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1. ^  _**a** _ _**b** _ _**c** _ _**d** _ _**e** _ _**f** _ _**g** _ _**h** _ _**i** _ _**j** _ _**k** _ _**l** _ _**m** _ Schultz, Wolfram (July 2015).  "Neuronal Reward and Decision Signals: From Theories to Data"  . _Physiological Reviews_ . **95** (3): 853–951.  doi  "Doi \(identifier\)") :  10.1152/physrev.00023.2014  .  PMC  "PMC \(identifier\)")  4491543  .  PMID  "PMID \(identifier\)")  26109341  .
2. ^  _**a** _ _**b** _ _**c** _ _**d** _ _**e** _ _**f** _ _**g** _ _**h** _ Berridge KC, Kringelbach ML (May 2015).  "Pleasure systems in the brain"  . _Neuron_ . **86** (3): 646–664.  doi  "Doi \(identifier\)") :  10.1016/j.neuron.2015.02.018  .  PMC  "PMC \(identifier\)")  4425246  .  PMID  "PMID \(identifier\)")  25950633  . " In the prefrontal cortex, recent evidence indicates that the [orbitofrontal cortex] OFC and insula cortex may each contain their own additional hot spots (D.C. Castro et al., Soc. Neurosci., abstract). In specific subregions of each area, either opioid-stimulating or orexin-stimulating microinjections appear to enhance the number of _liking_ reactions elicited by sweetness, similar to the [nucleus accumbens] NAc and [ventral pallidum] VP hot spots. Successful confirmation of hedonic hot spots in the OFC or insula would be important and possibly relevant to the orbitofrontal mid-anterior site mentioned earlier that especially tracks the subjective pleasure of foods in humans (Georgiadis et al., 2012; Kringelbach, 2005; Kringelbach et al., 2003; Small et al., 2001; Veldhuizen et al., 2010). Finally, in the brainstem, a hindbrain site near the parabrachial nucleus of dorsal pons also appears able to contribute to hedonic gains of function (Söderpalm and Berridge, 2000). A brainstem mechanism for pleasure may seem more surprising than forebrain hot spots to anyone who views the brainstem as merely reflexive, but the pontine parabrachial nucleus contributes to taste, pain, and many visceral sensations from the body and has also been suggested to play an important role in motivation (Wu et al., 2012) and in human emotion (especially related to the somatic marker hypothesis) (Damasio, 2010). "
3. ^  _**a** _ _**b** _ _**c** _ _**d** _ _**e** _ _**f** _ _**g** _ _**h** _ _**i** _ Schultz W (2015).  "Neuronal reward and decision signals: from theories to data"  . _Physiological Reviews_ . **95** (3): 853–951.  doi  "Doi \(identifier\)") :  10.1152/physrev.00023.2014  .  PMC  "PMC \(identifier\)")  4491543  .  PMID  "PMID \(identifier\)")  26109341  . " Rewards in operant conditioning are positive reinforcers. ... Operant behavior gives a good definition for rewards. Anything that makes an individual come back for more is a positive reinforcer and therefore a reward. Although it provides a good definition, positive reinforcement is only one of several reward functions. ... Rewards are attractive. They are motivating and make us exert an effort. ... Rewards induce approach behavior, also called appetitive or preparatory behavior, sexual behavior, and consummatory behavior. ... Thus any stimulus, object, event, activity, or situation that has the potential to make us approach and consume it is by definition a reward. ... Rewarding stimuli, objects, events, situations, and activities consist of several major components. First, rewards have basic sensory components (visual, auditory, somatosensory, gustatory, and olfactory) ... Second, rewards are salient and thus elicit attention, which are manifested as orienting responses. The salience of rewards derives from three principal factors, namely, their physical intensity and impact (physical salience), their novelty and surprise (novelty/surprise salience), and their general motivational impact shared with punishers (motivational salience). A separate form not included in this scheme, incentive salience, primarily addresses dopamine function in addiction and refers only to approach behavior (as opposed to learning) ... Third, rewards have a value component that determines the positively motivating effects of rewards and is not contained in, nor explained by, the sensory and attentional components. This component reflects behavioral preferences and thus is subjective and only partially determined by physical parameters. Only this component constitutes what we understand as a reward. It mediates the specific behavioral reinforcing, approach generating, and emotional effects of rewards that are crucial for the organism's survival and reproduction, whereas all other components are only supportive of these functions. ... Rewards can also be intrinsic to behavior. They contrast with extrinsic rewards that provide motivation for behavior and constitute the essence of operant behavior in laboratory tests. Intrinsic rewards are activities that are pleasurable on their own and are undertaken for their own sake, without being the means for getting extrinsic rewards. ... Intrinsic rewards are genuine rewards in their own right, as they induce learning, approach, and pleasure, like perfectioning, playing, and enjoying the piano. Although they can serve to condition higher order rewards, they are not conditioned, higher order rewards, as attaining their reward properties does not require pairing with an unconditioned reward. ... These emotions are also called liking (for pleasure) and wanting (for desire) in addiction research and strongly support the learning and approach generating functions of reward. "
4. ** ^  ** Guo, Rong; Böhmer, Wendelin; Hebart, Martin; Chien, Samson; Sommer, Tobias; Obermayer, Klaus; Gläscher, Jan (14 December 2016).  "Interaction of Instrumental and Goal-Directed Learning Modulates Prediction Error Representations in the Ventral Striatum"  . _The Journal of Neuroscience_ . **36** (50). Society for Neuroscience: 12650–12660.  doi  "Doi \(identifier\)") :   10.1523/jneurosci.1677-16.2016  .  ISSN  "ISSN \(identifier\)")  0270-6474  .  PMC  "PMC \(identifier\)")  6705659  .  PMID  "PMID \(identifier\)")  27974615  .
5. ** ^  ** Malenka RC, Nestler EJ, Hyman SE (2009). "Chapter 15: Reinforcement and Addictive Disorders". In Sydor A, Brown RY (eds.). _Molecular Neuropharmacology: A Foundation for Clinical Neuroscience_ (2nd ed.). New York: McGraw-Hill Medical. pp. 364–375.  ISBN  "ISBN \(identifier\)")  9780071481274   .
6. ^  _**a** _ _**b** _ _**c** _ Nestler EJ (December 2013).  "Cellular basis of memory for addiction"  . _Dialogues in Clinical Neuroscience_ . **15** (4): 431–443.  PMC  "PMC \(identifier\)")  3898681  .  PMID  "PMID \(identifier\)")  24459410  . " Despite the importance of numerous psychosocial factors, at its core, drug addiction involves a biological process: the ability of repeated exposure to a drug of abuse to induce changes in a vulnerable brain that drive the compulsive seeking and taking of drugs, and loss of control over drug use, that define a state of addiction. ... A large body of literature has demonstrated that such ΔFosB induction in D1-type [nucleus accumbens] neurons increases an animal's sensitivity to drug as well as natural rewards and promotes drug self-administration, presumably through a process of positive reinforcement ... Another ΔFosB target is cFos: as ΔFosB accumulates with repeated drug exposure it represses c-Fos and contributes to the molecular switch whereby ΔFosB is selectively induced in the chronic drug-treated state.  41  . ... Moreover, there is increasing evidence that, despite a range of genetic risks for addiction across the population, exposure to sufficiently high doses of a drug for long periods of time can transform someone who has relatively lower genetic loading into an addict. "
7. ** ^  ** Volkow ND, Koob GF, McLellan AT (January 2016).  "Neurobiologic Advances from the Brain Disease Model of Addiction"  . _New England Journal of Medicine_ . **374** (4): 363–371.  doi  "Doi \(identifier\)") :  10.1056/NEJMra1511480  .  PMC  "PMC \(identifier\)")  6135257  .  PMID  "PMID \(identifier\)")  26816013  . " Substance-use disorder: A diagnostic term in the fifth edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-5) referring to recurrent use of alcohol or other drugs that causes clinically and functionally significant impairment, such as health problems, disability, and failure to meet major responsibilities at work, school, or home. Depending on the level of severity, this disorder is classified as mild, moderate, or severe.
Addiction: A term used to indicate the most severe, chronic stage of
substance-use disorder, in which there is a substantial loss of self-control,
as indicated by compulsive drug taking despite the desire to stop taking the
drug. In the DSM-5, the term addiction is synonymous with the classification
of severe substance-use disorder. "

8. ^  _**a** _ _**b** _ _**c** _ _**d** _ _**e** _ Kolb, Bryan; Whishaw, Ian Q. (2001).  _An Introduction to Brain and Behavior_  (1st ed.). New York: Worth. pp.  438–441  .  ISBN  "ISBN \(identifier\)")  9780716751694   .
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13. ^  _**a** _ _**b** _ _**c** _ _**d** _ _**e** _ _**f** _ _**g** _ Yager LM, Garcia AF, Wunsch AM, Ferguson SM (August 2015).  "The ins and outs of the striatum: Role in drug addiction"  . _Neuroscience_ . **301** : 529–541.  doi  "Doi \(identifier\)") :  10.1016/j.neuroscience.2015.06.033  .  PMC  "PMC \(identifier\)")  4523218  .  PMID  "PMID \(identifier\)")  26116518  . " [The striatum] receives dopaminergic inputs from the ventral tegmental area (VTA) and the substantia nigra (SNr) and glutamatergic inputs from several areas, including the cortex, hippocampus, amygdala, and thalamus (Swanson, 1982; Phillipson and Griffiths, 1985; Finch, 1996; Groenewegen et al., 1999; Britt et al., 2012). These glutamatergic inputs make contact on the heads of dendritic spines of the striatal GABAergic medium spiny projection neurons (MSNs) whereas dopaminergic inputs synapse onto the spine neck, allowing for an important and complex interaction between these two inputs in modulation of MSN activity ... It should also be noted that there is a small population of neurons in the [nucleus accumbens] NAc that coexpress both D1 and D2 receptors, though this is largely restricted to the NAc shell (Bertran- Gonzalez et al., 2008). ... Neurons in the NAc core and NAc shell subdivisions also differ functionally. The NAc core is involved in the processing of conditioned stimuli whereas the NAc shell is more important in the processing of unconditioned stimuli; Classically, these two striatal MSN populations are thought to have opposing effects on basal ganglia output. Activation of the dMSNs causes a net excitation of the thalamus resulting in a positive cortical feedback loop; thereby acting as a 'go' signal to initiate behavior. Activation of the iMSNs, however, causes a net inhibition of thalamic activity resulting in a negative cortical feedback loop and therefore serves as a 'brake' to inhibit behavior ... there is also mounting evidence that iMSNs play a role in motivation and addiction (Lobo and Nestler, 2011; Grueter et al., 2013). For example, optogenetic activation of NAc core and shell iMSNs suppressed the development of a cocaine CPP whereas selective ablation of NAc core and shell iMSNs ... enhanced the development and the persistence of an amphetamine CPP (Durieux et al., 2009; Lobo et al., 2010). These findings suggest that iMSNs can bidirectionally modulate drug reward. ... Together these data suggest that iMSNs normally act to restrain drug-taking behavior and recruitment of these neurons may in fact be protective against the development of compulsive drug use. "
14. ** ^  ** Taylor SB, Lewis CR, Olive MF (2013).  "The neurocircuitry of illicit psychostimulant addiction: acute and chronic effects in humans"  . _Subst Abuse Rehabil_ . **4** : 29–43.  doi  "Doi \(identifier\)") :   10.2147/SAR.S39684  .  PMC  "PMC \(identifier\)")  3931688  .  PMID  "PMID \(identifier\)")  24648786  . " Regions of the basal ganglia, which include the dorsal and ventral striatum, internal and external segments of the globus pallidus, subthalamic nucleus, and dopaminergic cell bodies in the substantia nigra, are highly implicated not only in fine motor control but also in [prefrontal cortex] PFC function.43 Of these regions, the [nucleus accumbens] NAc (described above) and the [dorsal striatum] DS (described below) are most frequently examined with respect to addiction. Thus, only a brief description of the modulatory role of the basal ganglia in addiction-relevant circuits will be mentioned here. The overall output of the basal ganglia is predominantly via the thalamus, which then projects back to the PFC to form cortico-striatal-thalamo-cortical (CSTC) loops. Three CSTC loops are proposed to modulate executive function, action selection, and behavioral inhibition. In the dorsolateral prefrontal circuit, the basal ganglia primarily modulate the identification and selection of goals, including rewards.44 The [orbitofrontal cortex] OFC circuit modulates decision-making and impulsivity, and the anterior cingulate circuit modulates the assessment of consequences.44 These circuits are modulated by dopaminergic inputs from the [ventral tegmental area] VTA to ultimately guide behaviors relevant to addiction, including the persistence and narrowing of the behavioral repertoire toward drug seeking, and continued drug use despite negative consequences.43–45 "
15. ** ^  ** Grall-Bronnec M, Sauvaget A (2014).  "The use of repetitive transcranial magnetic stimulation for modulating craving and addictive behaviours: a critical literature review of efficacy, technical and methodological considerations"  . _Neurosci. Biobehav. Rev_ . **47** : 592–613.  doi  "Doi \(identifier\)") :   10.1016/j.neubiorev.2014.10.013  .  PMID  "PMID \(identifier\)")  25454360  . " Studies have shown that cravings are underpinned by activation of the reward and motivation circuits (McBride et al., 2006, Wang et al., 2007, Wing et al., 2012, Goldman et al., 2013, Jansen et al., 2013 and Volkow et al., 2013). According to these authors, the main neural structures involved are: the nucleus accumbens, dorsal striatum, orbitofrontal cortex, anterior cingulate cortex, dorsolateral prefrontal cortex (DLPFC), amygdala, hippocampus and insula. "
16. ^  _**a** _ _**b** _ Malenka RC, Nestler EJ, Hyman SE (2009). Sydor A, Brown RY (eds.). _Molecular Neuropharmacology: A Foundation for Clinical Neuroscience_ (2nd ed.). New York: McGraw-Hill Medical. pp. 365–366, 376.  ISBN  "ISBN \(identifier\)")  978-0-07-148127-4   . " The neural substrates that underlie the perception of reward and the phenomenon of positive reinforcement are a set of interconnected forebrain structures called brain reward pathways; these include the nucleus accumbens (NAc; the major component of the ventral striatum), the basal forebrain (components of which have been termed the extended amygdala, as discussed later in this chapter), hippocampus, hypothalamus, and frontal regions of cerebral cortex. These structures receive rich dopaminergic innervation from the ventral tegmental area (VTA) of the midbrain. Addictive drugs are rewarding and reinforcing because they act in brain reward pathways to enhance either dopamine release or the effects of dopamine in the NAc or related structures, or because they produce effects similar to dopamine. ... A macrostructure postulated to integrate many of the functions of this circuit is described by some investigators as the extended amygdala. The extended amygdala is said to comprise several basal forebrain structures that share similar morphology, immunocytochemical features, and connectivity and that are well suited to mediating aspects of reward function; these include the bed nucleus of the stria terminalis, the central medial amygdala, the shell of the NAc, and the sublenticular substantia innominata. "
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 Figure 3: Neural circuits underlying motivated 'wanting' and hedonic
'liking'. 

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39. ^  _**a** _ _**b** _ _**c** _ Castro, DC; Berridge, KC (24 October 2017).  "Opioid and orexin hedonic hotspots in rat orbitofrontal cortex and insula"  . _Proceedings of the National Academy of Sciences of the United States of America_ . **114** (43): E9125–E9134.  Bibcode  "Bibcode \(identifier\)") :  2017PNAS..114E9125C  .  doi  "Doi \(identifier\)") :   10.1073/pnas.1705753114  .  PMC  "PMC \(identifier\)")  5664503  .  PMID  "PMID \(identifier\)")  29073109  . " Here, we show that opioid or orexin stimulations in orbitofrontal cortex and insula causally enhance hedonic "liking" reactions to sweetness and find a third cortical site where the same neurochemical stimulations reduce positive hedonic impact. "
40. ** ^  ** Kringelbach ML, Berridge KC (2012).  "The Joyful Mind"  (PDF)  . _Scientific American_ . **307** (2): 44–45.  Bibcode  "Bibcode \(identifier\)") :  2012SciAm.307b..40K  .  doi  "Doi \(identifier\)") :  10.1038/scientificamerican0812-40  .  PMID  "PMID \(identifier\)")  22844850  . Archived from  the original  (PDF)  on 29 March 2017  . Retrieved  17 January  2017  . " So it makes sense that the real pleasure centers in the brain – those directly responsible for generating pleasurable sensations – turn out to lie within some of the structures previously identified as part of the reward circuit. One of these so-called hedonic hotspots lies in a subregion of the nucleus accumbens called the medial shell. A second is found within the ventral pallidum, a deep-seated structure near the base of the forebrain that receives most of its signals from the nucleus accumbens. ...
On the other hand, intense euphoria is harder to come by than everyday
pleasures. The reason may be that strong enhancement of pleasure – like the
chemically induced pleasure bump we produced in lab animals – seems to require
activation of the entire network at once. Defection of any single component
dampens the high.
Whether the pleasure circuit – and in particular, the ventral pallidum – works
the same way in humans is unclear. "