References analysis of the Wikipedia article "Sistema di ricompensa" in the Italian version

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Schultz W, Neuronal reward and decision signals: from theories to data (PDF), in Physiological Reviews, vol. 95, n. 3, 2015, pp. 853-951, DOI:10.1152/physrev.00023.2014. URL consultato il 27 novembre 2016 (archiviato dall'url originale il 22 settembre 2015).

Berridge KC, Kringelbach ML, Pleasure systems in the brain, in Neuron, vol. 86, n. 3, maggio 2015, pp. 646-664, DOI:10.1016/j.neuron.2015.02.018, PMC 4425246, PMID 25950633.

«In the prefrontal cortex, recent evidence indicates that the 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 NAc and 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).»

Volkow ND, Koob GF, McLellan AT, Neurobiologic Advances from the Brain Disease Model of Addiction, in N. Engl. J. Med., vol. 374, n. 4, gennaio 2016, pp. 363-371, DOI:10.1056/NEJMra1511480, PMID 26816013.

Salamone JD, Correa M, The Mysterious Motivational Functions of Mesolimbic Dopamine, in Neuron, vol. 76, n. 3, 2012, pp. 470-485, DOI:10.1016/j.neuron.2012.10.021, PMC 4450094, PMID 23141060.

Yager LM, Garcia AF, Wunsch AM, Ferguson SM, The ins and outs of the striatum: Role in drug addiction, in Neuroscience, vol. 301, August 2015, pp. 529-541, DOI:10.1016/j.neuroscience.2015.06.033, PMID 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 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.»

Taylor SB, Lewis CR, Olive MF, The neurocircuitry of illicit psychostimulant addiction: acute and chronic effects in humans, in Subst Abuse Rehabil, vol. 4, 2013, pp. 29-43, DOI:10.2147/SAR.S39684, PMC 3931688, PMID 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 PFC function.43 Of these regions, the NAc (described above) and the 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 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 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»

Grall-Bronnec M, Sauvaget A, The use of repetitive transcranial magnetic stimulation for modulating craving and addictive behaviours: a critical literature review of efficacy, technical and methodological considerations, in Neurosci. Biobehav. Rev., vol. 47, 2014, pp. 592-613, DOI:10.1016/j.neubiorev.2014.10.013, PMID 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.»

Richard JM, Castro DC, Difeliceantonio AG, Robinson MJ, Berridge KC, Mapping brain circuits of reward and motivation: in the footsteps of Ann Kelley, in Neurosci. Biobehav. Rev., vol. 37, 9 Pt A, novembre 2013, pp. 1919-1931, DOI:10.1016/j.neubiorev.2012.12.008, PMC 3706488, PMID 23261404.

«
Figure 3: Neural circuits underlying motivated 'wanting' and hedonic 'liking'.»

Dumitriu D, Laplant Q, Grossman YS, Dias C, Janssen WG, Russo SJ, Morrison JH, Nestler EJ, Subregional, dendritic compartment, and spine subtype specificity in cocaine regulation of dendritic spines in the nucleus accumbens, in J. Neurosci., vol. 32, n. 20, 2012, pp. 6957-66, DOI:10.1523/JNEUROSCI.5718-11.2012, PMC 3360066, PMID 22593064.

«The enduring spine density change in core but not shell fits well with the established idea that the shell is preferentially involved in the development of addiction, while the core mediates the long-term execution of learned addiction-related behaviors (Ito et al., 2004; Di Chiara, 2002; Meredith et al., 2008). Consistent with the idea of NAc core being the locus of long-lasting drug-induced neuroplasticity, several studies have shown that electrophysiological changes in core persist longer than their shell counterparts. ... Furthermore, data presented here support the idea that NAc shell is preferentially involved in immediate drug reward, while the core might play a more explicit role in longer-term aspects of addiction.»

Trantham-Davidson H., Neely L. C., Lavin A. e Seamans J. K., Mechanisms underlying differential D1 versus D2 dopamine receptor regulation of inhibition in prefrontal cortex, in The Journal of Neuroscience, vol. 24, n. 47, 2004, pp. 10652-10659, DOI:10.1523/jneurosci.3179-04.2004.

DC Castro, SL Cole e KC Berridge, Lateral hypothalamus, nucleus accumbens, and ventral pallidum roles in eating and hunger: interactions between homeostatic and reward circuitry, in Frontiers in Systems Neuroscience, vol. 9, 2015, p. 90, DOI:10.3389/fnsys.2015.00090, PMC 4466441, PMID 26124708.

Jr Carlezon WA e MJ Thomas, Biological substrates of reward and aversion: a nucleus accumbens activity hypothesis, in Neuropharmacology, 56 Suppl 1, 2009, pp. 122-32, DOI:10.1016/j.neuropharm.2008.06.075, PMC 2635333, PMID 18675281.

Wise RA, Rompre PP, Brain dopamine and reward, in Annual Review of Psychology, vol. 40, 1989, pp. 191-225, DOI:10.1146/annurev.ps.40.020189.001203, PMID 2648975.

Wise RA, Brain reward circuitry: insights from unsensed incentives, in Neuron, vol. 36, n. 2, ottobre 2002, pp. 229-240, DOI:10.1016/S0896-6273(02)00965-0, PMID 12383779.

DC Castro e KC Berridge, Opioid and orexin hedonic hotspots in rat orbitofrontal cortex and insula, in Proceedings of the National Academy of Sciences of the United States of America, vol. 114, n. 43, 24 ottobre 2017, pp. E9125–E9134, DOI:10.1073/pnas.1705753114, PMC 5664503, PMID 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.»

Kringelbach ML, Berridge KC, The Joyful Mind (PDF), in Scientific American, vol. 307, n. 2, 2012, pp. 44-45, Bibcode:2012SciAm.307b..40K, DOI:10.1038/scientificamerican0812-40. URL consultato il 17 gennaio 2017 (archiviato dall'url originale il 29 marzo 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.»

Berridge KC, From prediction error to incentive salience: mesolimbic computation of reward motivation, in Eur. J. Neurosci., vol. 35, n. 7, aprile 2012, pp. 1124-1143, DOI:10.1111/j.1460-9568.2012.07990.x, PMC 3325516, PMID 22487042.

«Here I discuss how mesocorticolimbic mechanisms generate the motivation component of incentive salience. Incentive salience takes Pavlovian learning and memory as one input and as an equally important input takes neurobiological state factors (e.g. drug states, appetite states, satiety states) that can vary independently of learning. Neurobiological state changes can produce unlearned fluctuations or even reversals in the ability of a previously learned reward cue to trigger motivation. Such fluctuations in cue-triggered motivation can dramatically depart from all previously learned values about the associated reward outcome. ... Associative learning and prediction are important contributors to motivation for rewards. Learning gives incentive value to arbitrary cues such as a Pavlovian conditioned stimulus (CS) that is associated with a reward (unconditioned stimulus or UCS). Learned cues for reward are often potent triggers of desires. For example, learned cues can trigger normal appetites in everyone, and can sometimes trigger compulsive urges and relapse in addicts.
Cue-triggered 'wanting’ for the UCS
A brief CS encounter (or brief UCS encounter) often primes a pulse of elevated motivation to obtain and consume more reward UCS. This is a signature feature of incentive salience.
Cue as attractive motivational magnets
When a Pavlovian CS+ is attributed with incentive salience it not only triggers 'wanting’ for its UCS, but often the cue itself becomes highly attractive – even to an irrational degree. This cue attraction is another signature feature of incentive salience ... Two recognizable features of incentive salience are often visible that can be used in neuroscience experiments: (i) UCS-directed 'wanting’ – CS-triggered pulses of intensified 'wanting’ for the UCS reward; and (ii) CS-directed 'wanting’ – motivated attraction to the Pavlovian cue, which makes the arbitrary CS stimulus into a motivational magnet.»

Berridge KC, Kringelbach ML, Neuroscience of affect: brain mechanisms of pleasure and displeasure, in Current Opinion in Neurobiology, vol. 23, n. 3, 1º giugno 2013, pp. 294-303, DOI:10.1016/j.conb.2013.01.017, PMC 3644539, PMID 23375169.

«For instance, mesolimbic dopamine, probably the most popular brain neurotransmitter candidate for pleasure two decades ago, turns out not to cause pleasure or liking at all. Rather dopamine more selectively mediates a motivational process of incentive salience, which is a mechanism for wanting rewards but not for liking them .... Rather opioid stimulation has the special capacity to enhance liking only if the stimulation occurs within an anatomical hotspot»

Salamone JD, Correa M, The mysterious motivational functions of mesolimbic dopamine, in Neuron, vol. 76, n. 3, 8 novembre 2012, pp. 470-485, DOI:10.1016/j.neuron.2012.10.021, ISSN 1097-4199 (WC · ACNP), PMC 4450094, PMID 23141060.

ES Calipari, RC Bagot, I Purushothaman, TJ Davidson, JT Yorgason, CJ Peña, DM Walker, ST Pirpinias, KG Guise, C Ramakrishnan, K Deisseroth e EJ Nestler, In vivo imaging identifies temporal signature of D1 and D2 medium spiny neurons in cocaine reward, in Proceedings of the National Academy of Sciences of the United States of America, vol. 113, n. 10, 8 marzo 2016, pp. 2726-31, Bibcode:2016PNAS..113.2726C, DOI:10.1073/pnas.1521238113, PMC 4791010, PMID 26831103.

MN Baliki, A Mansour, AT Baria, L Huang, SE Berger, HL Fields e AV Apkarian, Parceling human accumbens into putative core and shell dissociates encoding of values for reward and pain, in The Journal of Neuroscience, vol. 33, n. 41, 9 ottobre 2013, pp. 16383-93, DOI:10.1523/JNEUROSCI.1731-13.2013, PMC 3792469, PMID 24107968.

C Soares-Cunha, B Coimbra, N Sousa e AJ Rodrigues, Reappraising striatal D1- and D2-neurons in reward and aversion, in Neuroscience and Biobehavioral Reviews, vol. 68, settembre 2016, pp. 370-386, DOI:10.1016/j.neubiorev.2016.05.021, PMID 27235078.

«Evidence strongly suggests that the canonical view of striatal D1R signalling as pro-reward/reinforcing and D2R signalling as pro-aversive is too simplistic. It is naïve to assume that D1R- and D2R-expressing neurons play completely independent (and con- trasting) roles.»

NS Bamford, RM Wightman e D Sulzer, Dopamine's Effects on Corticostriatal Synapses during Reward-Based Behaviors, in Neuron, vol. 97, n. 3, 7 febbraio 2018, pp. 494-510, DOI:10.1016/j.neuron.2018.01.006, PMC 5808590, PMID 29420932.

«Soares-Cunha and coworkers showed that op- togenetic activation of D1R- or D2R-containing SPNs in dorsal striatum both enhance motivation in mice (Soares-Cunha et al., 2016b). Consistent with this, optogenetic inhibition of D2R-con- taining neurons decreases motivation. This study, in agreement with the results obtained with microiontophoresis, suggests that D2R-containing SPNs play a more prominent role in promoting motivation than originally anticipated.»

C Soares-Cunha, B Coimbra, A David-Pereira, S Borges, L Pinto, P Costa, N Sousa e AJ Rodrigues, Activation of D2 dopamine receptor-expressing neurons in the nucleus accumbens increases motivation, in Nature Communications, vol. 7, 23 giugno 2016, p. 11829, Bibcode:2016NatCo...711829S, DOI:10.1038/ncomms11829, PMC 4931006, PMID 27337658.

Carina Soares-Cunha, Bárbara Coimbra, Ana Verónica Domingues, Nivaldo Vasconcelos, Nuno Sousa e Ana João Rodrigues, Nucleus Accumbens Microcircuit Underlying D2-MSN-Driven Increase in Motivation, in eNeuro, vol. 5, n. 2, 19 aprile 2018, pp. ENEURO.0386–18.2018, DOI:10.1523/ENEURO.0386-18.2018, PMC 5957524, PMID 29780881.

«Importantly, optogenetic activation of D2-MSN terminals in the VP was sufficient to recapitulate the motivation enhancement. In summary, our data suggests that optogenetic stimulation of NAc D2-MSNs indirectly modulates VTA dopaminergic activity, contributing for increased motivation.»

Berridge KC, Kringelbach ML, Affective neuroscience of pleasure: reward in humans and animals (PDF), in Psychopharmacology, vol. 199, n. 3, 2008, pp. 457-480, DOI:10.1007/s00213-008-1099-6, ISSN 0033-3158 (WC · ACNP), PMC 3004012, PMID 18311558. URL consultato il 20 ottobre 2012 (archiviato dall'url originale il 25 luglio 2012).

HH Yin, SB Ostlund e BW Balleine, Reward-guided learning beyond dopamine in the nucleus accumbens: the integrative functions of cortico-basal ganglia networks, in The European Journal of Neuroscience, vol. 28, n. 8, ottobre 2008, pp. 1437-48, DOI:10.1111/j.1460-9568.2008.06422.x, PMC 2756656, PMID 18793321.

P Dayan e KC Berridge, Model-based and model-free Pavlovian reward learning: revaluation, revision, and revelation, in Cognitive, Affective & Behavioral Neuroscience, vol. 14, n. 2, giugno 2014, pp. 473-92, DOI:10.3758/s13415-014-0277-8, PMC 4074442, PMID 24647659.

BW Balleine, RW Morris e BK Leung, Thalamocortical integration of instrumental learning and performance and their disintegration in addiction, in Brain Research, vol. 1628, Pt A, 2 dicembre 2015, pp. 104-16, DOI:10.1016/j.brainres.2014.12.023, PMID 25514336.

«Importantly, we found evidence of increased activity in the direct pathway; both intracellular changes in the expression of the plasticity marker pERK and AMPA/NMDA ratios evoked by stimulating cortical afferents were increased in the D1-direct pathway neurons. In contrast, D2 neurons showed an opposing change in plasticity; stimulation of cortical afferents reduced AMPA/NMDA ratios on those neurons (Shan et al., 2014).»

S Nakanishi, T Hikida e S Yawata, Distinct dopaminergic control of the direct and indirect pathways in reward-based and avoidance learning behaviors, in Neuroscience, vol. 282, 12 dicembre 2014, pp. 49-59, DOI:10.1016/j.neuroscience.2014.04.026, PMID 24769227.

MW Shiflett e BW Balleine, Molecular substrates of action control in cortico-striatal circuits, in Progress in Neurobiology, vol. 95, n. 1, 15 settembre 2011, pp. 1-13, DOI:10.1016/j.pneurobio.2011.05.007, PMC 3175490, PMID 21704115.

W Schultz, Updating dopamine reward signals, in Current Opinion in Neurobiology, vol. 23, n. 2, aprile 2013, pp. 229-38, DOI:10.1016/j.conb.2012.11.012, PMC 3866681, PMID 23267662.

MW Shiflett e BW Balleine, Contributions of ERK signaling in the striatum to instrumental learning and performance, in Behavioural Brain Research, vol. 218, n. 1, 17 marzo 2011, pp. 240-7, DOI:10.1016/j.bbr.2010.12.010, PMC 3022085, PMID 21147168.

Wise RA, Addictive drugs and brain stimulation reward, in Annu. Rev. Neurosci., vol. 19, 1996, pp. 319-340, DOI:10.1146/annurev.ne.19.030196.001535, PMID 8833446.

Ruffle JK, Molecular neurobiology of addiction: what's all the (Δ)FosB about?, in Am. J. Drug Alcohol Abuse, vol. 40, n. 6, novembre 2014, pp. 428-437, DOI:10.3109/00952990.2014.933840, PMID 25083822.

«
The strong correlation between chronic drug exposure and ΔFosB provides novel opportunities for targeted therapies in addiction (118), and suggests methods to analyze their efficacy (119). Over the past two decades, research has progressed from identifying ΔFosB induction to investigating its subsequent action (38). It is likely that ΔFosB research will now progress into a new era – the use of ΔFosB as a biomarker. ...
Conclusions
ΔFosB is an essential transcription factor implicated in the molecular and behavioral pathways of addiction following repeated drug exposure. The formation of ΔFosB in multiple brain regions, and the molecular pathway leading to the formation of AP-1 complexes is well understood. The establishment of a functional purpose for ΔFosB has allowed further determination as to some of the key aspects of its molecular cascades, involving effectors such as GluR2 (87,88), Cdk5 (93) and NFkB (100). Moreover, many of these molecular changes identified are now directly linked to the structural, physiological and behavioral changes observed following chronic drug exposure (60,95,97,102). New frontiers of research investigating the molecular roles of ΔFosB have been opened by epigenetic studies, and recent advances have illustrated the role of ΔFosB acting on DNA and histones, truly as a molecular switch (34). As a consequence of our improved understanding of ΔFosB in addiction, it is possible to evaluate the addictive potential of current medications (119), as well as use it as a biomarker for assessing the efficacy of therapeutic interventions (121,122,124). Some of these proposed interventions have limitations (125) or are in their infancy (75). However, it is hoped that some of these preliminary findings may lead to innovative treatments, which are much needed in addiction.»

Olsen CM, Natural rewards, neuroplasticity, and non-drug addictions, in Neuropharmacology, vol. 61, n. 7, dicembre 2011, pp. 1109-1122, DOI:10.1016/j.neuropharm.2011.03.010, PMC 3139704, PMID 21459101.

«Functional neuroimaging studies in humans have shown that gambling (Breiter et al, 2001), shopping (Knutson et al, 2007), orgasm (Komisaruk et al, 2004), playing video games (Koepp et al, 1998; Hoeft et al, 2008) and the sight of appetizing food (Wang et al, 2004a) activate many of the same brain regions (i.e., the mesocorticolimbic system and extended amygdala) as drugs of abuse (Volkow et al, 2004). ... Cross-sensitization is also bidirectional, as a history of amphetamine administration facilitates sexual behavior and enhances the associated increase in NAc DA ... As described for food reward, sexual experience can also lead to activation of plasticity-related signaling cascades. The transcription factor delta FosB is increased in the NAc, PFC, dorsal striatum, and VTA following repeated sexual behavior (Wallace et al., 2008; Pitchers et al., 2010b). This natural increase in delta FosB or viral overexpression of delta FosB within the NAc modulates sexual performance, and NAc blockade of delta FosB attenuates this behavior (Hedges et al, 2009; Pitchers et al., 2010b). Further, viral overexpression of delta FosB enhances the conditioned place preference for an environment paired with sexual experience (Hedges et al., 2009). ... In some people, there is a transition from "normal" to compulsive engagement in natural rewards (such as food or sex), a condition that some have termed behavioral or non-drug addictions (Holden, 2001; Grant et al., 2006a). ... In humans, the role of dopamine signaling in incentive-sensitization processes has recently been highlighted by the observation of a dopamine dysregulation syndrome in some patients taking dopaminergic drugs. This syndrome is characterized by a medication-induced increase in (or compulsive) engagement in non-drug rewards such as gambling, shopping, or sex (Evans et al, 2006; Aiken, 2007; Lader, 2008)."»

Table 1: Summary of plasticity observed following exposure to drug or natural reinforcers"

Pitchers KK, Vialou V, Nestler EJ, Laviolette SR, Lehman MN, Coolen LM, Natural and drug rewards act on common neural plasticity mechanisms with ΔFosB as a key mediator, in The Journal of Neuroscience, vol. 33, n. 8, febbraio 2013, pp. 3434-3442, DOI:10.1523/JNEUROSCI.4881-12.2013, PMC 3865508, PMID 23426671.

«Drugs of abuse induce neuroplasticity in the natural reward pathway, specifically the nucleus accumbens (NAc), thereby causing development and expression of addictive behavior. ... Together, these findings demonstrate that drugs of abuse and natural reward behaviors act on common molecular and cellular mechanisms of plasticity that control vulnerability to drug addiction, and that this increased vulnerability is mediated by ΔFosB and its downstream transcriptional targets. ... Sexual behavior is highly rewarding (Tenk et al., 2009), and sexual experience causes sensitized drug-related behaviors, including cross-sensitization to amphetamine (Amph)-induced locomotor activity (Bradley and Meisel, 2001; Pitchers et al., 2010a) and enhanced Amph reward (Pitchers et al., 2010a). Moreover, sexual experience induces neural plasticity in the NAc similar to that induced by psychostimulant exposure, including increased dendritic spine density (Meisel and Mullins, 2006; Pitchers et al., 2010a), altered glutamate receptor trafficking, and decreased synaptic strength in prefrontal cortex-responding NAc shell neurons (Pitchers et al., 2012). Finally, periods of abstinence from sexual experience were found to be critical for enhanced Amph reward, NAc spinogenesis (Pitchers et al., 2010a), and glutamate receptor trafficking (Pitchers et al., 2012). These findings suggest that natural and drug reward experiences share common mechanisms of neural plasticity»

Beloate LN, Weems PW, Casey GR, Webb IC, Coolen LM, Nucleus accumbens NMDA receptor activation regulates amphetamine cross-sensitization and deltaFosB expression following sexual experience in male rats, in Neuropharmacology, vol. 101, febbraio 2016, pp. 154-164, DOI:10.1016/j.neuropharm.2015.09.023, PMID 26391065.

Robison AJ, Nestler EJ, Transcriptional and epigenetic mechanisms of addiction, in Nat. Rev. Neurosci., vol. 12, n. 11, novembre 2011, pp. 623-637, DOI:10.1038/nrn3111, PMC 3272277, PMID 21989194.

«ΔFosB serves as one of the master control proteins governing this structural plasticity. ... ΔFosB also represses G9a expression, leading to reduced repressive histone methylation at the cdk5 gene. The net result is gene activation and increased CDK5 expression. ... In contrast, ΔFosB binds to the c-fos gene and recruits several co-repressors, including HDAC1 (histone deacetylase 1) and SIRT 1 (sirtuin 1). ... The net result is c-fos gene repression.»

Figure 4: Epigenetic basis of drug regulation of gene expression

Hitchcock LN, Lattal KM, Histone-mediated epigenetics in addiction, in Prog Mol Biol Transl Sci, Progress in Molecular Biology and Translational Science, vol. 128, 2014, pp. 51-87, DOI:10.1016/B978-0-12-800977-2.00003-6, ISBN 978-0-12-800977-2, PMC 5914502, PMID 25410541.

Walker DM, Nestler EJ, Neuroepigenetics and addiction, in Handbook of Clinical Neurology, vol. 148, 2018, pp. 747-765, DOI:10.1016/B978-0-444-64076-5.00048-X, ISBN 978-0-444-64076-5, PMC 5868351, PMID 29478612.

Goeders N.E., Smith J.E., Cortical dopaminergic involvement in cocaine reinforcement, in Science, vol. 221, n. 4612, 1983, pp. 773-775, Bibcode:1983Sci...221..773G, DOI:10.1126/science.6879176.

Clarke, Hommer D.W., Pert A., Skirboll L.R., Electrophysiological actions of nicotine on substantia nigra single units, in Br. J. Pharmacol., vol. 85, n. 4, 1985, pp. 827-835, DOI:10.1111/j.1476-5381.1985.tb11081.x, PMC 1916681, PMID 4041681.

K Rømer Thomsen, PC Whybrow e ML Kringelbach, Reconceptualizing anhedonia: novel perspectives on balancing the pleasure networks in the human brain, in Frontiers in Behavioral Neuroscience, vol. 9, 2015, p. 49, DOI:10.3389/fnbeh.2015.00049, PMC 4356228, PMID 25814941.

KR Thomsen, Measuring anhedonia: impaired ability to pursue, experience, and learn about reward, in Frontiers in Psychology, vol. 6, 2015, p. 1409, DOI:10.3389/fpsyg.2015.01409, PMC 4585007, PMID 26441781.

JJ Olney, SM Warlow, EE Naffziger e KC Berridge, Current perspectives on incentive salience and applications to clinical disorders, in Current Opinion in Behavioral Sciences, vol. 22, agosto 2018, pp. 59-69, DOI:10.1016/j.cobeha.2018.01.007, PMC 5831552, PMID 29503841.

B Zhang, P Lin, H Shi, D Öngür, RP Auerbach, X Wang, S Yao e X Wang, Mapping anhedonia-specific dysfunction in a transdiagnostic approach: an ALE meta-analysis, in Brain Imaging and Behavior, vol. 10, n. 3, settembre 2016, pp. 920-39, DOI:10.1007/s11682-015-9457-6, PMC 4838562, PMID 26487590.

JD Salamone, SE Yohn, L López-Cruz, N San Miguel e M Correa, Activational and effort-related aspects of motivation: neural mechanisms and implications for psychopathology, in Brain: A Journal of Neurology, vol. 139, Pt 5, maggio 2016, pp. 1325-47, DOI:10.1093/brain/aww050, PMC 5839596, PMID 27189581.

SJ Russo e EJ Nestler, The brain reward circuitry in mood disorders, in Nature Reviews. Neuroscience, vol. 14, n. 9, settembre 2013, pp. 609-25, DOI:10.1038/nrn3381, PMC 3867253, PMID 23942470.

MT Treadway e DH Zald, Reconsidering anhedonia in depression: lessons from translational neuroscience, in Neuroscience and Biobehavioral Reviews, vol. 35, n. 3, gennaio 2011, pp. 537-55, DOI:10.1016/j.neubiorev.2010.06.006, PMC 3005986, PMID 20603146.

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S Lammel, BK Lim e RC Malenka, Reward and aversion in a heterogeneous midbrain dopamine system, in Neuropharmacology, 76 Pt B, gennaio 2014, pp. 351-9, DOI:10.1016/j.neuropharm.2013.03.019, PMC 3778102, PMID 23578393.

D Knowland e BK Lim, Circuit-based frameworks of depressive behaviors: The role of reward circuitry and beyond, in Pharmacology Biochemistry and Behavior, 5 gennaio 2018, DOI:10.1016/j.pbb.2017.12.010, PMID 29309799.

S Lammel, KM Tye e MR Warden, Progress in understanding mood disorders: optogenetic dissection of neural circuits, in Genes, Brain, and Behavior, vol. 13, n. 1, gennaio 2014, pp. 38-51, DOI:10.1111/gbb.12049, PMID 23682971.

P Bucci e S Galderisi, Categorizing and assessing negative symptoms, in Current Opinion in Psychiatry, vol. 30, n. 3, maggio 2017, pp. 201-208, DOI:10.1097/YCO.0000000000000322, PMID 28212174.

«They also provide a separate assessment of the consummatory anhedonia (reduced experience of pleasure derived from ongoing enjoyable activities) and anticipatory anhedonia (reduced ability to anticipate future pleasure). In fact, the former one seems to be relatively intact in schizophrenia, whereas the latter one seems to be impaired [32 – 34]. However, discrepant data have also been reported [35].»

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Nestler EJ, Cellular basis of memory for addiction, in Dialogues Clin. Neurosci., vol. 15, n. 4, dicembre 2013, pp. 431-443, PMC 3898681, PMID 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.»

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«
Figure 3: Neural circuits underlying motivated 'wanting' and hedonic 'liking'.»

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Wise RA, Brain reward circuitry: insights from unsensed incentives, in Neuron, vol. 36, n. 2, ottobre 2002, pp. 229-240, DOI:10.1016/S0896-6273(02)00965-0, PMID 12383779.

W Schultz, Updating dopamine reward signals, in Current Opinion in Neurobiology, vol. 23, n. 2, aprile 2013, pp. 229-38, DOI:10.1016/j.conb.2012.11.012, PMC 3866681, PMID 23267662.

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Table 1: Summary of plasticity observed following exposure to drug or natural reinforcers"

Biliński P, Wojtyła A, Kapka-Skrzypczak L, Chwedorowicz R, Cyranka M, Studziński T, Epigenetic regulation in drug addiction, in Ann. Agric. Environ. Med., vol. 19, n. 3, 2012, pp. 491-496, PMID 23020045.

«For these reasons, ΔFosB is considered a primary and causative transcription factor in creating new neural connections in the reward centre, prefrontal cortex, and other regions of the limbic system. This is reflected in the increased, stable and long-lasting level of sensitivity to cocaine and other drugs, and tendency to relapse even after long periods of abstinence. These newly constructed networks function very efficiently via new pathways as soon as drugs of abuse are further taken ... In this way, the induction of CDK5 gene expression occurs together with suppression of the G9A gene coding for dimethyltransferase acting on the histone H3. A feedback mechanism can be observed in the regulation of these 2 crucial factors that determine the adaptive epigenetic response to cocaine. This depends on ΔFosB inhibiting G9a gene expression, i.e. H3K9me2 synthesis which in turn inhibits transcription factors for ΔFosB. For this reason, the observed hyper-expression of G9a, which ensures high levels of the dimethylated form of histone H3, eliminates the neuronal structural and plasticity effects caused by cocaine by means of this feedback which blocks ΔFosB transcription»

Robison AJ, Nestler EJ, Transcriptional and epigenetic mechanisms of addiction, in Nat. Rev. Neurosci., vol. 12, n. 11, novembre 2011, pp. 623-637, DOI:10.1038/nrn3111, PMC 3272277, PMID 21989194.

Figure 4: Epigenetic basis of drug regulation of gene expression

Goeders N.E., Smith J.E., Intracranial cocaine self-administration into the medial prefrontal cortex increases dopamine turnover in the nucleus accumbens, in J. Pharmacol. Exp. Ther., vol. 265, n. 2, 1993, pp. 592-600, PMID 8496810.

SJ Russo e EJ Nestler, The brain reward circuitry in mood disorders, in Nature Reviews. Neuroscience, vol. 14, n. 9, settembre 2013, pp. 609-25, DOI:10.1038/nrn3381, PMC 3867253, PMID 23942470.

P Bucci e S Galderisi, Categorizing and assessing negative symptoms, in Current Opinion in Psychiatry, vol. 30, n. 3, maggio 2017, pp. 201-208, DOI:10.1097/YCO.0000000000000322, PMID 28212174.

oadoi.org

Wise RA, Rompre PP, Brain dopamine and reward, in Annual Review of Psychology, vol. 40, 1989, pp. 191-225, DOI:10.1146/annurev.ps.40.020189.001203, PMID 2648975.

Wise RA, Brain reward circuitry: insights from unsensed incentives, in Neuron, vol. 36, n. 2, ottobre 2002, pp. 229-240, DOI:10.1016/S0896-6273(02)00965-0, PMID 12383779.

Wise RA, Addictive drugs and brain stimulation reward, in Annu. Rev. Neurosci., vol. 19, 1996, pp. 319-340, DOI:10.1146/annurev.ne.19.030196.001535, PMID 8833446.

Goeders N.E., Smith J.E., Cortical dopaminergic involvement in cocaine reinforcement, in Science, vol. 221, n. 4612, 1983, pp. 773-775, Bibcode:1983Sci...221..773G, DOI:10.1126/science.6879176.

P Bucci e S Galderisi, Categorizing and assessing negative symptoms, in Current Opinion in Psychiatry, vol. 30, n. 3, maggio 2017, pp. 201-208, DOI:10.1097/YCO.0000000000000322, PMID 28212174.

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Glossary of Terms, su Mount Sinai School of Medicine, Department of Neuroscience. URL consultato il 9 febbraio 2015 (archiviato dall'url originale il 10 maggio 2019).

Positive Reinforcement Produced by Electrical Stimulation of Septal Area and Other Regions of Rat Brain, su wadsworth.com. URL consultato il 2 dicembre 2018 (archiviato dall'url originale il 5 febbraio 2012).

Sistema di ricompensa (Italian Wikipedia)

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