reward system reward system the reward system (the mesocorticolimbic circuit) is a group of neural structures responsible for incentive salience (i.e., "wanting"; desire or craving for a reward and motivation), associative learning (primarily positive reinforcement and classical conditioning), and positively-valenced emotions, particularly ones involving pleasure as a core component (e.g., joy, euphoria and ecstasy). reward is the attractive and motivational property of a stimulus that induces appetitive behavior, also known as approach behavior, and consummatory behavior. a rewarding stimulus has been described as "any stimulus, object, event, activity, or situation that has the potential to make us approach and consume it is by definition a reward". in operant conditioning, rewarding stimuli function as positive reinforcers; however, the converse statement also holds true: positive reinforcers are rewarding. examples of primary rewards. clockwise from top left: water, food, parental care, and sex. addiction and dependence glossary addiction – a biopsychosocial disorder characterized by persistent use of drugs (including alcohol) despite substantial harm and adverse consequences addictive drug – psychoactive substances that with repeated use are associated with significantly higher rates of substance use disorders, due in large part to the drug's effect on brain reward systems dependence – an adaptive state associated with a withdrawal syndrome upon cessation of repeated exposure to a stimulus (e.g., drug intake) drug sensitization or reverse tolerance – the escalating effect of a drug resulting from repeated administration at a given dose drug withdrawal – symptoms that occur upon cessation of repeated drug use physical dependence – dependence that involves persistent physical–somatic withdrawal symptoms (e.g., fatigue and delirium tremens) psychological dependence – dependence that involves emotional–motivational withdrawal symptoms (e.g., dysphoria and anhedonia) reinforcing stimuli – stimuli that increase the probability of repeating behaviors paired with them rewarding stimuli – stimuli that the brain interprets as intrinsically positive and desirable or as something to approach sensitization – an amplified response to a stimulus resulting from repeated exposure to it substance use disorder – a condition in which the use of substances leads to clinically and functionally significant impairment or distress tolerance – the diminishing effect of a drug resulting from repeated administration at a given dose the reward system motivates animals to approach stimuli or engage in behaviour that increases fitness (sex, energy-dense foods, etc.). survival for most animal species depends upon maximizing contact with beneficial stimuli and minimizing contact with harmful stimuli. reward cognition serves to increase the likelihood of survival and reproduction by causing associative learning, eliciting approach and consummatory behavior, and triggering positively-valenced emotions. thus, reward is a mechanism that evolved to help increase the adaptive fitness of animals. in drug addiction, certain substances over-activate the reward circuit, leading to compulsive substance-seeking behavior resulting from synaptic plasticity in the circuit. primary rewards are a class of rewarding stimuli which facilitate the survival of one's self and offspring, and they include homeostatic (e.g., palatable food) and reproductive (e.g., sexual contact and parental investment) rewards. intrinsic rewards are unconditioned rewards that are attractive and motivate behavior because they are inherently pleasurable. extrinsic rewards (e.g., money or seeing one's favorite sports team winning a game) are conditioned rewards that are attractive and motivate behavior but are not inherently pleasurable. extrinsic rewards derive their motivational value as a result of a learned association (i.e., conditioning) with intrinsic rewards. extrinsic rewards may also elicit pleasure (e.g., euphoria from winning a lot of money in a lottery) after being classically conditioned with intrinsic rewards. definition in neuroscience, the reward system is a collection of brain structures and neural pathways that are responsible for reward-related cognition, including associative learning (primarily classical conditioning and operant reinforcement), incentive salience (i.e., motivation and "wanting", desire, or craving for a reward), and positively-valenced emotions, particularly emotions that involve pleasure (i.e., hedonic "liking"). terms that are commonly used to describe behavior related to the "wanting" or desire component of reward include appetitive behavior, approach behavior, preparatory behavior, instrumental behavior, anticipatory behavior, and seeking. terms that are commonly used to describe behavior related to the "liking" or pleasure component of reward include consummatory behavior and taking behavior. the three primary functions of rewards are their capacity to: produce associative learning (i.e., classical conditioning and operant reinforcement); affect decision-making and induce approach behavior (via the assignment of motivational salience to rewarding stimuli); elicit positively-valenced emotions, particularly pleasure. neuroanatomy overview the brain structures that compose the reward system are located primarily within the cortico-basal ganglia-thalamo-cortical loop; the basal ganglia portion of the loop drives activity within the reward system. most of the pathways that connect structures within the reward system are glutamatergic interneurons, gabaergic medium spiny neurons (msns), and dopaminergic projection neurons, although other types of projection neurons contribute (e.g., orexinergic projection neurons). the reward system includes the ventral tegmental area, ventral striatum (i.e., the nucleus accumbens and olfactory tubercle), dorsal striatum (i.e., the caudate nucleus and putamen), substantia nigra (i.e., the pars compacta and pars reticulata), prefrontal cortex, anterior cingulate cortex, insular cortex, hippocampus, hypothalamus (particularly, the orexinergic nucleus in the lateral hypothalamus), thalamus (multiple nuclei), subthalamic nucleus, globus pallidus (both external and internal), ventral pallidum, parabrachial nucleus, amygdala, and the remainder of the extended amygdala. the dorsal raphe nucleus and cerebellum appear to modulate some forms of reward-related cognition (i.e., associative learning, motivational salience, and positive emotions) and behaviors as well. the laterodorsal tegmental nucleus (ltd), pedunculopontine nucleus (pptg), and lateral habenula (lhb) (both directly and indirectly via the rostromedial tegmental nucleus) are also capable of inducing aversive salience and incentive salience through their projections to the ventral tegmental area (vta). the ldt and pptg both send glutaminergic projections to the vta that synapse on dopaminergic neurons, both of which can produce incentive salience. the lhb sends glutaminergic projections, the majority of which synapse on gabaergic rmtg neurons that in turn drive inhibition of dopaminergic vta neurons, although some lhb projections terminate on vta interneurons. these lhb projections are activated both by aversive stimuli and by the absence of an expected reward, and excitation of the lhb can induce aversion. most of the dopamine pathways (i.e., neurons that use the neurotransmitter dopamine to communicate with other neurons) that project out of the ventral tegmental area are part of the reward system; in these pathways, dopamine acts on d1-like receptors or d2-like receptors to either stimulate (d1-like) or inhibit (d2-like) the production of camp. the gabaergic medium spiny neurons of the striatum are components of the reward system as well. the glutamatergic projection nuclei in the subthalamic nucleus, prefrontal cortex, hippocampus, thalamus, and amygdala connect to other parts of the reward system via glutamate pathways. the medial forebrain bundle, which is a set of many neural pathways that mediate brain stimulation reward (i.e., reward derived from direct electrochemical stimulation of the lateral hypothalamus), is also a component of the reward system. two theories exist with regard to the activity of the nucleus accumbens and the generation liking and wanting. the inhibition (or hyper­polar­ization) hypothesis proposes that the nucleus accumbens exerts tonic inhibitory effects on downstream structures such as the ventral pallidum, hypothalamus or ventral tegmental area, and that in inhibiting msns in the nucleus accumbens (nacc), these structures are excited, "releasing" reward related behavior. while gaba receptor agonists are capable of eliciting both "liking" and "wanting" reactions in the nucleus accumbens, glutaminergic inputs from the basolateral amygdala, ventral hippocampus, and medial prefrontal cortex can drive incentive salience. furthermore, while most studies find that nacc neurons reduce firing in response to reward, a number of studies find the opposite response. this had led to the proposal of the disinhibition (or depolarization) hypothesis, that proposes that excitation or nacc neurons, or at least certain subsets, drives reward related behavior. after nearly 50 years of research on brain-stimulation reward, experts have certified that dozens of sites in the brain will maintain intracranial self-stimulation. regions include the lateral hypothalamus and medial forebrain bundles, which are especially effective. stimulation there activates fibers that form the ascending pathways; the ascending pathways include the mesolimbic dopamine pathway, which projects from the ventral tegmental area to the nucleus accumbens. there are several explanations as to why the mesolimbic dopamine pathway is central to circuits mediating reward. first, there is a marked increase in dopamine release from the mesolimbic pathway when animals engage in intracranial self-stimulation. second, experiments consistently indicate that brain-stimulation reward stimulates the reinforcement of pathways that are normally activated by natural rewards, and drug reward or intracranial self-stimulation can exert more powerful activation of central reward mechanisms because they activate the reward center directly rather than through the peripheral nerves. third, when animals are administered addictive drugs or engage in naturally rewarding behaviors, such as feeding or sexual activity, there is a marked release of dopamine within the nucleus accumbens. however, dopamine is not the only reward compound in the brain. key pathway diagram showing some of the key components of the mesocorticolimbic ("reward") circuit. ventral tegmental area the ventral tegmental area (vta) is important in responding to stimuli and cues that indicate a reward is present. rewarding stimuli (and all addictive drugs) act on the circuit by triggering the vta to release dopamine signals to the nucleus accumbens, either directly or indirectly. the vta has two important pathways: the mesolimbic pathway projecting to limbic (striatal) regions and underpinning the motivational behaviors and processes, and the mesocortical pathway projecting to the prefrontal cortex, underpinning cognitive functions, such as learning external cues, etc. dopaminergic neurons in this region converts the amino acid tyrosine into dopa using the enzyme tyrosine hydroxylase, which is then converted to dopamine using the enzyme dopa-decarboxylase. striatum (nucleus accumbens) the striatum is broadly involved in acquiring and eliciting learned behaviors in response to a rewarding cue. the vta projects to the striatum, and activates the gaba-ergic medium spiny neurons via d1 and d2 receptors within the ventral (nucleus accumbens) and dorsal striatum. the ventral striatum (the nucleus accumbens) is broadly involved in acquiring behavior when fed into by the vta, and eliciting behavior when fed into by the pfc. the nac shell projects to the pallidum and the vta, regulating limbic and autonomic functions. this modulates the reinforcing properties of stimuli, and short term aspects of reward. the nac core projects to the substantia nigra and is involved in the development of reward-seeking behaviors and its expression. it is involved in spatial learning, conditional response, and impulsive choice; the long term elements of reward. the dorsal striatum is involved in learning, the dorsal medial striatum in goal directed learning, and the dorsal lateral striatum in stimulus-response learning foundational to pavlovian response. on repeated activation by a stimuli, the nucleus accumbens can activate the dorsal striatum via an intrastriatal loop. the transition of signals from the nac to the ds allows reward associated cues to activate the ds without the reward itself being present. this can activate cravings and reward-seeking behaviors (and is responsible for triggering relapse during abstinence in addiction). prefrontal cortex the vta dopaminergic neurons project to the pfc, activating glutaminergic neurons that project to multiple other regions, including the dorsal striatum and nac, ultimately allowing the pfc to mediate salience and conditional behaviors in response to stimuli. notably, abstinence from addicting drugs activates the pfc, glutamatergic projection to the nac, which leads to strong cravings, and modulates reinstatement of addiction behaviors resulting from abstinence. the pfc also interacts with the vta through the mesocortical pathway, and helps associate environmental cues with the reward. hippocampus the hippocampus has multiple functions, including in the creation and storage of memories . in the reward circuit, it serves to contextual memories and associated cues. it ultimately underpins the reinstatement of reward-seeking behaviors via cues, and contextual triggers. amygdala the amy receives input from the vta, and outputs to the nac. the amygdala is important in creating powerful emotional flashbulb memories, and likely underpins the creation of strong cue-associated memories. it also is important in mediating the anxiety effects of withdrawal, and increased drug intake in addiction. pleasure centers pleasure is a component of reward, but not all rewards are pleasurable (e.g., money does not elicit pleasure unless this response is conditioned). stimuli that are naturally pleasurable, and therefore attractive, are known as intrinsic rewards, whereas stimuli that are attractive and motivate approach behavior, but are not inherently pleasurable, are termed extrinsic rewards.