The nucleus accumbens

The nucleus accumbens (NAc or NAcc), also known as the accumbens nucleus or as the nucleus accumbens septi (Latin fornucleus adjacent to the septum) is a region in the basal forebrain rostral to the preoptic area of the hypothalamus.[1] The nucleus accumbens and the olfactory tubercle collectively form the ventral striatum, which is part of […]

The nucleus accumbens (NAc or NAcc), also known as the accumbens nucleus or as the nucleus accumbens septi (Latin fornucleus adjacent to the septum) is a region in the basal forebrain rostral to the preoptic area of the hypothalamus.[1] The nucleus accumbens and the olfactory tubercle collectively form the ventral striatum, which is part of the basal ganglia.[2] Each cerebral hemisphere has its own nucleus accumbens, which can be divided into two structures: the nucleus accumbens core and the nucleus accumbens shell. These substructures have different morphology and functions.

Different NAcc subregions (core vs shell) and neuron subpopulations within each region (D1-type vs D2-type medium spiny neurons) are responsible for different cognitive functions.[3][4] As a whole, the nucleus accumbens has a significant role in the cognitive processing of aversion, motivation, pleasure, reward and reinforcement learning;[5][6][7] hence, it has a significant role inaddiction.[6][7] It plays a lesser role in processing fear (a form of aversion), impulsivity, and the placebo effect.[8][9][10] It is involved in the encoding of new motor programs as well.[6]

Major inputs to the nucleus accumbens include the prefrontal cortex, basolateral amygdala, and dopaminergic neurons located in the ventral tegmental area (VTA), which connect via the mesolimbic pathway. Thus the nucleus accumbens is often described as one part of a cortico–basal ganglia–thalamic loop.[11]

Dopaminergic input from the VTA modulate the activity of neurons within the nucleus accumbens. These neurons are activated directly or indirectly by euphoriant drugs (e.g.,amphetamine, opiates, etc.) and by participating in rewarding experiences (e.g., sex, music, exercise, etc.).[12][13]

Another major source of input comes from the CA1 and ventral subiculum of the hippocampus to the dorsomedial area of the nucleus accumbens. The neurons of the hippocampus have a noteworthy correlation to slight depolarizations of cells in the nucleus accumbens, which makes them more positive and therefore more excitable. The correlated cells of these excited states of the medium spiny neurons in the nucleus accumbens are shared equally between the subiculum and CA1. The subiculum neurons are found to hyperpolarize (increase negativity) while the CA1 neurons “ripple” (fire > 50 Hz) in order to accomplish this priming.[14]

The nucleus accumbens is one of the few regions that receive histaminergic projections from the tuberomammillary nucleus (the sole source of histamine neurons in the brain).[15]


The output neurons of the nucleus accumbens send axon projections to the basal ganglia and the ventral analog of the globus pallidus, known as the ventral pallidum (VP). The VP, in turn, projects to the medial dorsal nucleus of the dorsal thalamus, which projects to the prefrontal cortex as well as the striatum. Other efferents from the nucleus accumbens include connections with the tail of the ventral tegmental area,[16] substantia nigra, and the reticular formation of the pons.[1]


Dopamine: Dopamine is related to recreational drugs including amphetamines, cocaine, and morphine, which increase extracellular levels of dopamine in both the NAc shell and the NAc core, but the effect of these increases is more pronounced in the shell. Only amphetamine at high levels increases extracellular levels of dopamine to similar levels in both the shell and the core. All of this points to a ‘functional heterogeneity’ in the nucleus accumbens between the shell region and the core region.[26] Similarly to drug rewards, non-drug rewards also increase levels of extracellular dopamine in the NAc shell, but drug induced DA increase is more resilient to habituation when exposed repeatedly to drug-stimuli, unlike non-drug rewarding stimuli induced dopamine increases, which do succumb to habituation. Recent[when?] studies have shown that the repeated influence of drug-inducing DA projection has an abnormal strengthening effect on stimulus-drug associations and increases the drug-reward stimuli’s resistance to extinction. This may be a contributing factor to addiction. This effect was more pronounced in the NAc shell than in the NAc core.[19][27]

Phenethylamine and tyramine: Phenethylamine and tyramine are trace amine compounds which are synthesized in several types of CNS neurons, including all dopamine neurons.[28] Specifically, these neurotransmitters act within the dopaminergic inputs to the NAcc. These substances regulate the presynaptic release of dopamine through their interactions with VMAT2 and TAAR1, analogous to amphetamine.

Glucocorticoids and dopamine: Glucocorticoid receptors are the only corticosteroid receptors in the nucleus accumbens shell. L-DOPA, steroids, and specifically glucocorticoids are currently known to be the only known endogenous compounds that can induce psychotic problems, so understanding the hormonal control over dopaminergic projections with regards to glucocorticoid receptors could lead to new treatments for psychotic symptoms. A recent study demonstrated that suppression of the glucocorticoid receptors led to a decrease in the release of dopamine, which may lead to future research involving anti-glucocorticoid drugs to potentially relieve psychotic symptoms.[29]

Glucocorticoids (GCs) are a class of corticosteroids, which are a class of steroid hormones. Glucocorticoids are corticosteroids that bind to the glucocorticoid receptor (GR),[1] that is present in almost every vertebrate animal cell. The name glucocorticoid (glucose +cortex + steroid) is composed from its role in regulation of glucose metabolisms synthesis in the adrenal cortex, and its steroidalstructure (see structure to the right). A less common synonym is glucocorticosteroid.

GCs are part of the feedback mechanism in the immune system which reduces certain aspects of immune function, such as reduction of inflammation. They are therefore used in medicine to treat diseases caused by an overactive immune system, such as allergies, asthma, autoimmune diseases, and sepsis. GCs have many diverse (pleiotropic) effects, including potentially harmful side effects, and as a result are rarely sold over the counter.[2] They also interfere with some of the abnormal mechanisms in cancer cells, so they are used in high doses to treat cancer. This includes: inhibitory effects on lymphocyte proliferation as in the treatment of lymphomas and leukemias; and the mitigation of side effects of anticancer drugs.

GCs affect cells by binding to the glucocorticoid receptor (GR). The activated GR complex, in turn, up-regulates the expression of anti-inflammatory proteins in the nucleus (a process known as transactivation) and represses the expression of proinflammatory proteins in the cytosol by preventing the translocation of other transcription factors from the cytosol into the nucleus (transrepression).[2]

Glucocorticoids are distinguished from mineralocorticoids and sex steroids by their specific receptors, target cells, and effects. In technical terms, “corticosteroid” refers to both glucocorticoids and mineralocorticoids (as both are mimics of hormones produced by the adrenal cortex), but is often used as a synonym for “glucocorticoid.” Glucocorticoids are chiefly produced in the zona fasciculataof the adrenal cortex, whereas mineralocorticoids are synthesized in the zona glomerulosa.

Cortisol (or hydrocortisone) is the most important human glucocorticoid. It is essential for life, and it regulates or supports a variety of important cardiovascular, metabolic, immunologic, and homeostatic functions. Various synthetic glucocorticoids are available; these are used either as replacement therapy in glucocorticoid deficiency or to suppress the immune system.

Glucocorticoids act on the hippocampus, amygdala, and frontal lobes. Along with adrenaline, these enhance the formation of flashbulb memories of events associated with strong emotions, both positive and negative.[5] This has been confirmed in studies, whereby blockade of either glucocorticoids or noradrenaline activity impaired the recall of emotionally relevant information. Additional sources have shown subjects whose fear learning was accompanied by high cortisol levels had better consolidation of this memory (this effect was more important in men). The effect that glucocorticoids have on memory may be due to damage specifically to the CA1 area of the hippocampal formation. In multiple animal studies, prolonged stress (causing prolonged increases in glucocorticoid levels) have shown destruction of the neurons in this area of the brain, which has been connected to memory performance.[6][7][8]

Glucocorticoids have also been shown to have a significant impact on vigilance (attention deficit disorder) and cognition (memory). This appears to follow the Yerkes-Dodson curve, as studies have shown circulating levels of glucocorticoids vs. memory performance follow an upside-down U pattern, much like the Yerkes-Dodson curve. For example, long-term potentiation (LTP; the process of forming long-term memories) is optimal when glucocorticoid levels are mildly elevated, whereas significant decreases of LTP are observed after adrenalectomy (low-GC state) or after exogenous glucocorticoid administration (high-GC state). Elevated levels of glucocorticoids enhance memory for emotionally arousing events, but lead more often than not to poor memory for material unrelated to the source of stress/emotional arousal.[9] In contrast to the dose-dependent enhancing effects of glucocorticoids on memory consolidation, these stress hormones have been shown to inhibit the retrieval of already stored information.[10] Long-term exposure to glucocorticoid medications, such as asthma and anti-inflammatory medication, has been shown to create deficits in memory and attention both during and, to a lesser extent, after treatment,[11][12] a condition known as “steroid dementia.”[13]

GABA: A recent study on rats that used GABA agonists and antagonists indicated that GABAA receptors in the NAc shell have inhibitory control on turning behavior influenced by dopamine, and GABAB receptors have inhibitory control over turning behavior mediated by acetylcholine.[19][30]

Glutamate: Studies have shown that local blockade of glutamatergic NMDA receptors in the NAcc core impaired spatial learning.[31] Another study demonstrated that both NMDA and AMPA (both glutamate receptors) play important roles in regulating instrumental learning.[32]

Serotonin (5-HT): Overall, 5-HT synapses are more abundant and have a greater number of synaptic contacts in the NAc shell than in the core. They are also larger and thicker, and contain more large dense core vesicles than their counterparts in the core.

Reward and reinforcement

The nucleus accumbens, being one part of the reward system, plays an important role in processing rewarding stimuli, reinforcing stimuli (e.g., food and water), and those which are both rewarding and reinforcing (addictive drugs, sex, and exercise).[6][33] The nucleus accumbens is selectively activated during the perception of pleasant, emotionally arousing pictures and during mental imagery of pleasant, emotional scenes.[34][35] A 2005 study found that it is involved in the regulation of emotions induced by music,[36]perhaps consequent to its role in mediating dopamine release. The nucleus accumbens plays a role in rhythmic timing and is considered to be of central importance to the limbic-motor interface (Mogensen).[citation needed]

In the 1950s, James Olds and Peter Milner implanted electrodes into the septal area of the rat and found that the rat chose to press a lever which stimulated it. It continued to prefer this even over stopping to eat or drink. This suggests that the area is the “pleasure center” of the brain and is involved in reinforcement learning.[37] In rats, stimulation of the ventral tegmental area causes the release of dopamine in the nucleus accumbens much in the same way as addictive drugs and natural reinforcers, such as water or food, initiate the release of dopamine in the nucleus accumbens.[38] The same results have been seen in human subjects in functional imaging studies. For example, increased dopamine concentration is seen in the extracellular fluid of the nucleus accumbens when subjects believed they were being given money[citation needed], and increased activation (i.e., increased fMRI BOLD signal-change) was observed among heterosexual males viewing pictures of attractive women.[39]


Activation of D1-type MSNs in the nucleus accumbens is involved in reward, whereas the activation of D2-type MSNs in the nucleus accumbens promotes aversion.[4]

Maternal behavior

An fMRI study conducted in 2005 found that when mother rats were in the presence of their pups the regions of the brain involved in reinforcement, including the nucleus accumbens, were highly active.[40] Levels of dopamine increase in the nucleus accumbens during maternal behavior, while lesions in this area upset maternal behavior.[41] When women are presented pictures of unrelated infants, fMRIs show increased brain activity in the nucleus accumbens and adjacent caudate nucleus, proportionate to the degree to which the women find these infants “cute”.[42]

Placebo effect

Activation of the NAcc has been shown to occur in the anticipation of effectiveness of a drug when a user is given a placebo, indicating a contributing role of the nucleus accumbens in the placebo effect.[9][52]


Dopamine is an organic chemical of the catecholamine and phenethylamine families that plays several important roles in the brain and body. Its name is derived from its chemical structure: it is an amine synthesized by removing a carboxyl group from a molecule of its precursor chemical L-DOPA, which is synthesized in the brain and kidneys. […]

Dopamine is an organic chemical of the catecholamine and phenethylamine families that plays several important roles in the brain and body. Its name is derived from its chemical structure: it is an amine synthesized by removing a carboxyl group from a molecule of its precursor chemical L-DOPA, which is synthesized in the brain and kidneys. Dopamine is also synthesized in plants and most multicellular animals.

In the brain, dopamine functions as a neurotransmitter—a chemical released by neurons (nerve cells) to send signals to other nerve cells. The brain includes several distinct dopamine pathways, one of which plays a major role in reward-motivated behavior. Most types of reward increase the level of dopamine in the brain, and most addictive drugs increase dopamine neuronal activity. Other brain dopamine pathways are involved in motor control and in controlling the release of various hormones. These pathways and cell groups form a dopamine system which is neuromodulatory.

Outside the central nervous system, dopamine functions in several parts of the peripheral nervous system as a local chemical messenger. In blood vessels, it inhibits norepinephrine release and acts as a vasodilator (at normal concentrations); in the kidneys, it increases sodium excretion and urine output; in the pancreas, it reduces insulin production; in the digestive system, it reducesgastrointestinal motility and protects intestinal mucosa; and in the immune system, it reduces the activity of lymphocytes. With the exception of the blood vessels, dopamine in each of these peripheral systems is synthesized locally and exerts its effects near the cells that release it.

Several important diseases of the nervous system are associated with dysfunctions of the dopamine system, and some of the key medications used to treat them work by altering the effects of dopamine. Parkinson’s disease, a degenerative condition causing tremor and motor impairment, is caused by a loss of dopamine-secreting neurons in an area of the midbrain called the substantia nigra. Its metabolic precursor L-DOPA can be manufactured, and in its pure form marketed as Levodopa is the most widely used treatment for the condition. There is evidence that schizophrenia involves altered levels of dopamine activity, and most antipsychotic drugs used to treat this are dopamine antagonists which reduce dopamine activity.[2] Similar dopamine antagonist drugs are also some of the most effective anti-nausea agents. Restless legs syndrome and attention deficit hyperactivity disorder (ADHD) are associated with decreased dopamine activity.[3] Dopaminergic stimulants can be addictive in high doses, but some are used at lower doses to treat ADHD. Dopamine itself is available as a manufactured medication for intravenous injection: although it cannot reach the brain from the bloodstream, its peripheral effects make it useful in the treatment of heart failure or shock, especially in newborn babies.

Dopamine exerts its effects by binding to and activating cell surface receptors.[8] In mammals, five subtypes of dopamine receptors have been identified, labeled from D1 to D5.[8] All of them function as metabotropic, G protein-coupled receptors, meaning that they exert their effects via a complex second messenger system.[17] These receptors can be divided into two families, known as D1-like and D2-like.[8] For receptors located on neurons in the nervous system, the ultimate effect of D1-like activation (D1 and D5) can be excitation (via opening of sodium channels) or inhibition (via opening of potassium channels); the ultimate effect of D2-like activation (D2, D3, and D4) is usually inhibition of the target neuron.[17] Consequently, it is incorrect to describe dopamine itself as either excitatory or inhibitory: its effect on a target neuron depends on which types of receptors are present on the membrane of that neuron and on the internal responses of that neuron to the second messenger cAMP.[17] D1 receptors are the most numerous dopamine receptors in the human nervous system; D2 receptors are next; D3, D4, and D5 receptors are present at significantly lower levels.[17]

Inside the brain, dopamine functions as a neurotransmitter and neuromodulator, and is controlled by a set of mechanisms common to allmonoamine neurotransmitters.[8] After synthesis, dopamine is transported from the cytosol into synaptic vesicles by a solute carrier—avesicular monoamine transporter, VMAT2.[18] Dopamine is stored in these vesicles until it is ejected into the synaptic cleft through a process called exocytosis. In most cases exocytosis is caused by action potentials, but it can also be caused by the activity of an intracellular trace amine-associated receptor, TAAR1.[16] TAAR1 is a high-affinity receptor for dopamine, trace amines, and certainsubstituted amphetamines that is located along membranes in the intracellular milieu of the presynaptic cell;[16] activation of the receptor can regulate dopamine signaling by producing reuptake inhibition and neurotransmitter efflux and inhibiting neuronal firing through a diverse set of mechanisms.[16][19]

Once in the synapse, dopamine binds to and activates dopamine receptors. These can be the D2Lh type, located on the postsynaptictarget cells or the D2Sh autoreceptor type located on the membrane of the presynaptic cell.[8] After an action potential, the dopamine molecules quickly become unbound from their receptors. They are then absorbed back into the presynaptic cell, via reuptake mediated either by the dopamine transporter or by the plasma membrane monoamine transporter.[20] Once back in the cytosol, dopamine can either be broken down by a monoamine oxidase or repackaged into vesicles by VMAT2, making it available for future release.[18]

In the brain the level of extracellular dopamine is modulated by two mechanisms: phasic and tonic transmission.[21] Phasic dopamine release, like most neurotransmitter release in the nervous system, is driven directly by action potentials in the dopamine-containing cells.[21] Tonic dopamine transmission occurs when small amounts of dopamine are released without being preceded by presynaptic action potentials.[21] Tonic transmission is regulated by a variety of factors, including the activity of other neurons and neurotransmitter reuptake.[21]

Inside the brain, dopamine plays important roles in executive functions, motor control, motivation, arousal, reinforcement, and reward, as well as lower-level functions including lactation, sexual gratification, and nausea. The dopaminergic cell groups and pathways make up the dopamine system which is neuromodulatory.

Dopaminergic neurons (dopamine-producing nerve cells) are comparatively few in number—a total of around 400,000 in the human brain[22]—and their cell bodies are confined in groups to a few relatively small brain areas.[23] However their axons project to many other brain areas, and they exert powerful effects on their targets.[23] These dopaminergic cell groups were first mapped in 1964 by Annica Dahlström and Kjell Fuxe, who assigned them labels starting with the letter “A” (for “aminergic”).[24] In their scheme, areas A1 through A7 contain the neurotransmitter norepinephrine, whereas A8 through A14 contain dopamine. The dopaminergic areas they identified are thesubstantia nigra (groups 8 and 9); the ventral tegmental area (group 10); the posterior hypothalamus (group 11); the arcuate nucleus(group 12); the zona incerta (group 13) and the periventricular nucleus (group 14).[24]

The substantia nigra is a small midbrain area that forms a component of the basal ganglia. This has two parts—an input area called thepars compacta and an output area the pars reticulata. The dopaminergic neurons are found mainly in the pars compacta (cell group A8) and nearby (group A9).[23] In humans, the projection of dopaminergic neurons from the substantia nigra pars compacta to the dorsal striatum, termed the nigrostriatal pathway, plays a significant role in the control of motor function and in learning new motor skills.[25]These neurons are especially vulnerable to damage, and when a large number of them die, the result is a parkinsonian syndrome.[26]

The ventral tegmental area (VTA) is another midbrain area. The most prominent group of VTA dopaminergic neurons projects to theprefrontal cortex via the mesocortical pathway and another smaller group projects to the nucleus accumbens via the mesolimbic pathway. Together, these two pathways are collectively termed the mesocorticolimbic projection.[23][25] The VTA also sends dopaminergic projections to the amygdala, cingulate gyrus, hippocampus, and olfactory bulb.[23][25] Mesocorticolimbic neurons play a central role in reward and other aspects of motivation.[25]

The posterior hypothalamus has dopamine neurons that project to the spinal cord, but their function is not well established.[27] There is some evidence that pathology in this area plays a role in restless legs syndrome, a condition in which people have difficulty sleeping due to an overwhelming compulsion to constantly move parts of the body, especially the legs.[27]

The arcuate nucleus and the periventricular nucleus of the hypothalamus have dopamine neurons that form an important projection—the tuberoinfundibular pathway which goes to the pituitary gland, where it influences the secretion of the hormone prolactin.[28] Dopamine is the primary neuroendocrine inhibitor of the secretion of prolactin from theanterior pituitary gland.[28] Dopamine produced by neurons in the arcuate nucleus is secreted into the hypophyseal portal system of the median eminence, which supplies thepituitary gland.[28] The prolactin cells that produce prolactin, in the absence of dopamine, secrete prolactin continuously; dopamine inhibits this secretion.[28] In the context of regulating prolactin secretion, dopamine is occasionally called prolactin-inhibiting factor, prolactin-inhibiting hormone, or prolactostatin.[28]

The zona incerta, grouped between the arcuate and periventricular nuclei, projects to several areas of the hypothalamus, and participates in the control of gonadotropin-releasing hormone, which is necessary to activate the development of the male and female reproductive systems, following puberty.[28]

An additional group of dopamine-secreting neurons is found in the retina of the eye.[29] These neurons are amacrine cells, meaning that they have no axons.[29] They release dopamine into the extracellular medium, and are specifically active during daylight hours, becoming silent at night.[29] This retinal dopamine acts to enhance the activity of cone cells in the retina while suppressing rod cells—the result is to increase sensitivity to color and contrast during bright light conditions, at the cost of reduced sensitivity when the light is dim.[29]

Basal ganglia

At the top, a line drawing of a side view of the human brain, with a cross section pulled out showing the basal ganglia structures in color near the center.  At the bottom an expanded line drawing of the basal ganglia structures, showing outlines of each structure and broad arrows for their connection pathways.

Main circuits of the basal ganglia. The dopaminergic pathway from the substantia nigra pars compacta to the striatum is shown in light blue.

The largest and most important sources of dopamine in the vertebrate brain are the substantia nigra and ventral tegmental area.[23] These structures are closely related to each other and functionally similar in many respects.[23] Both are components of the basal ganglia, a complex network of structures located mainly at the base of the forebrain.[23] The largest component of the basal ganglia is the striatum.[30] The substantia nigra sends a dopaminergic projection to the dorsal striatum, while the ventral tegmental area sends a similar type of dopaminergic projection to the ventral striatum.[23]

Progress in understanding the functions of the basal ganglia has been slow.[30] The most popular hypotheses, broadly stated, propose that the basal ganglia play a central role in action selection.[31] The action selection theory in its simplest form proposes that when a person or animal is in a situation where several behaviors are possible, activity in the basal ganglia determines which of them is executed, by releasing that response from inhibition while continuing to inhibit other motor systems that if activated would generate competing behaviors.[32] Thus the basal ganglia, in this concept, are responsible for initiating behaviors, but not for determining the details of how they are carried out. In other words, they essentially form a decision-making system.[32]

The basal ganglia can be divided into several sectors, and each is involved in controlling particular types of actions.[33] The ventral sector of the basal ganglia (containing the ventral striatum and ventral tegmental area) operates at the highest level of the hierarchy, selecting actions at the whole-organism level.[32] The dorsal sectors (containing the dorsal striatum and substantia nigra) operate at lower levels, selecting the specific muscles and movements that are used to implement a given behavior pattern.[33]

Dopamine contributes to the action selection process in at least two important ways. First, it sets the “threshold” for initiating actions.[31] The higher the level of dopamine activity, the lower the impetus required to evoke a given behavior.[31] As a consequence, high levels of dopamine lead to high levels of motor activity and impulsive behavior; low levels of dopamine lead to torpor and slowed reactions.[31] Parkinson’s disease, in which dopamine levels in the substantia nigra circuit are greatly reduced, is characterized by stiffness and difficulty initiating movement—however, when people with the disease are confronted with strong stimuli such as a serious threat, their reactions can be as vigorous as those of a healthy person.[34] In the opposite direction, drugs that increase dopamine release, such as cocaine or amphetamine, can produce heightened levels of activity, including at the extreme, psychomotor agitation and stereotyped movements.[35]

The second important effect of dopamine is as a “teaching” signal.[31] When an action is followed by an increase in dopamine activity, the basal ganglia circuit is altered in a way that makes the same response easier to evoke when similar situations arise in the future.[31] This is a form of operant conditioning, in which dopamine plays the role of a reward signal.[32]


Illustration of dopaminergic reward structures

In the reward system, reward is the attractive and motivational property of a stimulus that induces appetitive behavior (also known as approach behavior) – and consummatory behavior.[36] A rewarding stimulus is one that has the potential to cause an approach to it and a choice to be made to consume it or not.[36] Pleasure, learning (e.g., classical and operant conditioning), and approach behavior are the three main functions of reward.[36] As an aspect of reward, pleasure provides a definition of reward;[36] however, while all pleasurable stimuli are rewarding, not all rewarding stimuli are pleasurable (e.g., extrinstic rewards like money).[36][37] The motivational or desirable aspect of rewarding stimuli is reflected by the approach behavior that they induce, whereas the pleasurable component of intrinstic rewards is derived from the consummatory behavior that ensues upon acquiring them.[36] A neuropsychological model which distinguishes these two components of an intrinsically rewarding stimulus is the incentive salience model, where “wanting” or desire (less commonly, “seeking”[38]) corresponds to appetitive or approach behavior while “liking” or pleasure corresponds to consummatory behavior.[36][39][40] In human drug addicts, “wanting” becomes dissociated with “liking” as the desire to use an addictive drug increases, while the pleasure obtained from consuming it decreases due to drug tolerance.[39]

Within the brain, dopamine functions partly as a “global reward signal”, where an initial phasic dopamine response to a rewarding stimulus encodes information about the salience, value, and context of a reward.[36] In the context of reward-related learning, dopamine also functions as a reward prediction error signal, that is, the degree to which the value of a reward is unexpected.[36] According to this hypothesis of Wolfram Schultz, rewards that are expected do not produce a second phasic dopamine response in certain dopaminergic cells, but rewards that are unexpected, or greater than expected, produce a short-lasting increase in synaptic dopamine, whereas the omission of an expected reward actually causes dopamine release to drop below its background level.[36] The “prediction error” hypothesis has drawn particular interest from computational neuroscientists, because an influential computational-learning method known as temporal difference learning makes heavy use of a signal that encodes prediction error.[36] This confluence of theory and data has led to a fertile interaction between neuroscientists and computer scientists interested in machine learning.[36]

Evidence from microelectrode recordings from the brains of animals shows that dopamine neurons in the ventral tegmental area (VTA) and substantia nigra are strongly activated by a wide variety of rewarding events.[36] These reward-responsive dopamine neurons in the VTA and substantia nigra are crucial for reward-related cognition and serve as the central component of the reward system.[39][41][42] The function of dopamine varies in each axonal projection from the VTA and substantia nigra;[39] for example, the VTA–nucleus accumbens shell projection assigns incentive salience (“want”) to rewarding stimuli and its associated cues, the VTA–orbitofrontal cortex projection updates the value of different goals in accordance with their incentive salience, the VTA–amygdala and VTA–hippocampus projections mediate the consolidation of reward-related memories, and both the VTA–nucleus accumbens core and substantia nigra–dorsal striatum pathways are involved in learning motor responses that facilitate the acquisition of rewarding stimuli.[39][43]Some activity within the VTA dopaminergic projections appears to be associated with reward prediction as well.[39][43]

While dopamine has a central role in mediating “wanting” — associated with the appetitive or approach behavioral responses to rewarding stimuli, detailed studies have shown that dopamine cannot simply be equated with “liking” or pleasure, as reflected in the consummatory behavioral response.[37] Dopamine neurotransmission is involved in some but not all aspects of , since pleasure centers have been identified both within and outside the dopamine system (i.e., compartments within the nucleus accumbens shell and ventral pallidum, respectively).[37][40] For example, direct electrical stimulation of dopamine pathways, using electrodes implanted in the brain, is experienced as pleasurable, and many types of animals are willing to work to obtain it.[44] Antipsychotic drugs used to treat psychosis reduce dopamine levels and tend to causeanhedonia, a diminished ability to experience pleasure.[45] Many types of pleasurable experiences—such as sex, enjoying food, or playing video games—increase dopamine release.[46] All addictive drugs directly or indirectly affect dopamine neurotransmission in the nucleus accumbens;[39][44] these drugs increase drug “wanting”, leading to compulsive drug use, when repeatedly taken in high doses, presumably through the sensitization of incentive-salience.[40] Drugs that increase dopamine release includestimulants such as methamphetamine or cocaine. These produce increases in “wanting” behaviors, but do not greatly alter expressions of pleasure or change levels of satiation.[40][44] However, opiate drugs such as heroin or morphine produce increases in expressions of “liking” and “wanting” behaviors.[40] Moreover, animals in which the ventral tegmental dopamine system has been rendered inactive do not seek food, and will starve to death if left to themselves, but if food is placed in their mouths they will consume it and show expressions indicative of pleasure.[47]