extrinsic rewards (e.g., money) are rewarding as a result of a learned association with an intrinsic reward. in other words, extrinsic rewards function as motivational magnets that elicit "wanting", but not "liking" reactions once they have been acquired. the reward system contains pleasure centers or hedonic hotspots – i.e., brain structures that mediate pleasure or "liking" reactions from intrinsic rewards. as of october 2017, hedonic hotspots have been identified in subcompartments within the nucleus accumbens shell, ventral pallidum, parabrachial nucleus, orbitofrontal cortex (ofc), and insular cortex. the hotspot within the nucleus accumbens shell is located in the rostrodorsal quadrant of the medial shell, while the hedonic coldspot is located in a more posterior region. the posterior ventral pallidum also contains a hedonic hotspot, while the anterior ventral pallidum contains a hedonic coldspot. in rats, microinjections of opioids, endocannabinoids, and orexin are capable of enhancing liking reactions in these hotspots. the hedonic hotspots located in the anterior ofc and posterior insula have been demonstrated to respond to orexin and opioids in rats, as has the overlapping hedonic coldspot in the anterior insula and posterior ofc. on the other hand, the parabrachial nucleus hotspot has only been demonstrated to respond to benzodiazepine receptor agonists. hedonic hotspots are functionally linked, in that activation of one hotspot results in the recruitment of the others, as indexed by the induced expression of c-fos, an immediate early gene. furthermore, inhibition of one hotspot results in the blunting of the effects of activating another hotspot. therefore, the simultaneous activation of every hedonic hotspot within the reward system is believed to be necessary for generating the sensation of an intense euphoria. wanting and liking main article: incentive salience tuning of appetitive and defensive reactions in the nucleus accumbens shell. (above) ampa blockade requires d1 function in order to produce motivated behaviors, regardless of valence, and d2 function to produce defensive behaviors. gaba agonism, on the other hand, does not requires dopamine receptor function.(below)the expansion of the anatomical regions that produce defensive behaviors under stress, and appetitive behaviors in the home environment produced by ampa antagonism. this flexibility is less evident with gaba agonism. incentive salience is the "wanting" or "desire" attribute, which includes a motivational component, that is assigned to a rewarding stimulus by the nucleus accumbens shell (nacc shell). the degree of dopamine neurotransmission into the nacc shell from the mesolimbic pathway is highly correlated with the magnitude of incentive salience for rewarding stimuli. activation of the dorsorostral region of the nucleus accumbens correlates with increases in wanting without concurrent increases in liking. however, dopaminergic neurotransmission into the nucleus accumbens shell is responsible not only for appetitive motivational salience (i.e., incentive salience) towards rewarding stimuli, but also for aversive motivational salience, which directs behavior away from undesirable stimuli. in the dorsal striatum, activation of d1 expressing msns produces appetitive incentive salience, while activation of d2 expressing msns produces aversion. in the nacc, such a dichotomy is not as clear cut, and activation of both d1 and d2 msns is sufficient to enhance motivation, likely via disinhibiting the vta through inhibiting the ventral pallidum. robinson and berridge's 1993 incentive-sensitization theory proposed that reward contains separable psychological components: wanting (incentive) and liking (pleasure). to explain increasing contact with a certain stimulus such as chocolate, there are two independent factors at work – our desire to have the chocolate (wanting) and the pleasure effect of the chocolate (liking). according to robinson and berridge, wanting and liking are two aspects of the same process, so rewards are usually wanted and liked to the same degree. however, wanting and liking also change independently under certain circumstances. for example, rats that do not eat after receiving dopamine (experiencing a loss of desire for food) act as though they still like food. in another example, activated self-stimulation electrodes in the lateral hypothalamus of rats increase appetite, but also cause more adverse reactions to tastes such as sugar and salt; apparently, the stimulation increases wanting but not liking. such results demonstrate that the reward system of rats includes independent processes of wanting and liking. the wanting component is thought to be controlled by dopaminergic pathways, whereas the liking component is thought to be controlled by opiate-benzodiazepine systems. anti-reward system koobs & le moal proposed that there exists a separate circuit responsible for the attenuation of reward-pursuing behavior, which they termed the anti-reward circuit. this component acts as brakes on the reward circuit, thus preventing the over pursuit of food, sex, etc. this circuit involves multiple parts of the amygdala (the bed nucleus of the stria terminalis, the central nucleus), the nucleus accumbens, and signal molecules including norepinephrine, corticotropin-releasing factor, and dynorphin. this circuit is also hypothesized to mediate the unpleasant components of stress, and is thus thought to be involved in addiction and withdrawal. while the reward circuit mediates the initial positive reinforcement involved in the development of addiction, it is the anti-reward circuit that later dominates via negative reinforcement that motivates the pursuit of the rewarding stimuli. learning rewarding stimuli can drive learning in both the form of classical conditioning (pavlovian conditioning) and operant conditioning (instrumental conditioning). in classical conditioning, a reward can act as an unconditioned stimulus that, when associated with the conditioned stimulus, causes the conditioned stimulus to elicit both musculoskeletal (in the form of simple approach and avoidance behaviors) and vegetative responses. in operant conditioning, a reward may act as a reinforcer in that it increases or supports actions that lead to itself. learned behaviors may or may not be sensitive to the value of the outcomes they lead to; behaviors that are sensitive to the contingency of an outcome on the performance of an action as well as the outcome value are goal-directed, while elicited actions that are insensitive to contingency or value are called habits. this distinction is thought to reflect two forms of learning, model free and model based. model free learning involves the simple caching and updating of values. in contrast, model based learning involves the storage and construction of an internal model of events that allows inference and flexible prediction. although pavlovian conditioning is generally assumed to be model-free, the incentive salience assigned to a conditioned stimulus is flexible with regard to changes in internal motivational states. distinct neural systems are responsible for learning associations between stimuli and outcomes, actions and outcomes, and stimuli and responses. although classical conditioning is not limited to the reward system, the enhancement of instrumental performance by stimuli (i.e., pavlovian-instrumental transfer) requires the nucleus accumbens. habitual and goal directed instrumental learning are dependent upon the lateral striatum and the medial striatum, respectively. during instrumental learning, opposing changes in the ratio of ampa to nmda receptors and phosphorylated erk occurs in the d1-type and d2-type msns that constitute the direct and indirect pathways, respectively. these changes in synaptic plasticity and the accompanying learning is dependent upon activation of striatal d1 and nmda receptors. the intracellular cascade activated by d1 receptors involves the recruitment of protein kinase a, and through resulting phosphorylation of darpp-32, the inhibition of phosphatases that deactivate erk. nmda receptors activate erk through a different but interrelated ras-raf-mek-erk pathway. alone nmda mediated activation of erk is self-limited, as nmda activation also inhibits pka mediated inhibition of erk deactivating phosphatases. however, when d1 and nmda cascades are co-activated, they work synergistically, and the resultant activation of erk regulates synaptic plasticity in the form of spine restructuring, transport of ampa receptors, regulation of creb, and increasing cellular excitability via inhibiting kv4.2 disorders addiction main article: addiction δfosb (deltafosb) – a gene transcription factor – overexpression in the d1-type medium spiny neurons of the nucleus accumbens is the crucial common factor among virtually all forms of addiction (i.e., behavioral addictions and drug addictions) that induces addiction-related behavior and neural plasticity. in particular, δfosb promotes self-administration, reward sensitization, and reward cross-sensitization effects among specific addictive drugs and behaviors. certain epigenetic modifications of histone protein tails (i.e., histone modifications) in specific regions of the brain are also known to play a crucial role in the molecular basis of addictions. addictive drugs and behaviors are rewarding and reinforcing (i.e., are addictive) due to their effects on the dopamine reward pathway. the lateral hypothalamus and medial forebrain bundle has been the most-frequently-studied brain-stimulation reward site, particularly in studies of the effects of drugs on brain stimulation reward. the neurotransmitter system that has been most-clearly identified with the habit-forming actions of drugs-of-abuse is the mesolimbic dopamine system, with its efferent targets in the nucleus accumbens and its local gabaergic afferents. the reward-relevant actions of amphetamine and cocaine are in the dopaminergic synapses of the nucleus accumbens and perhaps the medial prefrontal cortex. rats also learn to lever-press for cocaine injections into the medial prefrontal cortex, which works by increasing dopamine turnover in the nucleus accumbens. nicotine infused directly into the nucleus accumbens also enhances local dopamine release, presumably by a presynaptic action on the dopaminergic terminals of this region. nicotinic receptors localize to dopaminergic cell bodies and local nicotine injections increase dopaminergic cell firing that is critical for nicotinic reward. some additional habit-forming drugs are also likely to decrease the output of medium spiny neurons as a consequence, despite activating dopaminergic projections. for opiates, the lowest-threshold site for reward effects involves actions on gabaergic neurons in the ventral tegmental area, a secondary site of opiate-rewarding actions on medium spiny output neurons of the nucleus accumbens. thus the following form the core of currently characterised drug-reward circuitry; gabaergic afferents to the mesolimbic dopamine neurons (primary substrate of opiate reward), the mesolimbic dopamine neurons themselves (primary substrate of psychomotor stimulant reward), and gabaergic efferents to the mesolimbic dopamine neurons (a secondary site of opiate reward). motivation main article: motivational salience dysfunctional motivational salience appears in a number of psychiatric symptoms and disorders. anhedonia, traditionally defined as a reduced capacity to feel pleasure, has been re-examined as reflecting blunted incentive salience, as most anhedonic populations exhibit intact “liking”. on the other end of the spectrum, heightened incentive salience that is narrowed for specific stimuli is characteristic of behavioral and drug addictions. in the case of fear or paranoia, dysfunction may lie in elevated aversive salience. neuroimaging studies across diagnoses associated with anhedonia have reported reduced activity in the ofc and ventral striatum. one meta analysis reported anhedonia was associated with reduced neural response to reward anticipation in the caudate nucleus, putamen, nucleus accumbens and medial prefrontal cortex (mpfc). mood disorders certain types of depression are associated with reduced motivation, as assessed by willingness to expend effort for reward. these abnormalities have been tentatively linked to reduced activity in areas of the striatum, and while dopaminergic abnormalities are hypothesized to play a role, most studies probing dopamine function in depression have reported inconsistent results. although postmortem and neuroimaging studies have found abnormalities in numerous regions of the reward system, few findings are consistently replicated. some studies have reported reduced nacc, hippocampus, medial prefrontal cortex (mpfc), and orbitofrontal cortex (ofc) activity, as well as elevated basolateral amygdala and subgenual cingulate cortex (sgacc) activity during tasks related to reward or positive stimuli. these neuroimaging abnormalities are complemented by little post mortem research, but what little research has been done suggests reduced excitatory synapses in the mpfc. reduced activity in the mpfc during reward related tasks appears to be localized to more dorsal regions(i.e. the pregenual cingulate cortex), while the more ventral sgacc is hyperactive in depression. attempts to investigate underlying neural circuitry in animal models has also yielded conflicting results. two paradigms are commonly used to simulate depression, chronic social defeat (csds), and chronic mild stress (cms), although many exist. csds produces reduced preference for sucrose, reduced social interactions, and increased immobility in the forced swim test. cms similarly reduces sucrose preference, and behavioral despair as assessed by tail suspension and forced swim tests. animals susceptible to csds exhibit increased phasic vta firing, and inhibition of vta-nacc projections attenuates behavioral deficits induced by csds. however, inhibition of vta-mpfc projections exacerbates social withdrawal. on the other hand, cms associated reductions in sucrose preference and immobility were attenuated and exacerbated by vta excitation and inhibition, respectively. although these differences may be attributable to different stimulation protocols or poor translational paradigms, variable results may also lie in the heterogenous functionality of reward related regions. optogenetic