains debated [ ]. Swerdlow and colleagues [ ] persuasively suggested that PPI deficits are a useful psychophysiological outcome for basic studies in humans and animals to probe neural circuitry and as a pharmacological screen. Indeed, PPI testing is commonly used in screening for potential antipsychotic drugs that act via antagonism of mesolimbic DA transmission.

Studies in mice have indicated that administration of direct-acting DA agonists such as apomorphine and indirect DA agonists such as cocaine to mice disrupt PPI primarily via D 1 receptors [ ], whereas D 2 receptors seem to modulate amphetamine-induced PPI deficits [ ]. By contrast, both apomorphine-induced and amphetamine-induced PPI disruptions in rats are blocked by DA D 2 antagonists [ ]. In addition, normalizing PPI deficits in rodent models has enabled drug discovery for potential antipsychotic medications [ ], some of which have proven successful in treating schizophrenia [ , ].

Mice lacking the DAT gene display markedly increased levels of DA in the mesolimbic system and striatum [ ], that results in hyperlocomoter behaviors [ , ] and also deficits in PPI [ , ]. The DAT knockout mice phenotypes resemble amphetamine-like effects, and both hyperlocomotion and PPI deficits can be reversed with either D 1 or D 2 receptor antagonists [ ], the atypical antipsychotics clozapine and quetiapine [ ], various antidepressant drugs, and monoamine transporter inhibitors [ ]. Thus, the DAT knockout mouse may be a useful animal model for predicting the efficacy of novel drugs for disorders such as schizophrenia that are characterized by a dysregulated limbic DA system.

In alignment with the DA hypothesis of schizophrenia, an increased level of striatal D 2 receptors has been seen in patients with schizophrenia who are not on medication [ 78 ], which may result in D 2 receptor supersensitivity in the ventral striatum contributing to psychosis [ 79 ]. To study the behavioral consequences of D 2 receptor upregulation in the striatum, the mice were analyzed using a battery of behavioral tasks, and were shown to have several abnormal cognitive phenotypes, including working-memory deficits, reversal-learning impairment and decreased social interactions.

In a follow-up study, Li and colleagues [ ] reported that this D 2 receptor overexpression in the striatum causes an increase in the firing activity of layer V cortical pyramidal neurons, and also a decrease in both the frequency and amplitude of spontaneous inhibitory post-synaptic currents, indicating reduced inhibitory transmission in the prefrontal cortex. Taken together, the mouse model suggests that overexpression of D 2 receptors similar to that seen in some individuals with schizophrenia will alter striatal MSN activity, resulting in dysregulated GABA transmission and inhibitory activity in the cortex [ ].

Because a core symptom of schizophrenia is cognitive impairment for example, deficits in working memory, attention, executive function , this mouse model may provide a link explaining how altered mesostriatal and mesolimbic DA receptors and DA transmission can alter cognitive processes in the frontal cortex, possibly by dysregulating circuit pathways that link connectivity between the striatum and pre-frontal cortex [ ]. The reader is referred to other seminal reviews of schizophrenia animal models that highlight altered DA and reward-pathway transmission [ - ].

Patterns of responses to rewards by patients with schizophrenia are complex. Patients report normal intrapsychic emotional experience, but communicate symptoms of anhedonia during structured interview [ ]. Split and merge into it. Ward Taylor has written: Fiction, World War, What has the author Winifred Ward written?

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