Schultz, W. Predictive reward signal of dopamine neurons. J. Neurophysiol. 80, 1–27 (1998).
Stuber, G. D., Wightman, R. M. & Carelli, R. M. Extinction of cocaine self-administration reveals functionally and temporally distinct dopaminergic signals in the nucleus accumbens. Neuron 46, 661–669 (2005).
Volkow, N. D. & Baler, R. D. NOW versus LATER brain circuits: implications for obesity and addiction. Trends Neurosci. 38, 345–352 (2015).
Tomasi, D. et al. Overlapping patterns of brain activation to food and cocaine cues in cocaine abusers: association to striatal D2/D3 receptors. Hum. Brain Mapp. 36, 120–136 (2015).
Volkow, N. D., Wang, G. J., Fowler, J. S. & Telang, F. Overlapping neuronal circuits in addiction and obesity: evidence of systems pathology. Philos. Trans. R. Soc. Lond. B Biol. Sci. 363, 3191–3200 (2008).
Appelhans, B. M. et al. Inhibiting food reward: delay discounting, food reward sensitivity, and palatable food intake in overweight and obese women. Obesity 19, 2175–2182 (2011).
Wise, R. A. Dopamine, learning and motivation. Nat. Rev. Neurosci. 5, 483–494 (2004).
Tang, Y. Y., Posner, M. I., Rothbart, M. K. & Volkow, N. D. Circuitry of self-control and its role in reducing addiction. Trends Cogn. Sci. 19, 439–444 (2015).
Corwin, R. L., Avena, N. M. & Boggiano, M. M. Feeding and reward: perspectives from three rat models of binge eating. Physiol. Behav. 104, 87–97 (2011).
Parsons, L. H. & Hurd, Y. L. Endocannabinoid signalling in reward and addiction. Nat. Rev. Neurosci. 16, 579–594 (2015).
Peciña, S., Cagniard, B., Berridge, K. C., Aldridge, J. W. & Zhuang, X. Hyperdopaminergic mutant mice have higher “wanting” but not “liking” for sweet rewards. J. Neurosci. 23, 9395–9402 (2003).
Sotak, B. N., Hnasko, T. S., Robinson, S., Kremer, E. J. & Palmiter, R. D. Dysregulation of dopamine signaling in the dorsal striatum inhibits feeding. Brain Res. 1061, 88–96 (2005).
Palmiter, R. D. Dopamine signaling in the dorsal striatum is essential for motivated behaviors: lessons from dopamine-deficient mice. Ann. NY Acad. Sci. 1129, 35–46 (2008).
Hnasko, T. S., Sotak, B. N. & Palmiter, R. D. Cocaine-conditioned place preference by dopamine-deficient mice is mediated by serotonin. J. Neurosci. 27, 12484–12488 (2007).
Yager, L. M., Garcia, A. F., Wunsch, A. M. & Ferguson, S. M. The ins and outs of the striatum: role in drug addiction. Neuroscience 301, 529–541 (2015).
Wise, R. A. Roles for nigrostriatal — not just mesocorticolimbic — dopamine in reward and addiction. Trends Neurosci. 32, 517–524 (2009).
Howard, C. D., Li, H., Geddes, C. E. & Jin, X. Dynamic nigrostriatal dopamine biases action selection. Neuron 93, 1436–1450.e8 (2017).
Parkes, S. L., Bradfield, L. A. & Balleine, B. W. Interaction of insular cortex and ventral striatum mediates the effect of incentive memory on choice between goal-directed actions. J. Neurosci. 35, 6464–6471 (2015).
Vo, K., Rutledge, R. B., Chatterjee, A. & Kable, J. W. Dorsal striatum is necessary for stimulus-value but not action-value learning in humans. Brain 137, 3129–3135 (2014).
Voorn, P., Vanderschuren, L. J., Groenewegen, H. J., Robbins, T. W. & Pennartz, C. M. Putting a spin on the dorsal-ventral divide of the striatum. Trends Neurosci. 27, 468–474 (2004).
Marcellino, D., Kehr, J., Agnati, L. F. & Fuxe, K. Increased affinity of dopamine for D2-like versus D1-like receptors. Relevance for volume transmission in interpreting PET findings. Synapse 66, 196–203 (2012).
Richfield, E. K., Penney, J. B. & Young, A. B. Anatomical and affinity state comparisons between dopamine D1 and D2 receptors in the rat central nervous system. Neuroscience 30, 767–777 (1989).
Bromberg-Martin, E. S., Matsumoto, M. & Hikosaka, O. Dopamine in motivational control: rewarding, aversive, and alerting. Neuron 68, 815–834 (2010).
Danjo, T., Yoshimi, K., Funabiki, K., Yawata, S. & Nakanishi, S. Aversive behavior induced by optogenetic inactivation of ventral tegmental area dopamine neurons is mediated by dopamine D2 receptors in the nucleus accumbens. Proc. Natl Acad. Sci. USA 111, 6455–6460 (2014).
Dreyer, J. K., Herrik, K. F., Berg, R. W. & Hounsgaard, J. D. Influence of phasic and tonic dopamine release on receptor activation. J. Neurosci. 30, 14273–14283 (2010).
Trifilieff, P. et al. Increasing dopamine D2 receptor expression in the adult nucleus accumbens enhances motivation. Mol. Psychiatry 18, 1025–1033 (2013).
Zweifel, L. S. et al. Disruption of NMDAR-dependent burst firing by dopamine neurons provides selective assessment of phasic dopamine-dependent behavior. Proc. Natl Acad. Sci. USA 106, 7281–7288 (2009).
Garris, P. A., Ciolkowski, E. L., Pastore, P. & Wightman, R. M. Efflux of dopamine from the synaptic cleft in the nucleus accumbens of the rat brain. J. Neurosci. 14, 6084–6093 (1994).
Lammel, S., Lim, B. K. & Malenka, R. C. Reward and aversion in a heterogeneous midbrain dopamine system. Neuropharmacology 76, 351–359 (2014).
Morales, M. & Margolis, E. B. Ventral tegmental area: cellular heterogeneity, connectivity and behaviour. Nat. Rev. Neurosci. 18, 73–85 (2017).
Marinelli, M. & McCutcheon, J. E. Heterogeneity of dopamine neuron activity across traits and states. Neuroscience 282, 176–197 (2014).
Saddoris, M. P., Cacciapaglia, F., Wightman, R. M. & Carelli, R. M. Differential dopamine release dynamics in the nucleus accumbens core and shell reveal complementary signals for error prediction and incentive motivation. J. Neurosci. 35, 11572–11582 (2015).
Robinson, D. L., Zitzman, D. L. & Williams, S. K. Mesolimbic dopamine transients in motivated behaviors: focus on maternal behavior. Front. Psychiatry 2, 23 (2011).
Schultz, W. Updating dopamine reward signals. Curr. Opin. Neurobiol. 23, 229–238 (2013).
Floresco, S. B., West, A. R., Ash, B., Moore, H. & Grace, A. A. Afferent modulation of dopamine neuron firing differentially regulates tonic and phasic dopamine transmission. Nat. Neurosci. 6, 968–973 (2003).
Wang, L. P. et al. NMDA receptors in dopaminergic neurons are crucial for habit learning. Neuron 72, 1055–1066 (2011).
Grace, A. A., Floresco, S. B., Goto, Y. & Lodge, D. J. Regulation of firing of dopaminergic neurons and control of goal-directed behaviors. Trends Neurosci. 30, 220–227 (2007).
Huerta-Ocampo, I., Mena-Segovia, J. & Bolam, J. P. Convergence of cortical and thalamic input to direct and indirect pathway medium spiny neurons in the striatum. Brain Struct. Function 219, 1787–1800 (2014).
Gerfen, C. R. & Surmeier, D. J. Modulation of striatal projection systems by dopamine. Annu. Rev. Neurosci. 34, 441–466 (2011).
Namburi, P., Al-Hasani, R., Calhoon, G. G., Bruchas, M. R. & Tye, K. M. Architectural representation of valence in the limbic system. Neuropsychopharmacology 41, 1697–1715 (2016).
Luo, Z., Volkow, N. D., Heintz, N., Pan, Y. & Du, C. Acute cocaine induces fast activation of D1 receptor and progressive deactivation of D2 receptor striatal neurons: in vivo optical microprobe [Ca2+]i imaging. J. Neurosci. 31, 13180–13190 (2011).
This study provides preliminary evidence that the rate dependency of the effect of acute cocaine may relate to its fast and short-lasting activation of D1R-expressing striatal neurons in contrast to the slower and longer-lasting deactivation of D2R-expressing neurons. It also corroborates that DA activates D1R-expressing neurons and inhibits D2R-expressing neurons in the striatum.
Ferre, S. The GPCR heterotetramer: challenging classical pharmacology. Trends Pharmacol Sci. 36, 145–152 (2015).
Fiorentini, C., Busi, C., Spano, P. & Missale, C. Dimerization of dopamine D1 and D3 receptors in the regulation of striatal function. Curr. Opin. Pharmacol. 10, 87–92 (2010).
Kravitz, A. V., Tye, L. D. & Kreitzer, A. C. Distinct roles for direct and indirect pathway striatal neurons in reinforcement. Nat. Neurosci. 15, 816–818 (2012).
This study uses optogenetic stimulation to demonstrate that the activation of the striatal direct pathway is sufficient for persistent reinforcement, whereas activation of the indirect pathway is sufficient for transient punishment. It also shows that reinforcement is more effective than punishment at modifying long-term behaviour.
Hikida, T., Kimura, K., Wada, N., Funabiki, K. & Nakanishi, S. Distinct roles of synaptic transmission in direct and indirect striatal pathways to reward and aversive behavior. Neuron 66, 896–907 (2010).
This study shows that both direct and indirect pathways are engaged by psychostimulant rewards: the direct pathway is active in distinguishing associative rewarding stimuli from non-associative ones, and the indirect pathway is involved with rapid memory formation to avoid aversive stimuli.
Cui, G. et al. Concurrent activation of striatal direct and indirect pathways during action initiation. Nature 494, 238–242 (2013).
This study uses optogenetics to retest the classic model of direct versus indirect pathway in animals performing an operant task. The investigators report that during an operant task, there were transient increases in neural activity in both direct-pathway and indirect-pathway spiny projection neurons when animals initiated actions but not when they were inactive, which challenges some classical views of basal ganglia function.
Nakanishi, S., Hikida, T. & Yawata, S. Distinct dopaminergic control of the direct and indirect pathways in reward-based and avoidance learning behaviors. Neuroscience 282, 49–59 (2014).
Vicente, A. M., Galvao-Ferreira, P., Tecuapetla, F. & Costa, R. M. Direct and indirect dorsolateral striatum pathways reinforce different action strategies. Curr. Biol. 26, R267–R269 (2016).
Kupchik, Y. M. et al. Coding the direct/indirect pathways by D1 and D2 receptors is not valid for accumbens projections. Nat. Neurosci. 18, 1230–1232 (2015).
This study provides optogenetic and electrophysiological evidence to suggest that the model in which D1R -expressing MSNs convey information directly to the output nuclei of the basal ganglia, whereas D2R-expressing neurons do so indirectly via pallidal neurons, may not apply to the projections from the accumbens to the ventral pallidum.
Calabresi, P., Picconi, B., Tozzi, A., Ghiglieri, V. & Di Filippo, M. Direct and indirect pathways of basal ganglia: a critical reappraisal. Nat. Neurosci. 17, 1022–1030 (2014).
This Review provides an updated model of the direct and indirect pathways presumed to have facilitating and inhibitory effects on movement, respectively that incorporates the role of intrastriatal connections during movement.
Koob, G. F., Everitt, E. J. & Robbins, T. W. in Fundamental Neuroscience 3rd edn (eds Squire, L. et al.) 987–1016 (Academic Press, 2008).
Volkow, N. D., Wang, G. J., Tomasi, D. & Baler, R. D. Unbalanced neuronal circuits in addiction. Curr. Opin. Neurobiol. 23, 639–648 (2013).
Volkow, N. D. & Morales, M. The brain on drugs: from reward to addiction. Cell 162, 712–725 (2015).
This review provides an in-depth update of the circuit- and cell-level mechanisms underlying the addictive state and its co-option of pathways regulating reward, self-control and affect.
Chen, J., Papies, E. K. & Barsalou, L. W. A core eating network and its modulations underlie diverse eating phenomena. Brain Cogn. 110, 20–42 (2016).
Day, J. J., Jones, J. L., Wightman, R. M. & Carelli, R. M. Phasic nucleus accumbens dopamine release encodes effort- and delay-related costs. Biol. Psychiatry 68, 306–309 (2010).
Hamid, A. A. et al. Mesolimbic dopamine signals the value of work. Nat. Neurosci. 19, 117–126 (2016).
Parsons, L. H. & Justice, J. B. Jr. Extracellular concentration and in vivo recovery of dopamine in the nucleus accumbens using microdialysis. J. Neurochem. 58, 212–218 (1992).
Keithley, R. B. et al. Higher sensitivity dopamine measurements with faster-scan cyclic voltammetry. Anal. Chem. 83, 3563–3571 (2011).
Wightman, R. M. & Robinson, D. L. Transient changes in mesolimbic dopamine and their association with 'reward'. J. Neurochem. 82, 721–735 (2002).
Small, D. M., Zatorre, R. J., Dagher, A., Evans, A. C. & Jones-Gotman, M. Changes in brain activity related to eating chocolate: from pleasure to aversion. Brain 124, 1720–1733 (2001).
Sun, X. et al. The neural signature of satiation is associated with ghrelin response and triglyceride metabolism. Physiol. Behav. 136, 63–73 (2014).
Wise, R. A. et al. Fluctuations in nucleus accumbens dopamine concentration during intravenous cocaine self-administration in rats. Psychopharmacology 120, 10–20 (1995).
Hyman, S. E. Addiction: a disease of learning and memory. Am. J. Psychiatry 162, 1414–1422 (2005).
Nair, S. G., Adams-Deutsch, T., Epstein, D. H. & Shaham, Y. The neuropharmacology of relapse to food seeking: methodology, main findings, and comparison with relapse to drug seeking. Prog. Neurobiol. 89, 18–45 (2009).
Harnett, M. T., Bernier, B. E., Ahn, K. C. & Morikawa, H. Burst-timing-dependent plasticity of NMDA receptor-mediated transmission in midbrain dopamine neurons. Neuron 62, 826–838 (2009).
Madhavan, A., Argilli, E., Bonci, A. & Whistler, J. L. Loss of D2 dopamine receptor function modulates cocaine-induced glutamatergic synaptic potentiation in the ventral tegmental area. J. Neurosci. 33, 12329–12336 (2013).
Wang, B. et al. Cocaine experience establishes control of midbrain glutamate and dopamine by corticotropin-releasing factor: a role in stress-induced relapse to drug seeking. J. Neurosci. 25, 5389–5396 (2005).
You, Z. B., Wang, B., Zitzman, D. & Wise, R. A. Acetylcholine release in the mesocorticolimbic dopamine system during cocaine seeking: conditioned and unconditioned contributions to reward and motivation. J. Neurosci. 28, 9021–9029 (2008).
Calabresi, P., Centonze, D., Gubellini, P., Marfia, G. A. & Bernardi, G. Glutamate-triggered events inducing corticostriatal long-term depression. J. Neurosci. 19, 6102–6110 (1999).
Graziane, N. M. et al. Opposing mechanisms mediate morphine- and cocaine-induced generation of silent synapses. Nat. Neurosci. 19, 915–925 (2016).
Vanderschuren, L. J., Di Ciano, P. & Everitt, B. J. Involvement of the dorsal striatum in cue-controlled cocaine seeking. J. Neurosci. 25, 8665–8670 (2005).
Kauer, J. A. & Malenka, R. C. Synaptic plasticity and addiction. Nat. Rev. Neurosci. 8, 844–858 (2007).
Conrad, K. L. et al. Formation of accumbens GluR2-lacking AMPA receptors mediates incubation of cocaine craving. Nature 454, 118–121 (2008).
Park, K., Volkow, N. D., Pan, Y. & Du, C. Chronic cocaine dampens dopamine signaling during cocaine intoxication and unbalances D1 over D2 receptor signaling. J. Neurosci. 33, 15827–15836 (2013).
This study uses optical imaging to compare adaptation in the D1R-expressing and D2R-expressing MSNs to chronic cocaine administration. It documents an imbalance associated with repeated cocaine exposure that favours D1R over D2R signalling, which could help explain the compulsive patterns of cocaine intake in addiction.
Mancino, S., Mendonça-Netto, S., Martín-García, E. & Maldonado, R. Role of DOR in neuronal plasticity changes promoted by food-seeking behaviour. Addict. Biol. 22, 1179–1190 (2016).
Gutierrez-Cuesta, J. et al. Effects of genetic deletion of endogenous opioid system components on the reinstatement of cocaine-seeking behavior in mice. Neuropsychopharmacology 39, 2974–2988 (2014).
Guegan, T. et al. Operant behavior to obtain palatable food modifies ERK activity in the brain reward circuit. Eur. Neuropsychopharmacol. 23, 240–252 (2013).
Ren, Z. et al. Dopamine D1 and N-methyl-D-aspartate receptors and extracellular signal-regulated kinase mediate neuronal morphological changes induced by repeated cocaine administration. Neuroscience 168, 48–60 (2010).
Nogueiras, R. et al. The opioid system and food intake: homeostatic and hedonic mechanisms. Obes. Facts 5, 196–207 (2012).
Gosnell, B. A. & Levine, A. S. Reward systems and food intake: role of opioids. Int. J. Obes. 33 (Suppl. 2), S54–S58 (2009).
Befort, K. Interactions of the opioid and cannabinoid systems in reward: Insights from knockout studies. Front. Pharmacol. 6, 6 (2015).
Wenzel, J. M. & Cheer, J. F. Endocannabinoid regulation of reward and reinforcement through interaction with dopamine and endogenous opioid signaling. Neuropsychopharmacology http://dx.doi.org/10.1038/npp.2017.126 (2017).
Ball, K. T., Best, O., Luo, J. & Miller, L. R. Chronic restraint stress causes a delayed increase in responding for palatable food cues during forced abstinence via a dopamine D1-like receptor-mediated mechanism. Behav. Brain Res. 319, 1–8 (2017).
Ball, K. T., Combs, T. A. & Beyer, D. N. Opposing roles for dopamine D1- and D2-like receptors in discrete cue-induced reinstatement of food seeking. Behav. Brain Res. 222, 390–393 (2011).
This study extends the applicability of a classical animal model of drug abuse relapse to the investigation of the reinstatement of food-seeking behaviours. It finds that pharmacological blockade of dopamine D1-like receptors abrogates discrete cue-induced reinstatement of food seeking, whereas D2-like receptor blockade increases responding during reinstatement tests.
Ball, K. T. et al. Effects of repeated yohimbine administration on reinstatement of palatable food seeking: involvement of dopamine D1-like receptors and food-associated cues. Addict. Biol. 21, 1140–1150 (2016).
Billes, S. K., Simonds, S. E. & Cowley, M. A. Leptin reduces food intake via a dopamine D2 receptor-dependent mechanism. Mol. Metab. 1, 86–93 (2012).
Han, W. et al. Striatal dopamine links gastrointestinal rerouting to altered sweet appetite. Cell Metab. 23, 103–112 (2016).
Adams, W. K. et al. Long-term, calorie-restricted intake of a high-fat diet in rats reduces impulse control and ventral striatal D2 receptor signalling — two markers of addiction vulnerability. Eur. J. Neurosci. 42, 3095–3104 (2015).
Johnson, P. M. & Kenny, P. J. Dopamine D2 receptors in addiction-like reward dysfunction and compulsive eating in obese rats. Nat. Neurosci. 13, 635–641 (2010).
van de Giessen, E. et al. High fat/carbohydrate ratio but not total energy intake induces lower striatal dopamine D2/3 receptor availability in diet-induced obesity. Int. J. Obes. 37, 754–757 (2013).
Tellez, L. A. et al. A gut lipid messenger links excess dietary fat to dopamine deficiency. Science 341, 800–802 (2013).
Zhu, X., Ottenheimer, D. & DiLeone, R. J. Activity of D1/2 receptor expressing neurons in the nucleus accumbens regulates running, locomotion, and food intake. Front. Behav. Neurosci. 10, 66 (2016).
Everitt, B. J. et al. Neural mechanisms underlying the vulnerability to develop compulsive drug-seeking habits and addiction. Philos. Trans. R. Soc. Lond. B Biol. Sci. 363, 3125–3135 (2008).
Szczypka, M. S. et al. Dopamine production in the caudate putamen restores feeding in dopamine-deficient mice. Neuron 30, 819–828 (2001).
Volkow, N. D. et al. “Nonhedonic” food motivation in humans involves dopamine in the dorsal striatum and methylphenidate amplifies this effect. Synapse 44, 175–180 (2002).
Epel, E. S. et al. The reward-based eating drive scale: a self-report index of reward-based eating. PLoS ONE 9, e101350 (2014).
Volkow, N. D., Koob, G. F. & McLellan, A. T. Neurobiologic advances from the brain disease model of addiction. N. Engl. J. Med. 374, 363–371 (2016).
Moffitt, T. E. et al. A gradient of childhood self-control predicts health, wealth, and public safety. Proc. Natl Acad. Sci. USA 108, 2693–2698 (2011).
Tarter, R. E. et al. Neurobehavioral disinhibition in childhood predicts early age at onset of substance use disorder. Am. J. Psychiatry 160, 1078–1085 (2003).
Volkow, N. D. & Fowler, J. S. Addiction, a disease of compulsion and drive: involvement of the orbitofrontal cortex. Cereb. Cortex 10, 318–325 (2000).
Volkow, N. D. et al. High levels of dopamine D2 receptors in unaffected members of alcoholic families: possible protective factors. Arch. Gen. Psychiatry 63, 999–1008 (2006).
Wang, G. J. et al. Brain dopamine and obesity. Lancet 357, 354–357 (2001).
van de Giessen, E., Celik, F., Schweitzer, D. H., van den Brink, W. & Booij, J. Dopamine D2/3 receptor availability and amphetamine-induced dopamine release in obesity. J. Psychopharmacol. 28, 866–873 (2014).
de Weijer, B. A. et al. Lower striatal dopamine D2/3 receptor availability in obese compared with non-obese subjects. EJNMMI Res. 1, 37 (2011).
Steele, K. E. et al. Alterations of central dopamine receptors before and after gastric bypass surgery. Obes. Surg. 20, 369–374 (2010).
Volkow, N. D. et al. Low dopamine striatal D2 receptors are associated with prefrontal metabolism in obese subjects: possible contributing factors. Neuroimage 42, 1537–1543 (2008).
Volkow, N. D. et al. Decreased dopamine D2 receptor availability is associated with reduced frontal metabolism in cocaine abusers. Synapse 14, 169–177 (1993).
Volkow, N. D. et al. Low level of brain dopamine D2 receptors in methamphetamine abusers: association with metabolism in the orbitofrontal cortex. Am. J. Psychiatry 158, 2015–2021 (2001).
Dunn, J. P. et al. Relationship of dopamine type 2 receptor binding potential with fasting neuroendocrine hormones and insulin sensitivity in human obesity. Diabetes Care 35, 1105–1111 (2012).
Karlsson, H. K. et al. Obesity is associated with decreased μ-opioid but unaltered dopamine D2 receptor availability in the brain. J. Neurosci. 35, 3959–3965 (2015).
Martinez, D. et al. Dopamine D1 receptors in cocaine dependence measured with PET and the choice to self-administer cocaine. Neuropsychopharmacology 34, 1774–1782 (2009).
Sinha, R. & Li, C. S. Imaging stress- and cue-induced drug and alcohol craving: association with relapse and clinical implications. Drug Alcohol Rev. 26, 25–31 (2007).
Weygandt, M. et al. Impulse control in the dorsolateral prefrontal cortex counteracts post-diet weight regain in obesity. Neuroimage 109, 318–327 (2015).
Tomasi, D. & Volkow, N. D. Striatocortical pathway dysfunctionin addiction and obesity: differences and similarities. Crit. Rev. Biochem. Mol. Biol. 48, 1–19 (2013).
Wang, G. J. et al. BMI modulates calorie-dependent dopamine changes in accumbens from glucose intake. PLoS ONE 9, e101585 (2014).
Cosgrove, K. P., Veldhuizen, M. G., Sandiego, C. M., Morris, E. D. & Small, D. M. Opposing relationships of BMI with BOLD and dopamine D2/3 receptor binding potential in the dorsal striatum. Synapse 69, 195–202 (2015).
Stice, E., Yokum, S., Blum, K. & Bohon, C. Weight gain is associated with reduced striatal response to palatable food. J. Neurosci. 30, 13105–13109 (2010).
Volkow, N. D. et al. Stimulant-induced dopamine increases are markedly blunted in active cocaine abusers. Mol. Psychiatry 19, 1037–1043 (2014).
Carelli, R. M. & West, E. A. When a good taste turns bad: neural mechanisms underlying the emergence of negative affect and associated natural reward devaluation by cocaine. Neuropharmacology 76, 360–369 (2014).
Parvaz, M. A., Alia-Klein, N., Woicik, P. A., Volkow, N. D. & Goldstein, R. Z. Neuroimaging for drug addiction and related behaviors. Rev. Neurosci. 22, 609–624 (2011).
Garcia-Garcia, I. et al. Functional connectivity in obesity during reward processing. Neuroimage 66, 232–239 (2013).
Volkow, N. D. et al. Motivation deficit in ADHD is associated with dysfunction of the dopamine reward pathway. Mol. Psychiatry 16, 1147–1154 (2011).
Volkow, N. D. et al. Methylphenidate-elicited dopamine increases in ventral striatum are associated with long-term symptom improvement in adults with attention deficit hyperactivity disorder. J. Neurosci. 32, 841–849 (2012).
Courtney, K. E., Schacht, J. P., Hutchison, K., Roche, D. J. & Ray, L. A. Neural substrates of cue reactivity: association with treatment outcomes and relapse. Addict. Biol. 21, 3–22 (2016).
Stice, E., Spoor, S., Bohon, C., Veldhuizen, M. G. & Small, D. M. Relation of reward from food intake and anticipated food intake to obesity: a functional magnetic resonance imaging study. J. Abnorm. Psychol. 117, 924–935 (2008).
Volkow, N. D. Opioid-dopamine interactions: implications for substance use disorders and their treatment. Biol. Psychiatry 68, 685–686 (2010).
Gilbert-Diamond, D. et al. Television food advertisement exposure and FTO rs9939609 genotype in relation to excess consumption in children. Int. J. Obes. 41, 23–29 (2017).
Rapuano, K. M. et al. Genetic risk for obesity predicts nucleus accumbens size and responsivity to real-world food cues. Proc. Natl Acad. Sci. USA 114, 160–165 (2017).
Koob, G. F. & Le Moal, M. Plasticity of reward neurocircuitry and the 'dark side' of drug addiction. Nat. Neurosci. 8, 1442–1444 (2005).
Gramsch, C., Blasig, J. & Herz, A. Changes in striatal dopamine metabolism during precipitated morphine withdrawal. Eur. J. Pharmacol. 44, 231–240 (1977).
Wang, G. J. et al. Dopamine D2 receptor availability in opiate-dependent subjects before and after naloxone-precipitated withdrawal. Neuropsychopharmacology 16, 174–182 (1997).
Koob, G. F. et al. Addiction as a stress surfeit disorder. Neuropharmacology 76, 370–382 (2014).
Colantuoni, C. et al. Evidence that intermittent, excessive sugar intake causes endogenous opioid dependence. Obes. Res. 10, 478–488 (2002).
Parylak, S. L., Koob, G. F. & Zorrilla, E. P. The dark side of food addiction. Physiol. Behav. 104, 149–156 (2011).
de Witt Huberts, J. C., Evers, C. & de Ridder, D. T. Double trouble: restrained eaters do not eat less and feel worse. Psychol. Health 28, 686–700 (2013).
Hill, A. J., Weaver, C. F. & Blundell, J. E. Food craving, dietary restraint and mood. Appetite 17, 187–197 (1991).
Sinha, R. & Jastreboff, A. M. Stress as a common risk factor for obesity and addiction. Biol. Psychiatry 73, 827–835 (2013).
Yau, Y. H. & Potenza, M. N. Stress and eating behaviors. Minerva Endocrinol. 38, 255–267 (2013).
de Araujo, I. E. et al. Food reward in the absence of taste receptor signaling. Neuron 57, 930–941 (2008).
Narayanaswami, V. & Dwoskin, L. P. Obesity: current and potential pharmacotherapeutics and targets. Pharmacol. Ther. 170, 116–147 (2017).
Collins, G. T., Gerak, L. R., Javors, M. A. & France, C. P. Lorcaserin reduces the discriminative stimulus and reinforcing effects of cocaine in rhesus monkeys. J. Pharmacol. Exp. Ther. 356, 85–95 (2016).
Neelakantan, H. et al. Lorcaserin suppresses oxycodone self-administration and relapse vulnerability in rats. ACS Chem. Neurosci. 8, 1065–1073 (2017).
Higgins, G. A. et al. The 5-HT2C receptor agonist lorcaserin reduces nicotine self-administration, discrimination, and reinstatement: relationship to feeding behavior and impulse control. Neuropsychopharmacology 37, 1177–1191 (2012).
Howell, L. L. & Cunningham, K. A. Serotonin 5-HT2 receptor interactions with dopamine function: implications for therapeutics in cocaine use disorder. Pharmacol Rev. 67, 176–197 (2015).
Mooney, M. E. et al. Bupropion and naltrexone for smoking cessation: a double-blind randomized placebo-controlled clinical trial. Clin. Pharmacol. Ther. 100, 344–352 (2016).
Wilcox, C. S. et al. An open-label study of naltrexone and bupropion combination therapy for smoking cessation in overweight and obese subjects. Addict. Behav. 35, 229–234 (2010).
Vallof, D. et al. The glucagon-like peptide 1 receptor agonist liraglutide attenuates the reinforcing properties of alcohol in rodents. Addict. Biol. 21, 422–437 (2016).
Cahill, K. & Ussher, M. Cannabinoid type 1 receptor antagonists for smoking cessation. Cochrane Database Syst. Rev. 3, CD005353 (2011).
Justinova, Z., Panlilio, L. V. & Goldberg, S. R. Drug addiction. Curr. Top. Behav. Neurosci. 1, 309–346 (2009).
King, W. C. et al. Prevalence of alcohol use disorders before and after bariatric surgery. JAMA 307, 2516–2525 (2012).
Svensson, P. A. et al. Alcohol consumption and alcohol problems after bariatric surgery in the Swedish obese subjects study. Obesity 21, 2444–2451 (2013).
Raebel, M. A. et al. Chronic use of opioid medications before and after bariatric surgery. JAMA 310, 1369–1376 (2013).
Polston, J. E. et al. Roux-en-Y gastric bypass increases intravenous ethanol self-administration in dietary obese rats. PLoS ONE 8, e83741 (2013).
Biegler, J. M., Freet, C. S., Horvath, N., Rogers, A. M. & Hajnal, A. Increased intravenous morphine self-administration following Roux-en-Y gastric bypass in dietary obese rats. Brain Res. Bull. 123, 47–52 (2016).
Steffen, K. J., Engel, S. G., Wonderlich, J. A., Pollert, G. A. & Sondag, C. Alcohol and other addictive disorders following bariatric surgery: prevalence, risk factors and possible etiologies. Eur. Eat Disord. Rev. 23, 442–450 (2015).
Bolloni, C. et al. Bilateral transcranial magnetic stimulation of the prefrontal cortex reduces cocaine intake: a pilot study. Front. Psychiatry 7, 133 (2016).
Val-Laillet, D. et al. Neuroimaging and neuromodulation approaches to study eating behavior and prevent and treat eating disorders and obesity. Neuroimage Clin. 8, 1–31 (2015).
Jauch-Chara, K. et al. Repetitive electric brain stimulation reduces food intake in humans. Am. J. Clin. Nutr. 100, 1003–1009 (2014).
Childs, J. E., DeLeon, J., Nickel, E. & Kroener, S. Vagus nerve stimulation reduces cocaine seeking and alters plasticity in the extinction network. Learn. Mem. 24, 35–42 (2017).
Wing, V. C. et al. Brain stimulation methods to treat tobacco addiction. Brain Stimul. 6, 221–230 (2013).
Ceccanti, M. et al. Deep TMS on alcoholics: effects on cortisolemia and dopamine pathway modulation. A pilot study. Can. J. Physiol. Pharmacol. 93, 283–290 (2015).
Terraneo, A. et al. Transcranial magnetic stimulation of dorsolateral prefrontal cortex reduces cocaine use: a pilot study. Eur. Neuropsychopharmacol. 26, 37–44 (2016).
Franco, R. et al. DBS for obesity. Brain Sci. 6, 21 (2016).
McClelland, J., Bozhilova, N., Campbell, I. & Schmidt, U. A systematic review of the effects of neuromodulation on eating and body weight: evidence from human and animal studies. Eur. Eat Disord. Rev. 21, 436–455 (2013).
Guiraud, D. et al. Vagus nerve stimulation: state of the art of stimulation and recording strategies to address autonomic function neuromodulation. J. Neural Eng. 13, 041002 (2016).
Muller, U. J. et al. Nucleus accumbens deep brain stimulation for alcohol addiction — safety and clinical long-term results of a pilot trial. Pharmacopsychiatry 49, 170–173 (2016).
Burgess, E., Hassmen, P. & Pumpa, K. L. Determinants of adherence to lifestyle intervention in adults with obesity: a systematic review. Clin. Obes. 7, 123–135 (2017).
Zhou, Y., Zhao, M., Zhou, C. & Li, R. Sex differences in drug addiction and response to exercise intervention: from human to animal studies. Front. Neuroendocrinol. 40, 24–41 (2016).
Kravitz, A. V., O'Neal, T. J. & Friend, D. M. Do dopaminergic impairments underlie physical inactivity in people with obesity? Front. Hum. Neurosci. 10, 514 (2016).
Chen, W. et al. Moderate intensity treadmill exercise alters food preference via dopaminergic plasticity of ventral tegmental area-nucleus accumbens in obese mice. Neurosci. Lett. 641, 56–61 (2017).
Volkow, N. D. et al. Evidence that sleep deprivation downregulates dopamine D2R in ventral striatum in the human brain. J. Neurosci. 32, 6711–6717 (2012).
Verwey, M., Dhir, S. & Amir, S. Circadian influences on dopamine circuits of the brain: regulation of striatal rhythms of clock gene expression and implications for psychopathology and disease. F1000Res 5, 2062 (2016).
Wiers, C. E. et al. Reduced sleep duration mediates decreases in striatal D2/D3 receptor availability in cocaine abusers. Transl Psychiatry 6, e752 (2016).
Carlucci, C., Petrof, E. O. & Allen-Vercoe, E. Fecal microbiota-based therapeutics for recurrent Clostridium difficile infection, ulcerative colitis and obesity. EBioMedicine 13, 37–45 (2016).
Jayasinghe, T. N., Chiavaroli, V., Holland, D. J., Cutfield, W. S. & O'Sullivan, J. M. The new era of treatment for obesity and metabolic disorders: evidence and expectations for gut microbiome transplantation. Front. Cell. Infect. Microbiol. 6, 15 (2016).
This study uses chemogenetics to show that GLP-1 released from nucleus of the tractus solitarius neurons reduces highly palatable food intake by suppressing mesolimbic DA signalling.
Engen, P. A., Green, S. J., Voigt, R. M., Forsyth, C. B. & Keshavarzian, A. The gastrointestinal microbiome: alcohol effects on the composition of intestinal microbiota. Alcohol Res. 37, 223–236 (2015).
This review discusses the bidirectional interactions between energy homeostasis signals and neural circuits that control motivation and food intake, with a focus on the activity of specific cell types in these networks.
Kiraly, D. D. et al. Alterations of the host microbiome affect behavioral responses to cocaine. Sci. Rep. 6, 35455 (2016).
Wang, X. F. et al. Endogenous glucagon-like peptide-1 suppresses high-fat food intake by reducing synaptic drive onto mesolimbic dopamine neurons. Cell Rep. 12, 726–733 (2015).
Ferrario, C. R. et al. Homeostasis meets motivation in the battle to control food intake. J. Neurosci. 36, 11469–11481 (2016).
Hommel, J. D. et al. Leptin receptor signaling in midbrain dopamine neurons regulates feeding. Neuron 51, 801–810 (2006).
Figlewicz, D. P., Evans, S. B., Murphy, J., Hoen, M. & Baskin, D. G. Expression of receptors for insulin and leptin in the ventral tegmental area/substantia nigra (VTA/SN) of the rat. Brain Res. 964, 107–115 (2003).
Labouebe, G. et al. Insulin induces long-term depression of ventral tegmental area dopamine neurons via endocannabinoids. Nat. Neurosci. 16, 300–308 (2013).
Skibicka, K. P., Hansson, C., Alvarez-Crespo, M., Friberg, P. A. & Dickson, S. L. Ghrelin directly targets the ventral tegmental area to increase food motivation. Neuroscience 180, 129–137 (2011).
This study uses optogenetics to investigate the role of GABAergic neurons in the lateral habenula VTA axis and documents that these neurons upregulate dopamine release in the nucleus accumbens by inhibiting local VTA GABAergic neurons; this finding is crucial for understanding how lateral habenula GABAergic cells increase the motivational salience of a stimulus.
Hahn, J. D. & Swanson, L. W. Distinct patterns of neuronal inputs and outputs of the juxtaparaventricular and suprafornical regions of the lateral hypothalamic area in the male rat. Brain Res. Rev. 64, 14–103 (2010).
Bonnavion, P., Mickelsen, L. E., Fujita, A., de Lecea, L. & Jackson, A. C. Hubs and spokes of the lateral hypothalamus: cell types, circuits and behaviour. J. Physiol. 594, 6443–6462 (2016).
Nieh, E. H. et al. Inhibitory input from the lateral hypothalamus to the ventral tegmental area disinhibits dopamine neurons and promotes behavioral activation. Neuron 90, 1286–1298 (2016).
Borgland, S. L., Storm, E. & Bonci, A. Orexin B/hypocretin 2 increases glutamatergic transmission to ventral tegmental area neurons. Eur. J. Neurosci. 28, 1545–1556 (2008).
Leinninger, G. M. et al. Leptin action via neurotensin neurons controls orexin, the mesolimbic dopamine system and energy balance. Cell Metab. 14, 313–323 (2011).
Kempadoo, K. A. et al. Hypothalamic neurotensin projections promote reward by enhancing glutamate transmission in the VTA. J. Neurosci. 33, 7618–7626 (2013).
Harris, G. C. & Aston-Jones, G. Arousal and reward: a dichotomy in orexin function. Trends Neurosci. 29, 571–577 (2006).
Baimel, C. et al. Orexin/hypocretin role in reward: implications for opioid and other addictions. Br. J. Pharmacol. 172, 334–348 (2015).
Sakurai, T. et al. Orexins and orexin receptors: a family of hypothalamic neuropeptides and G protein-coupled receptors that regulate feeding behavior. Cell 92, 573–585 (1998).
Sheng, Z., Santiago, A. M., Thomas, M. P. & Routh, V. H. Metabolic regulation of lateral hypothalamic glucose-inhibited orexin neurons may influence midbrain reward neurocircuitry. Mol. Cell Neurosci. 62, 30–41 (2014).
Cone, R. D. Anatomy and regulation of the central melanocortin system. Nat. Neurosci. 8, 571–578 (2005).
Pandit, R. et al. Melanocortin 3 receptor signaling in midbrain dopamine neurons increases the motivation for food reward. Neuropsychopharmacology 41, 2241–2251 (2016).
Cansell, C., Denis, R. G., Joly-Amado, A., Castel, J. & Luquet, S. Arcuate AgRP neurons and the regulation of energy balance. Front. Endocrinol. 3, 169 (2012).
Atasoy, D., Betley, J. N., Su, H. H. & Sternson, S. M. Deconstruction of a neural circuit for hunger. Nature 488, 172–177 (2012).
Fan, W., Boston, B. A., Kesterson, R. A., Hruby, V. J. & Cone, R. D. Role of melanocortinergic neurons in feeding and the agouti obesity syndrome. Nature 385, 165–168 (1997).
Baver, S. B. et al. Leptin modulates the intrinsic excitability of AgRP/NPY neurons in the arcuate nucleus of the hypothalamus. J. Neurosci. 34, 5486–5496 (2014).
Wang, Q. et al. Arcuate AgRP neurons mediate orexigenic and glucoregulatory actions of ghrelin. Mol. Metab. 3, 64–72 (2014).
Shen, M., Jiang, C., Liu, P., Wang, F. & Ma, L. Mesolimbic leptin signaling negatively regulates cocaine-conditioned reward. Transl Psychiatry 6, e972 (2016).
You, Z. B. et al. Reciprocal inhibitory interactions between the reward-related effects of leptin and cocaine. Neuropsychopharmacology 41, 1024–1033 (2016).
Pfaffly, J. et al. Leptin increases striatal dopamine D2 receptor binding in leptin-deficient obese (ob/ob) mice. Synapse 64, 503–510 (2010).
Kiefer, F. et al. Leptin: a modulator of alcohol craving? Biol. Psychiatry 49, 782–787 (2001).
Aguiar-Nemer, A. S., Toffolo, M. C., da Silva, C. J., Laranjeira, R. & Silva-Fonseca, V. A. Leptin influence in craving and relapse of alcoholics and smokers. J. Clin. Med. Res. 5, 164–167 (2013).
Reddy, I. A., Stanwood, G. D. & Galli, A. Moving beyond energy homeostasis: new roles for glucagon-like peptide-1 in food and drug reward. Neurochem. Int. 73, 49–55 (2014).
Sorensen, G. et al. The glucagon-like peptide 1 (GLP-1) receptor agonist exendin-4 reduces cocaine self-administration in mice. Physiol. Behav. 149, 262–268 (2015).
Engel, J. A. & Jerlhag, E. Role of appetite-regulating peptides in the pathophysiology of addiction: implications for pharmacotherapy. CNS Drugs 28, 875–886 (2014).
al'Absi, M., Lemieux, A. & Nakajima, M. Peptide YY and ghrelin predict craving and risk for relapse in abstinent smokers. Psychoneuroendocrinology 49, 253–259 (2014).
Jiang, H., Betancourt, L. & Smith, R. G. Ghrelin amplifies dopamine signaling by cross talk involving formation of growth hormone secretagogue receptor/dopamine receptor subtype 1 heterodimers. Mol. Endocrinol. 20, 1772–1785 (2006).
Kern, A., Albarran-Zeckler, R., Walsh, H. E. & Smith, R. G. Apo-ghrelin receptor forms heteromers with DRD2 in hypothalamic neurons and is essential for anorexigenic effects of DRD2 agonism. Neuron 73, 317–332 (2012).
Fetissov, S. O. Role of the gut microbiota in host appetite control: bacterial growth to animal feeding behaviour. Nat. Rev. Endocrinol. 13, 11–25 (2017).
Tremaroli, V. & Backhed, F. Functional interactions between the gut microbiota and host metabolism. Nature 489, 242–249 (2012).
Proctor, C., Thiennimitr, P., Chattipakorn, N. & Chattipakorn, S. C. Diet, gut microbiota and cognition. Metab. Brain Dis. 32, 1–17 (2017).
Zheng, P. et al. Gut microbiome remodeling induces depressive-like behaviors through a pathway mediated by the host's metabolism. Mol. Psychiatry 21, 786–796 (2016).
Lobo, M. K. et al. Cell type-specific loss of BDNF signaling mimics optogenetic control of cocaine reward. Science 330, 385–390 (2010).
Wolf, M. E. Regulation of AMPA receptor trafficking in the nucleus accumbens by dopamine and cocaine. Neurotox. Res. 18, 393–409 (2010).
al'Absi, M. et al. Circulating leptin levels are associated with increased craving to smoke in abstinent smokers. Pharmacol. Biochem. Behav. 97, 509–513 (2011).
Kiefer, F. et al. Increasing leptin precedes craving and relapse during pharmacological abstinence maintenance treatment of alcoholism. J. Psychiatr. Res. 39, 545–551 (2005).
von der Goltz, C. et al. Orexin and leptin are associated with nicotine craving: a link between smoking, appetite and reward. Psychoneuroendocrinology 35, 570–577 (2010).
Kraus, T. et al. Leptin is associated with craving in females with alcoholism. Addict. Biol. 9, 213–219 (2004).
Hillemacher, T. et al. Alteration of prolactin serum levels during alcohol withdrawal correlates with craving in female patients. Addict. Biol. 10, 337–343 (2005).
Wilhelm, J. et al. Prolactin serum levels during alcohol withdrawal are associated with the severity of alcohol dependence and withdrawal symptoms. Alcohol. Clin. Exp. Res. 35, 235–239 (2011).
Drazen, D. L., Vahl, T. P., D'Alessio, D. A., Seeley, R. J. & Woods, S. C. Effects of a fixed meal pattern on ghrelin secretion: evidence for a learned response independent of nutrient status. Endocrinology 147, 23–30 (2006).
Hong, S. I. et al. Phentermine induces conditioned rewarding effects via activation of the PI3K/Akt signaling pathway in the nucleus accumbens. Psychopharmacology 233, 1405–1413 (2016).
Rothman, R. B., Elmer, G. I., Shippenberg, T. S., Rea, W. & Baumann, M. H. Phentermine and fenfluramine. Preclinical studies in animal models of cocaine addiction. Ann. NY Acad. Sci. 844, 59–74 (1998).
Higgins, G. A., Sellers, E. M. & Fletcher, P. J. From obesity to substance abuse: therapeutic opportunities for 5-HT2C receptor agonists. Trends Pharmacol. Sci. 34, 560–570 (2013).
Schiffer, W. K. et al. Topiramate selectively attenuates nicotine-induced increases in monoamine release. Synapse 42, 196–198 (2001).
Arenas, M. C. et al. Topiramate increases the rewarding properties of cocaine in young-adult mice limiting its clinical usefulness. Psychopharmacology 233, 3849–3859 (2016).
Valenta, J. P. et al. μ-Opioid receptors in the stimulation of mesolimbic dopamine activity by ethanol and morphine in Long-Evans rats: a delayed effect of ethanol. Psychopharmacology 228, 389–400 (2013).
Ascher, J. A. et al. Bupropion: a review of its mechanism of antidepressant activity. J. Clin. Psychiatry 56, 395–401 (1995).
Fava, M. et al. 15 years of clinical experience with bupropion HCl: from bupropion to bupropion SR to bupropion XL. Prim. Care Companion J. Clin. Psychiatry 7, 106–113 (2005).
Aboujaoude, E. & Salame, W. O. Naltrexone: a pan-addiction treatment? CNS Drugs 30, 719–733 (2016).
Cabrera, E. A. et al. Neuroimaging the effectiveness of substance use disorder treatments. J. Neuroimmune Pharmacol. 11, 408–433 (2016).
Fortin, S. M. & Roitman, M. F. Central GLP-1 receptor activation modulates cocaine-evoked phasic dopamine signaling in the nucleus accumbens core. Physiol. Behav. 176, 17–25 (2017).
Reddy, I. A. et al. Glucagon-like peptide 1 receptor activation regulates cocaine actions and dopamine homeostasis in the lateral septum by decreasing arachidonic acid levels. Transl Psychiatry 6, e809 (2016).
Sorensen, G., Caine, S. B. & Thomsen, M. Effects of the GLP-1 agonist exendin-4 on intravenous ethanol self-administration in mice. Alcohol. Clin. Exp. Res. 40, 2247–2252 (2016).
Fink-Jensen, A. & Vilsboll, T. Glucagon-like peptide-1 (GLP-1) analogues: a potential new treatment for alcohol use disorder? Nord. J. Psychiatry 70, 561–562 (2016).