Critical features of human addiction are increasingly being incorporated into complementary animal models, including escalation of drug intake, punished drug seeking and taking, intermittent drug access, choice between drug and non-drug rewards, and assessment of individual differences based on criteria in the fourth edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-IV). Combined with new technologies, these models advanced our understanding of brain mechanisms of drug self-administration and relapse, but these mechanistic gains have not led to improvements in addiction treatment. This problem is not unique to addiction neuroscience, but it is an increasing source of disappointment and calls to regroup. Here we first summarize behavioural and neurobiological results from the animal models mentioned above. We then propose a reverse translational approach, whose goal is to develop models that mimic successful treatments: opioid agonist maintenance, contingency management and the community-reinforcement approach. These reverse-translated ‘treatments’ may provide an ecologically relevant platform from which to discover new circuits, test new medications and improve translation.
Subscribe to Journal
Get full journal access for 1 year
only $21.58 per issue
All prices are NET prices.
VAT will be added later in the checkout.
Rent or Buy article
Get time limited or full article access on ReadCube.
All prices are NET prices.
Association, A. P. Diagnostic and Statistical Manual of Mental Disorders: DSM-5. (American Psychiatric Association Publishing Incorporated, 2013).
Carvalho, A. F., Heilig, M., Perez, A., Probst, C. & Rehm, J. Alcohol use disorders. Lancet 394, 781–792 (2019).
Volkow, N. D. & Collins, F. S. The role of science in addressing the opioid crisis. N. Engl. J. Med. 377, 391–394 (2017).
Volkow, N. D. Stigma and the toll of addiction. N. Engl. J. Med. 382, 1289–1290 (2020).
Heilig, M., Epstein, D. H., Nader, M. A. & Shaham, Y. Time to connect: bringing social context into addiction neuroscience. Nat. Rev. Neurosci. 17, 592–599 (2016).
Pickard, H. Responsibility without blame for addiction. Neuroethics 10, 169–180 (2017).
Pickard, H. The purpose in chronic addiction. AJOB Neurosci. 3, 40–49 (2012).
Leshner, A. I. Addiction is a brain disease, and it matters. Science 278, 45–47 (1997). An influential opinion piece that popularized the notion of addiction as a brain disease.
Nestler, E. J. & Aghajanian, G. K. Molecular and cellular basis of addiction. Science 278, 58–63 (1997).
Koob, G. F. & Le Moal, M. Drug abuse: hedonic homeostatic dysregulation. Science 278, 52–58 (1997).
Steketee, J. D. & Kalivas, P. W. Drug wanting: behavioral sensitization and relapse to drug-seeking behavior. Pharmacol. Rev. 63, 348–365 (2011).
Russo, S. J. et al. The addicted synapse: mechanisms of synaptic and structural plasticity in nucleus accumbens. Trends Neurosci. 33, 267–276 (2010).
Koob, G. F. Neurobiology of opioid addiction: opponent process, hyperkatifeia, and negative reinforcement. Biol. Psychiatry 87, 44–53 (2020).
Jaramillo, A. A. et al. Functional role for suppression of the insular-striatal circuit in modulating interoceptive effects of alcohol. Addict. Biol. 23, 1020–1031 (2018).
Wise, R. A. & Koob, G. F. The development and maintenance of drug addiction. Neuropsychopharmacology 39, 254–262 (2014).
Jonkman, S. & Kenny, P. J. Molecular, cellular, and structural mechanisms of cocaine addiction: a key role for microRNAs. Neuropsychopharmacology 38, 198–211 (2013).
Peters, J., Kalivas, P. W. & Quirk, G. J. Extinction circuits for fear and addiction overlap in prefrontal cortex. Learn. Mem. 16, 279–288 (2009).
McNally, G. P. Extinction of drug seeking: neural circuits and approaches to augmentation. Neuropharmacology 76, 528–532 (2014).
Bossert, J. M., Marchant, N. J., Calu, D. J. & Shaham, Y. The reinstatement model of drug relapse: recent neurobiological findings, emerging research topics, and translational research. Psychopharmacology 229, 453–476 (2013).
Dong, Y., Taylor, J. R., Wolf, M. E. & Shaham, Y. Circuit and synaptic plasticity mechanisms of drug relapse. J. Neurosci. 37, 10867–10876 (2017).
Epstein, D. H., Heilig, M. & Shaham, Y. Science-based actions can help address the opioid crisis. Trends Pharmacol. Sci. 39, 911–916 (2018).
Nestler, E. J. & Hyman, S. E. Animal models of neuropsychiatric disorders. Nat. Neurosci. 13, 1161–1169 (2010).
Ahmed, S. H. Validation crisis in animal models of drug addiction: beyond non-disordered drug use toward drug addiction. Neurosci. Biobehav. Rev. 35, 172–184 (2010).
Field, M. & Kersbergen, I. Are animal models of addiction useful? Addiction 115, 6–12 (2020).
Ahmed, S. H. & Koob, G. F. Transition from moderate to excessive drug intake: change in hedonic set point. Science 282, 298–300 (1998). An influential article that introduces the escalation model currently used by numerous researchers.
Katz, J. L. & Higgins, S. T. The validity of the reinstatement model of craving and relapse to drug use. Psychopharmacology 168, 21–30 (2003).
Venniro, M., Caprioli, D. & Shaham, Y. Animal models of drug relapse and craving: from drug priming-induced reinstatement to incubation of craving after voluntary abstinence. Prog. Brain Res. 224, 25–52 (2016).
Epstein, D. H. & Preston, K. L. The reinstatement model and relapse prevention: a clinical perspective. Psychopharmacology 168, 31–41 (2003).
Markou, A. et al. Animal models of drug craving. Psychopharmacology 112, 163–182 (1993).
Sarter, M. & Bruno, J. P. in Biolotical Psychiatry (eds H. D’haenen, J.A. den Boer & Willner, P.) 1-8 (Johns Willey & Sons Ltd., 2002).
Sorge, R. E., Rajabi, H. & Stewart, J. Rats maintained chronically on buprenorphine show reduced heroin and cocaine seeking in tests of extinction and drug-induced reinstatement. Neuropsychopharmacology 30, 1681–1692 (2005).
Leri, F., Tremblay, A., Sorge, R. E. & Stewart, J. Methadone maintenance reduces heroin- and cocaine-induced relapse without affecting stress-induced relapse in a rodent model of poly-drug use. Neuropsychopharmacology 29, 1312–1320 (2004).
Spanagel, R. Alcoholism: a systems approach from molecular physiology to addictive behavior. Physiol.Rev. 89, 649–705 (2009).
Jorenby, D. E. et al. Efficacy of varenicline, an alpha4beta2 nicotinic acetylcholine receptor partial agonist, vs placebo or sustained-release bupropion for smoking cessation: a randomized controlled trial. JAMA 296, 56–63 (2006).
Jonas, D. E. et al. Pharmacotherapy for adults with alcohol use disorders in outpatient settings: a systematic review and meta-analysis. JAMA 311, 1889–1900 (2014).
Banks, M. L. & Negus, S. S. Insights from preclinical choice models on treating drug addiction. Trends Pharmacol. Sci. 38, 181–194 (2017).
Vanderschuren, L. J. M., Minnaard, A. M., Smeets, J. A. S. & Lesscher, H. M. B. Punishment models of addictive behavior. Cur Opin. Behav. Sci. 13, 77–84 (2017).
Kawa, A. B., Allain, F., Robinson, T. E. & Samaha, A. N. The transition to cocaine addiction: the importance of pharmacokinetics for preclinical models. Psychopharmacology 236, 1145–1157 (2019).
Ahmed, S. H. Trying to make sense of rodents’ drug choice behavior. Prog. Neuropsychopharmacol. Biol. Psychiatry 87, 3–10 (2018).
Deroche-Gamonet, V. & Piazza, P. V. Psychobiology of cocaine addiction: contribution of a multi-symptomatic animal model of loss of control. Neuropharmacology 76 Pt B, 437–449 (2014).
Perry, W. et al. A reverse-translational study of dysfunctional exploration in psychiatric disorders: from mice to men. Arch. Gen. Psychiatry 66, 1072–1080 (2009).
Bossert, J. M. et al. In a rat model of opioid maintenance, the G protein-biased mu opioid receptor agonist TRV130 decreases relapse to oxycodone seeking and taking and prevents oxycodone-induced brain hypoxia. Biol. Psychiatry https://doi.org/10.1016/j.biopsych.2020.02.014 (2020). A recent article where the authors use an animal model of opioid maintenance as a platform to identify new opioid agonist-based treatments.
Caprioli, D. et al. Effect of the novel positive allosteric modulator of metabotropic glutamate receptor 2 AZD8529 on incubation of methamphetamine craving after prolonged voluntary abstinence in a rat model. Biol. Psychiatry 78, 463–473 (2015). An article where the authors modify the classic food versus drug choice model to study relapse after contingency management (food choice-induced voluntary abstinence).
Venniro, M. et al. Volitional social interaction prevents drug addiction in rat models. Nat. Neurosci. 21, 1520–1529 (2018). A recent article where the authors show that rats trained to self-administer heroin or methamphetamine using gold standard addiction models strongly prefer operant social interaction over the drugs.
Deneau, G., Yanagita, T. & Seevers, M. H. Self-administration of psychoactive substances by the monkey. Psychopharmacologia 16, 30–48 (1969). A seminal early article demonstrating binge-like cocaine self-administration in a non-human primate model.
Yokel, R. A. & Pickens, R. Self-administration of optical isomers of amphetamine and methylamphetamine by rats. J. Pharmacol. Exp. Ther. 187, 27–33 (1973).
Johanson, C. E., Balster, R. L. & Bonese, K. Self-administration of psychomotor stimulant drugs: the effects of unlimited access. Pharmacol. Biochem. Behav. 4, 45–51 (1976).
Bozarth, M. A. & Wise, R. A. Toxicity associated with long-term intravenous heroin and cocaine self- administration in the rat. J. Am. Med. Assoc. 254, 81–83 (1985).
Badiani, A., Belin, D., Epstein, D., Calu, D. & Shaham, Y. Opiate versus psychostimulant addiction: the differences do matter. Nat. Rev. Neurosci. 12, 685–700 (2011).
Heilig, M. & Koob, G. F. A key role for corticotropin-releasing factor in alcohol dependence. Trends Neurosci. 30, 399–406 (2007).
Tornatzky, W. & Miczek, K. A. Cocaine self-administration “binges”: transition from behavioral and autonomic regulation toward homeostatic dysregulation in rats. Psychopharmacology 148, 289–298 (2000).
Zernig, G. et al. Explaining the escalation of drug use in substance dependence: models and appropriate animal laboratory tests. Pharmacology 80, 65–119 (2007).
Vanderschuren, L. J. & Ahmed, S. H. Animal studies of addictive behavior. Cold Spring Harb. Perspect. Med. 3, a011932 (2013).
Pelloux, Y., Everitt, B. J. & Dickinson, A. Compulsive drug seeking by rats under punishment: effects of drug taking history. Psychopharmacology 194, 127–137 (2007).
Mantsch, J. R., Baker, D. A., Funk, D., Le, A. D. & Shaham, Y. Stress-induced reinstatement of drug seeking: 20 years of progress. Neuropsychopharmacology 41, 335–356 (2016).
Koob, G. F. A role for brain stress systems in addiction. Neuron 59, 11–34 (2008).
Wee, S. & Koob, G. F. The role of the dynorphin-kappa opioid system in the reinforcing effects of drugs of abuse. Psychopharmacology 210, 121–135 (2010).
Grieder, T. E. et al. VTA CRF neurons mediate the aversive effects of nicotine withdrawal and promote intake escalation. Nat. Neurosci. 17, 1751–1758 (2014).
Schlosburg, J. E. et al. Long-term antagonism of kappa opioid receptors prevents escalation of and increased motivation for heroin intake. J. Neurosci. 33, 19384–19392 (2013).
Schmeichel, B. E., Herman, M. A., Roberto, M. & Koob, G. F. Hypocretin neurotransmission within the central amygdala mediates escalated cocaine self-administration and stress-induced reinstatement in rats. Biol. Psychiatry 81, 606–615 (2017).
Kallupi, M. et al. Nociceptin attenuates the escalation of oxycodone self-administration by normalizing CeA-GABA transmission in highly addicted rats. Proc. Natl Acad. Sci. USA 117, 2140–2148 (2020).
Funk, C. K., O’Dell, L. E., Crawford, E. F. & Koob, G. F. Corticotropin-releasing factor within the central nucleus of the amygdala mediates enhanced ethanol self-administration in withdrawn, ethanol-dependent rats. J. Neurosci. 26, 11324–11332 (2006).
Hollander, J. A. et al. Striatal microRNA controls cocaine intake through CREB signalling. Nature 466, 197–202 (2010).
Im, H. I., Hollander, J. A., Bali, P. & Kenny, P. J. MeCP2 controls BDNF expression and cocaine intake through homeostatic interactions with microRNA-212. Nat. Neurosci. 13, 1120–1127 (2010).
Ahmed, S. H. et al. Gene expression evidence for remodeling of lateral hypothalamic circuitry in cocaine addiction. Proc. Natl Acad. Sci. USA 102, 11533–11538 (2005).
Ben-Shahar, O. et al. Extended daily access to cocaine results in distinct alterations in Homer 1b/c and NMDA receptor subunit expression within the medial prefrontal cortex. Synapse 63, 598–609 (2009).
Calipari, E. S., Ferris, M. J. & Jones, S. R. Extended access of cocaine self-administration results in tolerance to the dopamine-elevating and locomotor-stimulating effects of cocaine. J. Neurochem. 128, 224–232 (2014).
Willuhn, I., Burgeno, L. M., Groblewski, P. A. & Phillips, P. E. Excessive cocaine use results from decreased phasic dopamine signaling in the striatum. Nat. Neurosci. 17, 704–709 (2014).
Reed, B., Butelman, E. R., Fry, R. S., Kimani, R. & Kreek, M. J. Repeated administration of opra kappa (LY2456302), a novel, short-acting, selective KOP-r antagonist, in persons with and without cocaine dependence. Neuropsychopharmacology 43, 739–750 (2018).
Banks, M. L. The rise and fall of kappa-opioid receptors in drug abuse research. Handb. Exp. Pharmacol. 258, 147–165 (2019).
Kwako, L. E. et al. The corticotropin releasing hormone-1 (CRH1) receptor antagonist pexacerfont in alcohol dependence: a randomized controlled experimental medicine study. Neuropsychopharmacology 40, 1053–1063 (2015). A study, together with that of Schwandt et al. (2016), that shows lack of efficacy of a CRFR1 antagonist (a major target for addiction treatment on the basis of results from animal models since the 1990s) in human laboratory studies.
Schwandt, M. L. et al. The CRF1 antagonist verucerfont in anxious alcohol-dependent women: Translation of neuroendocrine, but not of anti-craving effects. Neuropsychopharmacology 41, 2818–2829 (2016).
Shaham, Y. & de Wit, H. Lost in translation: CRF1 receptor antagonists and addiction treatment. Neuropsychopharmacology 41, 2795–2797 (2016).
Deroche-Gamonet, V. et al. The glucocorticoid receptor as a potential target to reduce cocaine abuse. J. Neurosci. 23, 4785–4790 (2003).
Mantsch, J. R. et al. Surgical adrenalectomy with diurnal corticosterone replacement slows escalation and prevents the augmentation of cocaine-induced reinstatement in rats self-administering cocaine under long-access conditions. Neuropsychopharmacology 33, 814–826 (2008).
Vendruscolo, L. F. et al. Glucocorticoid receptor antagonism decreases alcohol seeking in alcohol-dependent individuals. J. Clin. Invest. 125, 3193–3197 (2015). A rare example of a potential successful forward translation (see Vendruscolo et al. (2012)) showing the efficacy of a glucocorticoid receptor antagonist in both an animal model and a clinical study.
Vendruscolo, L. F. et al. Corticosteroid-dependent plasticity mediates compulsive alcohol drinking in rats. J. Neurosci. 32, 7563–7571 (2012).
Roberts, D. C., Brebner, K., Vincler, M. & Lynch, W. J. Patterns of cocaine self-administration in rats produced by various access conditions under a discrete trials procedure. Drug Alcohol Depend. 67, 291–299 (2002).
Zimmer, B. A., Oleson, E. B. & Roberts, D. C. The motivation to self-administer is increased after a history of spiking brain levels of cocaine. Neuropsychopharmacology 37, 1901–1910 (2012). An important study introducing the increasingly popular intermittent drug access animal model of addiction.
Allain, F., Minogianis, E. A., Roberts, D. C. & Samaha, A. N. How fast and how often: the pharmacokinetics of drug use are decisive in addiction. Neurosci. Biobehav. Rev. 56, 166–179 (2015).
Kawa, A. B., Valenta, A. C., Kennedy, R. T. & Robinson, T. E. Incentive and dopamine sensitization produced by intermittent but not long access cocaine self-administration. Eur. J. Neurosci. 50, 2663–2682 (2019).
Xue, Y., Steketee, J. D. & Sun, W. Inactivation of the central nucleus of the amygdala reduces the effect of punishment on cocaine self-administration in rats. Eur. J. Neurosci. 35, 775–783 (2012).
Kawa, A. B., Bentzley, B. S. & Robinson, T. E. Less is more: prolonged intermittent access cocaine self-administration produces incentive-sensitization and addiction-like behavior. Psychopharmacology 233, 3587–3602 (2016).
Hao, Y., Martin-Fardon, R. & Weiss, F. Behavioral and functional evidence of metabotropic glutamate receptor 2/3 and metabotropic glutamate receptor 5 dysregulation in cocaine-escalated rats: factor in the transition to dependence. Biol. Psychiatry 68, 240–248 (2010).
Allain, F., Roberts, D. C. S., Levesque, D. & Samaha, A. N. Intermittent intake of rapid cocaine injections promotes robust psychomotor sensitization, increased incentive motivation for the drug and mGlu2/3 receptor dysregulation. Neuropharmacology 117, 227–237 (2017).
James, M. H. et al. Increased number and activity of a lateral subpopulation of hypothalamic orexin/hypocretin neurons underlies the expression of an addicted state in rats. Biol. Psychiatry 85, 925–935 (2019).
Nicolas, C. et al. Incubation of cocaine craving after intermittent-access self-administration: sex differences and estrous cycle. Biol. Psychiatry 85, 915–924 (2019).
Calipari, E. S., Ferris, M. J., Zimmer, B. A., Roberts, D. C. & Jones, S. R. Temporal pattern of cocaine intake determines tolerance vs sensitization of cocaine effects at the dopamine transporter. Neuropsychopharmacology 38, 2385–2392 (2013).
James, I. E. et al. A first time in human clinical study with TRV734, an orally bioavailable G-protein-biased ligand at the μ-opioid receptor. Clin. Pharmacol. Drug Dev. 9, 256–266 (2019).
O’Neal, T. J., Nooney, M. N., Thien, K. & Ferguson, S. M. Chemogenetic modulation of accumbens direct or indirect pathways bidirectionally alters reinstatement of heroin-seeking in high- but not low-risk rats. Neuropsychopharmacology 45, 1251–1262 (2019).
Bentzley, B. S., Fender, K. M. & Aston-Jones, G. The behavioral economics of drug self-administration: a review and new analytical approach for within-session procedures. Psychopharmacology 226, 113–125 (2013).
Mohammadkhani, A. et al. Orexin-1 receptor signaling in ventral pallidum regulates motivation for the opioid remifentanil. J. Neurosci. 39, 9831–9840 (2019).
Townsend, E. A., Negus, S. S., Caine, S. B., Thomsen, M. & Banks, M. L. Sex differences in opioid reinforcement under a fentanyl vs. food choice procedure in rats. Neuropsychopharmacology 44, 2022–2029 (2019).
Fragale, J. E., Pantazis, C. B., James, M. H. & Aston-Jones, G. The role of orexin-1 receptor signaling in demand for the opioid fentanyl. Neuropsychopharmacology 44, 1690–1697 (2019).
Goldberg, S. R. Stimuli associated with drug injections as events that control behavior. Pharmacol. Rev. 27, 325–340 (1975).
Goldberg, S. R. Comparable behavior maintained under fixed-ratio and second-order schedules of food presentation, cocaine injection or d-amphetamine injection in the squirrel monkey. J. Pharmacol. Exp. Ther. 186, 18–30 (1973).
Whitelaw, R. B., Markou, A., Robbins, T. W. & Everitt, B. J. Excitotoxic lesions of the basolateral amygdala impair the acquisition of cocaine-seeking behaviour under a second-order schedule of reinforcement. Psychopharmacology 127, 213–224 (1996).
Weissenborn, R., Robbins, T. W. & Everitt, B. J. Effects of medial prefrontal or anterior cingulate cortex lesions on responding for cocaine under fixed-ratio and second-order schedules of reinforcement in rats. Psychopharmacology 134, 242–257 (1997).
Wise, R. A. et al. Fluctuations in nucleus accumbens dopamine concentration during intravenous cocaine self-administration in rats. Psychopharmacology 120, 10–20 (1995).
Ito, R., Dalley, J. W., Howes, S. R., Robbins, T. W. & Everitt, B. J. Dissociation in conditioned dopamine release in the nucleus accumbens core and shell in response to cocaine cues and during cocaine-seeking behavior in rats. J. Neurosci. 20, 7489–7495 (2000).
Ito, R., Dalley, J. W., Robbins, T. W. & Everitt, B. J. Dopamine release in the dorsal striatum during cocaine-seeking behavior under the control of a drug-associated cue. J. Neurosci. 22, 6247–6253 (2002).
Ito, R., Robbins, T. W. & Everitt, B. J. Differential control over cocaine-seeking behavior by nucleus accumbens core and shell. Nat. Neurosci. 7, 389–397 (2004).
Hutcheson, D. M., Parkinson, J. A., Robbins, T. W. & Everitt, B. J. The effects of nucleus accumbens core and shell lesions on intravenous heroin self-administration and the acquisition of drug-seeking behaviour under a second-order schedule of heroin reinforcement. Psychopharmacology 153, 464–472 (2001).
Di Ciano, P. & Everitt, B. J. Direct interactions between the basolateral amygdala and nucleus accumbens core underlie cocaine-seeking behavior by rats. J. Neurosci. 24, 7167–7173 (2004).
Di Ciano, P. & Everitt, B. J. Contribution of the ventral tegmental area to cocaine-seeking maintained by a drug-paired conditioned stimulus in rats. Eur. J. Neurosci. 19, 1661–1667 (2004).
Wise, R. A. Neurobiology of addiction. Curr. Opin. Neurobiol. 6, 243–251 (1996).
Peak, J., Hart, G. & Balleine, B. W. From learning to action: the integration of dorsal striatal input and output pathways in instrumental conditioning. Eur. J. Neurosci. 49, 658–671 (2019).
Everitt, B. J. & Robbins, T. W. Drug addiction: updating actions to habits to compulsions ten years on. Annu. Rev. Psychol. 67, 23–50 (2016).
Zapata, A., Minney, V. L. & Shippenberg, T. S. Shift from goal-directed to habitual cocaine seeking after prolonged experience in rats. J. Neurosci. 30, 15457–15463 (2010).
Hodebourg, R. et al. Heroin seeking becomes dependent on dorsal striatal dopaminergic mechanisms and can be decreased by N-acetylcysteine. Eur. J. Neurosci. 50, 2036–2044 (2019).
Giuliano, C. et al. The Novel mu-opioid receptor antagonist GSK1521498 decreases both alcohol seeking and drinking: Evidence from a new preclinical model of alcohol seeking. Neuropsychopharmacology 40, 2981–2992 (2015).
Murray, J. E., Belin, D. & Everitt, B. J. Double dissociation of the dorsomedial and dorsolateral striatal control over the acquisition and performance of cocaine seeking. Neuropsychopharmacology 37, 2456–2466 (2012).
Belin, D. & Everitt, B. J. Cocaine seeking habits depend upon dopamine-dependent serial connectivity linking the ventral with the dorsal striatum. Neuron 57, 432–441 (2008).
Murray, J. E. et al. Basolateral and central amygdala differentially recruit and maintain dorsolateral striatum-dependent cocaine-seeking habits. Nat. Commun. 6, 10088 (2015).
Lukas, S. E., Mello, N. K., Drieze, J. M. & Mendelson, J. H. Buprenorphine-induced alterations of cocaine’s reinforcing effects in rhesus monkey: a dose-response analysis. Drug Alcohol Depend. 40, 87–98 (1995).
Newman, J. L., Negus, S. S., Lozama, A., Prisinzano, T. E. & Mello, N. K. Behavioral evaluation of modafinil and the abuse-related effects of cocaine in rhesus monkeys. Exp. Clin. Psychopharmacol. 18, 395–408 (2010).
Mello, N. K., Fivel, P. A., Kohut, S. J. & Bergman, J. Effects of chronic buspirone treatment on cocaine self-administration. Neuropsychopharmacology 38, 455–467 (2013).
Winhusen, T. M. et al. Multisite, randomized, double-blind, placebo-controlled pilot clinical trial to evaluate the efficacy of buspirone as a relapse-prevention treatment for cocaine dependence. J. Clin. Psychiatry 75, 757–764 (2014).
Ling, W. et al. Buprenorphine+naloxone plus naltrexone for the treatment of cocaine dependence: the Cocaine Use Reduction with Buprenorphine (CURB) study. Addiction 111, 1416–1427 (2016).
Sangroula, D. et al. Modafinil treatment of cocaine dependence: a systematic review and meta-analysis. Subst. Use Misuse 52, 1292–1306 (2017).
Di Ciano, P., Underwood, R. J., Hagan, J. J. & Everitt, B. J. Attenuation of cue-controlled cocaine-seeking by a selective D3 dopamine receptor antagonist SB-277011-A. Neuropsychopharmacology 28, 329–338 (2003).
Pilla, M. et al. Selective inhibition of cocaine-seeking behaviour by a partial dopamine D3 receptor agonist. Nature 400, 371–375 (1999).
Le Foll, B. et al. Dopamine D3 receptor ligands for drug addiction treatment: update on recent findings. Prog. Brain Res. 211, 255–275 (2014).
Leggio, G. M., Bucolo, C., Platania, C. B., Salomone, S. & Drago, F. Current drug treatments targeting dopamine D3 receptor. Pharmacol. Ther. 165, 164–177 (2016).
Gilbert, J. G. et al. Acute administration of SB-277011A, NGB 2904, or BP 897 inhibits cocaine cue-induced reinstatement of drug-seeking behavior in rats: role of dopamine D3 receptors. Synapse 57, 17–28 (2005).
Newman, A. H., Grundt, P. & Nader, M. A. Dopamine D3 receptor partial agonists and antagonists as potential drug abuse therapeutic agents. J. Med. Chem. 48, 3663–3679 (2005).
Spragg, S. D. S. Morphine addiction in chimpanzees. Comp. Psychol. Mono 15, 132 (1940).
Griffiths, R. R., Wurster, R. M. & Brady, J. V. Discrete-trial choice procedure: effects of naloxone and methadone on choice between food and heroin. Pharmacol. Rev. 27, 357–365 (1975).
Negus, S. S. Choice between heroin and food in nondependent and heroin-dependent rhesus monkeys: effects of naloxone, buprenorphine, and methadone. J. Pharmacol. Exp. Ther. 317, 711–723 (2006). An important study demonstrating that opioid dependence and withdrawal increase heroin choice in rhesus monkeys and that this effect is reversed by opioid agonist treatment (methadone or buprenorphine).
Lenoir, M., Cantin, L., Vanhille, N., Serre, F. & Ahmed, S. H. Extended heroin access increases heroin choices over a potent nondrug alternative. Neuropsychopharmacology 38, 1209–1220 (2013).
Townsend, E. A. et al. Conjugate vaccine produces long-lasting attenuation of fentanyl vs. food choice and blocks expression of opioid withdrawal-induced increases in fentanyl choice in rats. Neuropsychopharmacology 44, 1681–1689 (2019).
Banks, M. L. & Negus, S. S. Effects of extended cocaine access and cocaine withdrawal on choice between cocaine and food in rhesus monkeys. Neuropsychopharmacology 35, 493–504 (2010).
Hutsell, B. A., Negus, S. S. & Banks, M. L. Effects of 21-day d-amphetamine and risperidone treatment on cocaine vs food choice and extended-access cocaine intake in male rhesus monkeys. Drug Alcohol Depend. 168, 36–44 (2016).
Cantin, L. et al. Cocaine is low on the value ladder of rats: possible evidence for resilience to addiction. PLoS ONE 5, e11592 (2010).
Caprioli, D., Zeric, T., Thorndike, E. B. & Venniro, M. Persistent palatable food preference in rats with a history of limited and extended access to methamphetamine self-administration. Addict. Biol. 20, 913–926 (2015).
Badiani, A. & Spagnolo, P. A. Role of environmental factors in cocaine addiction. Curr. Pharm. Des. 19, 6996–7008 (2013).
Caprioli, D. et al. Ambience and drug choice: cocaine- and heroin-taking as a function of environmental context in humans and rats. Biol. Psychiatry 65, 893–899 (2009).
Johanson, C. E. & Aigner, T. Comparison of the reinforcing properties of cocaine and procaine in rhesus monkeys. Pharmacol. Biochem. Behav. 15, 49–53 (1981).
Nader, M. A. & Woolverton, W. L. Cocaine vs. food choice in rhesus monkeys: effects of increasing the response cost for cocaine. NIDA Res. Monogr. 105, 621 (1990).
Tunstall, B. J. & Kearns, D. N. Reinstatement in a cocaine versus food choice situation: reversal of preference between drug and non-drug rewards. Addict. Biol. 19, 838–848 (2014).
Woolverton, W. L. & Anderson, K. G. Effects of delay to reinforcement on the choice between cocaine and food in rhesus monkeys. Psychopharmacology 186, 99–106 (2006).
Lenoir, M., Serre, F., Cantin, L. & Ahmed, S. H. Intense sweetness surpasses cocaine reward. PLoS ONE 2, e698 (2007). The first in a series of important studies unexpectedly showing that rats strongly prefer palatable food over addictive drugs in the drug self-administration model.
Canchy, L., Girardeau, P., Durand, A., Vouillac-Mendoza, C. & Ahmed, S. H. Pharmacokinetics trumps pharmacodynamics during cocaine choice: a reconciliation with the dopamine hypothesis of addiction. Neuropsychopharmacology https://doi.org/10.1038/s41386-020-0786-9 (2020).
Foltin, R. W. et al. Development of translational preclinical models in substance abuse: effects of cocaine administration on cocaine choice in humans and non-human primates. Pharmacol. Biochem. Behav. 134, 12–21 (2015).
Lile, J. A. et al. Pharmacological validation of a translational model of cocaine use disorder: effects of d-amphetamine maintenance on choice between intravenous cocaine and a nondrug alternative in humans and rhesus monkeys. Exp. Clin. Psychopharmacol. 28, 169–180 (2020).
Higgins, S. T., Heil, S. H. & Lussier, J. P. Clinical implications of reinforcement as a determinant of substance use disorders. Annu. Rev. Psychol. 55, 431–461 (2004).
Guillem, K. & Ahmed, S. H. Preference for cocaine is represented in the orbitofrontal cortex by an increased proportion of cocaine use-coding neurons. Cereb. Cortex 28, 819–832 (2018).
Guillem, K. & Ahmed, S. H. A neuronal population code for resemblance between drug and nondrug reward outcomes in the orbitofrontal cortex. Brain Struct. Funct. 224, 883–890 (2019).
Cameron, C. M. & Carelli, R. M. Cocaine abstinence alters nucleus accumbens firing dynamics during goal-directed behaviors for cocaine and sucrose. Eur. J. Neurosci. 35, 940–951 (2012).
Carelli, R. M., Ijames, S. G. & Crumling, A. J. Evidence that separate neural circuits in the nucleus accumbens encode cocaine versus “natural” (water and food) reward. J. Neurosci. 20, 4255–4266 (2000).
Pfarr, S. et al. Choice for drug or natural reward engages largely overlapping neuronal ensembles in the infralimbic prefrontal cortex. J. Neurosci. 38, 3507–3519 (2018).
Warren, B. L. et al. Separate vmPFC ensembles control cocaine self-administration versus extinction in rats. J. Neurosci. 39, 7394–7407 (2019).
Warren, B. L. et al. Distinct Fos-expressing neuronal ensembles in the ventromedial prefrontal cortex mediate food reward and extinction memories. J. Neurosci. 36, 6691–6703 (2016).
Augier, E. et al. A molecular mechanism for choosing alcohol over an alternative reward. Science 360, 1321–1326 (2018).
Sikora, M. et al. Generalization of effects of environmental enrichment on seeking for different classes of drugs of abuse. Behav. Brain Res. 341, 109–113 (2018).
Chauvet, C., Goldberg, S. R., Jaber, M. & Solinas, M. Effects of environmental enrichment on the incubation of cocaine craving. Neuropharmacology 63, 635–641 (2012).
Solinas, M., Chauvet, C., Thiriet, N., El Rawas, R. & Jaber, M. Reversal of cocaine addiction by environmental enrichment. Proc. Natl Acad. Sci. USA 105, 17145–17150 (2008).
Zlebnik, N. E. & Carroll, M. E. Prevention of the incubation of cocaine seeking by aerobic exercise in female rats. Psychopharmacology 232, 3507–3513 (2015).
Zlebnik, N. E., Anker, J. J. & Carroll, M. E. Exercise to reduce the escalation of cocaine self-administration in adolescent and adult rats. Psychopharmacology 224, 387–400 (2012).
Zernig, G., Kummer, K. K. & Prast, J. M. Dyadic social interaction as an alternative reward to cocaine. Front. Psychiatry 4, 100 (2013).
Higgins, S. T. et al. A behavioral approach to achieving initial cocaine abstinence. Am. J. Psychiatry 148, 1218–1224 (1991).
Townsend, E. A., Negus, S. S., Poklis, J. L. & Banks, M. L. Lorcaserin maintenance fails to attenuate heroin vs. food choice in rhesus monkeys. Drug Alcohol Depend. 208, 107848 (2020).
Brandt, L. et al. Effects of lorcaserin on oxycodone self-administration and subjective responses in participants with opioid use disorder. Drug Alcohol Depend. 208, 107859 (2020).
Luscher, C., Robbins, T. W. & Everitt, B. J. The transition to compulsion in addiction. Nat. Rev. Neurosci. 21, 247–263 (2020).
Smith, S. G. & Davis, W. M. Punishment of amphetamine and morphine self-administration behavior. Psychol. Rec. 24, 477–480 (1974).
Wolffgramm, J. & Heyne, A. From controlled drug intake to loss of control: the irreversible development of drug addiction in the rat. Behav. Brain Res. 70, 77–94 (1995). An important early review of the authors’ efforts to develop animal models of compulsive drug use and loss of control.
Holtz, N. A. & Carroll, M. E. Escalation of i.v. cocaine intake in peri-adolescent vs. adult rats selectively bred for high (HiS) vs. low (LoS) saccharin intake. Psychopharmacology 227, 243–250 (2013).
Vanderschuren, L. J. & Everitt, B. J. Drug seeking becomes compulsive after prolonged cocaine self-administration. Science 305, 1017–1019 (2004).
Negus, S. S. Effects of punishment on choice between cocaine and food in rhesus monkeys. Psychopharmacology 181, 244–252 (2005).
Woolverton, W. L., Freeman, K. B., Myerson, J. & Green, L. Suppression of cocaine self-administration in monkeys: effects of delayed punishment. Psychopharmacology 220, 509–517 (2012).
Marchant, N. J., Campbell, E. J., Pelloux, Y., Bossert, J. M. & Shaham, Y. Context-induced relapse after extinction versus punishment: similarities and differences. Psychopharmacology 236, 439–448 (2019).
Jenkins, T. N., Warner, L. H. & Warden, C. J. Standard apparatus for the study of animal motivation. J. Comp. Psychol. 6, 361–382 (1926).
Panlilio, L., Thorndike, E. & Schindler, C. Reinstatement of punishment-suppressed opioid self-administration in rats: an alternative model of relapse to drug abuse. Psychopharmacology 168, 229–235 (2003).
Marchant, N. J., Khuc, T. N., Pickens, C. L., Bonci, A. & Shaham, Y. Context-induced relapse to alcohol seeking after punishment in a rat model. Biol. Psychiatry 73, 256–262 (2013).
Cooper, A., Barnea-Ygael, N., Levy, D., Shaham, Y. & Zangen, A. A conflict rat model of cue-induced relapse to cocaine seeking. Psychopharmacology 194, 117–125 (2007).
Fredriksson, I. et al. Effect of the dopamine stabilizer (-)-OSU6162 on potentiated incubation of opioid craving after electric barrier-induced voluntary abstinence. Neuropsychopharmacology 45, 770–779 (2020).
Chen, B. T. et al. Rescuing cocaine-induced prefrontal cortex hypoactivity prevents compulsive cocaine seeking. Nature 496, 359–362 (2013).
Siciliano, C. A. et al. A cortical-brainstem circuit predicts and governs compulsive alcohol drinking. Science 366, 1008–1012 (2019).
Seif, T. et al. Cortical activation of accumbens hyperpolarization-active NMDARs mediates aversion-resistant alcohol intake. Nat. Neurosci. 16, 1094–1100 (2013).
Pelloux, Y., Dilleen, R., Economidou, D., Theobald, D. & Everitt, B. J. Reduced forebrain serotonin transmission is causally involved in the development of compulsive cocaine seeking in rats. Neuropsychopharmacology 37, 2505–2514 (2012).
Pelloux, Y., Murray, J. E. & Everitt, B. J. Differential roles of the prefrontal cortical subregions and basolateral amygdala in compulsive cocaine seeking and relapse after voluntary abstinence in rats. Eur. J. Neurosci. 38, 3018–3026 (2013).
Jonkman, S., Pelloux, Y. & Everitt, B. J. Differential roles of the dorsolateral and midlateral striatum in punished cocaine seeking. J. Neurosci. 32, 4645–4650 (2012).
Hopf, F. W. & Lesscher, H. M. Rodent models for compulsive alcohol intake. Alcohol 48, 253–264 (2014).
Pascoli, V., Terrier, J., Hiver, A. & Luscher, C. Sufficiency of mesolimbic dopamine neuron stimulation for the progression to addiction. Neuron 88, 1054–1066 (2015).
Pascoli, V. et al. Stochastic synaptic plasticity underlying compulsion in a model of addiction. Nature 564, 366–371 (2018).
Krasnova, I. N. et al. Incubation of methamphetamine and palatable food craving after punishment-induced abstinence. Neuropsychopharmacology 39, 2008–2016 (2014).
Marchant, N. J. et al. Role of ventral subiculum in context-induced relapse to alcohol seeking after punishment-imposed abstinence. J. Neurosci. 36, 3281–3294 (2016).
Marchant, N. J. et al. A critical role of lateral hypothalamus in context-induced relapse to alcohol seeking after punishment-imposed abstinence. J. Neurosci. 34, 7447–7457 (2014).
Campbell, E. J. et al. Anterior insular cortex is critical for the propensity to relapse following punishment-imposed abstinence of alcohol seeking. J. Neurosci. 39, 1077–1087 (2019).
Farrell, M. R. et al. Ventral pallidum is essential for cocaine relapse after voluntary abstinence in rats. Neuropsychopharmacology 44, 2174–2185 (2019).
Pelloux, Y., Minier-Toribio, A., Hoots, J. K., Bossert, J. M. & Shaham, Y. Opposite effects of basolateral amygdala inactivation on context-induced relapse to cocaine seeking after extinction versus punishment. J. Neurosci. 38, 51–59 (2018).
Crombag, H. & Shaham, Y. Renewal of drug seeking by contextual cues after prolonged extinction in rats. Behav. Neurosci. 116, 169–173 (2002).
Saunders, B. T., Yager, L. M. & Robinson, T. E. Cue-evoked cocaine “craving”: role of dopamine in the accumbens core. J. Neurosci. 33, 13989–14000 (2013).
Pelloux, Y. et al. Context-induced relapse to cocaine seeking after punishment-imposed abstinence is associated with activation of cortical and subcortical brain regions. Addict. Biol. 23, 699–712 (2018).
Giuliano, C. et al. Evidence for a long-lasting compulsive alcohol seeking phenotype in rats. Neuropsychopharmacology 43, 728–738 (2018).
Ziauddeen, H. et al. Opioid antagonists and the A118G polymorphism in the mu-opioid receptor gene: effects of GSK1521498 and naltrexone in healthy drinkers stratified by OPRM1 genotype. Neuropsychopharmacology 41, 2647–2657 (2016).
Leggio, L., Garbutt, J. C. & Addolorato, G. Effectiveness and safety of baclofen in the treatment of alcohol dependent patients. CNS Neurol. Disord. Drug Targets 9, 33–44 (2010).
Marti-Prats, L. et al. Baclofen decreases compulsive alcohol drinking in rats characterised by reduced levels of GAT-3 in the central amygdala. Preprint at https://www.biorxiv.org/content/10.1101/2020.06.29.178236v1 (2020).
Anthony, J. C., Warner, L. A. & Kessler, R. C. Comparative epidemiology of dependence on tobacco, alcohol, controlled substances, and inhalants: basic findings from the National Comorbidity Survey. Drug Alcohol Depend. 2, 244–268 (1994).
Wikler, A. & Pescor, F. T. Classical conditioning of a morphine abstinence phenomenon, reinforcement of opioid-drinking behavior and “relapse” in morphine-addicted rats. Psychopharmacologia 10, 255–284 (1967).
Deroche-Gamonet, V., Belin, D. & Piazza, P. V. Evidence for addiction-like behavior in the rat. Science 305, 1014–1017 (2004). An important article describing the development of the conceptually influential individual differences DSM-IV rat model.
Belin, D., Mar, A. C., Dalley, J. W., Robbins, T. W. & Everitt, B. J. High impulsivity predicts the switch to compulsive cocaine-taking. Science 320, 1352–1355 (2008).
Kasanetz, F. et al. Transition to addiction is associated with a persistent impairment in synaptic plasticity. Science 328, 1709–1712 (2010).
Kasanetz, F. et al. Prefrontal synaptic markers of cocaine addiction-like behavior in rats. Mol. Psychiatry 18, 729–737 (2013).
Cannella, N. et al. The mGluR2/3 agonist LY379268 induced anti-reinstatement effects in rats exhibiting addiction-like behavior. Neuropsychopharmacology 38, 2048–2056 (2013).
Bock, R. et al. Strengthening the accumbal indirect pathway promotes resilience to compulsive cocaine use. Nat. Neurosci. 16, 632–638 (2013).
Piazza, P. V. & Deroche-Gamonet, V. A multistep general theory of transition to addiction. Psychopharmacology 229, 387–413 (2013).
Liechti, M. E. & Markou, A. Role of the glutamatergic system in nicotine dependence: implications for the discovery and development of new pharmacological smoking cessation therapies. CNS Drugs 22, 705–724 (2008).
Shaham, Y., Shalev, U., Lu, L., De Wit, H. & Stewart, J. The reinstatement model of drug relapse: history, methodology and major findings. Psychopharmacology 168, 3–20 (2003).
Dole, V. P. & Nyswander, M. A medical treatment for diacetylmorphine (heroin) addiction. A clinical trial with methadone hydrochloride. JAMA 193, 646–650 (1965).
Jasinski, D. R., Pevnick, J. S. & Griffith, J. D. Human pharmacology and abuse potential of the analgesic buprenorphine: a potential agent for treating narcotic addiction. Arch. Gen. Psychiatry 35, 501–516 (1978).
Hunt, G. M. & Azrin, N. H. A community-reinforcement approach to alcoholism. Behav. Res. Ther. 11, 91–104 (1973).
Shaham, Y., Rajabi, H. & Stewart, J. Relapse to heroin-seeking in rats under opioid maintenance: The effects of stress, heroin priming, and withdrawal. J. Neurosci. 16, 1957–1963 (1996).
Bossert, J. M. et al. Role of mu, but not delta or kappa, opioid receptors in context-induced reinstatement of oxycodone seeking. Eur. J. Neurosci. 50, 2075–2085 (2019).
DeWire, S. M. et al. A G protein-biased ligand at the mu-opioid receptor is potently analgesic with reduced gastrointestinal and respiratory dysfunction compared with morphine. J. Pharmacol. Exp. Ther. 344, 708–717 (2013).
Gillis, A. et al. Low intrinsic efficacy for G protein activation can explain the improved side effect profiles of new opioid agonists. Sci. Signal. 13, eaaz3140 (2020).
Viscusi, E. R. et al. A randomized, phase 2 study investigating TRV130, a biased ligand of the mu-opioid receptor, for the intravenous treatment of acute pain. Pain 157, 264–272 (2016).
Grabowski, J. et al. Dextroamphetamine for cocaine-dependence treatment: a double-blind randomized clinical trial. J. Clin. Psychopharmacol. 21, 522–526 (2001).
Siciliano, C. A. et al. Amphetamine reverses escalated cocaine intake via restoration of dopamine transporter conformation. J. Neurosci. 38, 484–497 (2018).
Negus, S. S. & Mello, N. K. Effects of chronic d-amphetamine treatment on cocaine- and food-maintained responding under a second-order schedule in rhesus monkeys. Drug Alcohol Depend. 70, 39–52 (2003).
Tardelli, V. S. et al. Prescription psychostimulants for the treatment of stimulant use disorder: a systematic review and meta-analysis. Psychopharmacology 237, 2233–2255 (2020).
Justinova, Z. et al. The novel metabotropic glutamate receptor 2 positive allosteric modulator, AZD8529, decreases nicotine self-administration and relapse in squirrel monkeys. Biol. Psychiatry 78, 452–462 (2015).
Venniro, M., Zhang, M., Shaham, Y. & Caprioli, D. Incubation of methamphetamine but not heroin craving after voluntary abstinence in male and female rats. Neuropsychopharmacology 42, 1126–1135 (2017).
Bedi, G. et al. Incubation of cue-induced cigarette craving during abstinence in human smokers. Biol. Psychiatry 69, 708–711 (2011).
Cruz, F. C. et al. New technologies for examining the role of neuronal ensembles in drug addiction and fear. Nat. Rev. Neurosci. 14, 743–754 (2013).
Caprioli, D. et al. Role of dorsomedial striatum neuronal ensembles in incubation of methamphetamine craving after voluntary abstinence. J. Neurosci. 37, 1014–1027 (2017).
Rossi, L. M. et al. Role of nucleus accumbens core but not shell in incubation of methamphetamine craving after voluntary abstinence. Neuropsychopharmacology 45, 256–265 (2020).
Venniro, M. et al. The anterior insular cortex–>central amygdala glutamatergic pathway Is critical to relapse after contingency management. Neuron 96, 414–427 e418 (2017).
Reiner, D. J. et al. Role of projections between piriform cortex and orbitofrontal cortex in relapse to fentanyl seeking after palatable food choice-induced voluntary abstinence. J. Neurosci. 40, 2485–2497 (2020).
Stitzer, M. L., Jones, H. E., Tuten, M. & Wong, C. in Handbook of Motivational Counseling: Goal-Based Approaches to Assessment and Intervention with Addiction and Other Problems (eds Cox, W. M. & Klinger, E.) (John Wiley & Sons Ltd, 2011).
Silverman, K., DeFulio, A. & Sigurdsson, S. O. Maintenance of reinforcement to address the chronic nature of drug addiction. Prev. Med. 55, S46–S53 (2012).
Mason, W. A., Hollins, J. H. & Sharpe, L. G. Differential responses of chimpanzees to social stimulation. J. Comp. Physiol. Psychol. 55, 1105–1110 (1962).
Venniro, M. & Shaham, Y. An operant social self-administration and choice model in rats. Nat. Protoc. 15, 1542–1559 (2020).
Venniro, M., Russell, T. I., Zhang, M. & Shaham, Y. Operant social reward decreases incubation of heroin craving in male and female rats. Biol. Psychiatry 86, 848–856 (2019).
Grundemann, J. & Luthi, A. Ensemble coding in amygdala circuits for associative learning. Curr. Opin. Neurobiol. 35, 200–206 (2015).
Venniro, M. et al. Abstinence-dependent dissociable central amygdala microcircuits control drug craving. Proc. Natl Acad. Sci. USA 117, 8126–8134 (2020).
Leboyer, M. et al. Psychiatric genetics: search for phenotypes. Trends Neurosci. 21, 102–105 (1998).
Swerdlow, N. R., Braff, D. L. & Geyer, M. A. Sensorimotor gating of the startle reflex: what we said 25 years ago, what has happened since then, and what comes next. J. Psychopharmacol. 30, 1072–1081 (2016).
Anderzhanova, E., Kirmeier, T. & Wotjak, C. T. Animal models in psychiatric research: the RDoC system as a new framework for endophenotype-oriented translational neuroscience. Neurobiol. Stress. 7, 47–56 (2017).
Falk, D. E. et al. Evaluation of drinking risk levels as outcomes in alcohol pharmacotherapy trials: A secondary analysis of 3 randomized clinical trials. JAMA Psychiatry 76, 374–381 (2019).
Center for Drug Evaluation and Research. Opioid use disorder: endpoints for demonstrating effectiveness of drugs for medication-assisted treatment guidance for industry. US Food and Drug Association https://www.fda.gov/regulatory-information/search-fda-guidance-documents/opioid-use-disorder-endpoints-demonstrating-effectiveness-drugs-medication-assisted-treatment (2018).
Heilig, M., Sommer, W. H. & Spanagel, R. The need for treatment responsive translational biomarkers in alcoholism research. Curr. Top. Behav. Neurosci. 28, 151–171 (2016).
Kakko, J. et al. A stepped care strategy using buprenorphine and methadone versus conventional methadone maintenance in heroin dependence: a randomized controlled trial. Am. J. Psychiatry 164, 797–803 (2007).
Zhu, Y. et al. Correlates of long-term opioid abstinence after randomization to methadone versus buprenorphine/naloxone in a multi-site trial. J. Neuroimmune Pharmacol. 13, 488–497 (2018).
Donny, E. C., Walsh, S. L., Bigelow, G. E., Eissenberg, T. & Stitzer, M. L. High-dose methadone produces superior opioid blockade and comparable withdrawal suppression to lower doses in opioid-dependent humans. Psychopharmacology 161, 202–212 (2002).
Mattick, R. P., Breen, C., Kimber, J. & Davoli, M. Buprenorphine maintenance versus placebo or methadone maintenance for opioid dependence. Cochrane Database Syst. Rev. https://doi.org/10.1002/14651858.CD002207.pub4 (2014).
Greenwald, M. K., Comer, S. D. & Fiellin, D. A. Buprenorphine maintenance and mu-opioid receptor availability in the treatment of opioid use disorder: implications for clinical use and policy. Drug Alcohol Depend. 144, 1–11 (2014).
Kliewer, A. et al. Morphine-induced respiratory depression is independent of beta-arrestin2 signalling. Br. J. Pharmacol. 177, 2923–2931 (2020).
Haight, B. R. et al. Efficacy and safety of a monthly buprenorphine depot injection for opioid use disorder: a multicentre, randomised, double-blind, placebo-controlled, phase 3 trial. Lancet 393, 778–790 (2019).
Lofwall, M. R. et al. Weekly and monthly subcutaneous buprenorphine depot formulations vs daily sublingual buprenorphine With naloxone for treatment of opioid use disorder: a randomized clinical trial. JAMA Intern. Med. 178, 764–773 (2018).
Moore, D. et al. Effectiveness and safety of nicotine replacement therapy assisted reduction to stop smoking: systematic review and meta-analysis. BMJ 338, b1024 (2009).
Cahill, K., Stevens, S., Perera, R. & Lancaster, T. Pharmacological interventions for smoking cessation: an overview and network meta-analysis. Cochrane Database Syst. Rev. https://doi.org/10.1002/14651858.CD009329.pub2 (2013).
van den Brink, W. et al. Efficacy and safety of sodium oxybate in alcohol-dependent patients with a very high drinking risk level. Addict. Biol. 23, 969–986 (2018).
D’Souza, D. C. et al. Efficacy and safety of a fatty acid amide hydrolase inhibitor (PF-04457845) in the treatment of cannabis withdrawal and dependence in men: a double-blind, placebo-controlled, parallel group, phase 2a single-site randomised controlled trial. Lancet Psychiatry 6, 35–45 (2019).
Mayo, L. M. et al. Elevated anandamide, enhanced recall of fear extinction, and attenuated stress responses following inhibition of fatty acid amide hydrolase: a randomized, controlled experimental medicine trial. Biol. Psychiatry 87, 538–547 (2020).
Dakwar, E. et al. a single ketamine infusion combined with motivational enhancement therapy for alcohol use disorder: a randomized midazolam-controlled pilot trial. Am. J. Psychiatry 177, 125–133 (2020).
Dakwar, E. et al. A single ketamine infusion combined with mindfulness-based behavioral modification to treat cocaine dependence: a randomized clinical trial. Am. J. Psychiatry 176, 923–930 (2019).
de Wit, H., Epstein, D. H. & Preston, K. L. Does human language limit translatability of clinical and preclinical addiction research? Neuropsychopharmacology 43, 1985–1988 (2018).
Czajkowski, S. M. et al. From ideas to efficacy: The ORBIT model for developing behavioral treatments for chronic diseases. Health Psychol. 34, 971–982 (2015).
Cabral, T. S. The 15th anniversary of the Portuguese drug policy: its history, its success and its future. Drug Sci. Policy Law https://doi.org/10.1177/2050324516683640 (2017).
Badiani, A. Substance-specific environmental influences on drug use and drug preference in animals and humans. Curr. Opin. Neurobiol. 23, 588–596 (2013).
Insel, T. R. Digital phenotyping: technology for a new science of behavior. JAMA 318, 1215–1216 (2017).
Negus, S. S. Rapid assessment of choice between cocaine and food in rhesus monkeys: effects of environmental manipulations and treatment with d-amphetamine and flupenthixol. Neuropsychopharmacology 28, 919–931 (2003).
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).
Pirtle, J. L. et al. The serotonin-2C agonist lorcaserin delays intravenous choice and modifies the subjective and cardiovascular effects of cocaine: A randomized, controlled human laboratory study. Pharmacol. Biochem. Behav. 180, 52–59 (2019).
Harvey-Lewis, C., Li, Z., Higgins, G. A. & Fletcher, P. J. The 5-HT2C receptor agonist lorcaserin reduces cocaine self-administration, reinstatement of cocaine-seeking and cocaine induced locomotor activity. Neuropharmacology 101, 237–245 (2016).
Negus, S. S. & Banks, M. L. Learning from lorcaserin: lessons from the negative clinical trial of lorcaserin to treat cocaine use disorder. Neuropsychopharmacology https://doi.org/10.1038/s41386-020-00815-4 (2020).
Karila, L. et al. Dopamine transporter correlates and occupancy by modafinil in cocaine-dependent patients: a controlled study with high-resolution PET and [11C]-PE2I. Neuropsychopharmacology 41, 2294–2302 (2016).
Hart, C. L., Haney, M., Vosburg, S. K., Rubin, E. & Foltin, R. W. Smoked cocaine self-administration is decreased by modafinil. Neuropsychopharmacology 33, 761–768 (2008).
Verrico, C. D. et al. Treatment with modafinil and escitalopram, alone and in combination, on cocaine-induced effects: a randomized, double blind, placebo-controlled human laboratory study. Drug Alcohol Depend. 141, 72–78 (2014).
Zhang, H. Y. et al. The novel modafinil analog, JJC8-016, as a potential cocaine abuse pharmacotherapeutic. Neuropsychopharmacology 42, 1871–1883 (2017).
Collins, G. T. & France, C. P. Effects of lorcaserin and buspirone, administered alone and as a mixture, on cocaine self-administration in male and female rhesus monkeys. Exp. Clin. Psychopharmacol. 26, 488–496 (2018).
Bolin, B. L. et al. Buspirone reduces sexual risk-taking intent but not cocaine self-administration. Exp. Clin. Psychopharmacol. 24, 162–173 (2016).
Haney, M., Gunderson, E. W., Jiang, H., Collins, E. D. & Foltin, R. W. Cocaine-specific antibodies blunt the subjective effects of smoked cocaine in humans. Biol. Psychiatry 67, 59–65 (2010).
Kosten, T. R. et al. Vaccine for cocaine dependence: a randomized double-blind placebo-controlled efficacy trial. Drug Alcohol Depend. 140, 42–47 (2014).
Wee, S. et al. Novel cocaine vaccine linked to a disrupted adenovirus gene transfer vector blocks cocaine psychostimulant and reinforcing effects. Neuropsychopharmacology 37, 1083–1091 (2012).
Bergman, J., Kamien, J. B. & Spealman, R. D. Antagonism of cocaine self-administration by selective dopamine D(1) and D(2) antagonists. Behav. Pharmacol. 1, 355–363 (1990).
Haney, M., Ward, A. S., Foltin, R. W. & Fischman, M. W. Effects of ecopipam, a selective dopamine D1 antagonist, on smoked cocaine self-administration by humans. Psychopharmacology 155, 330–337 (2001).
Nann-Vernotica, E., Donny, E. C., Bigelow, G. E. & Walsh, S. L. Repeated administration of the D1/5 antagonist ecopipam fails to attenuate the subjective effects of cocaine. Psychopharmacology 155, 338–347 (2001).
Maldonado, R., Robledo, P., Chover, A. J., Caine, S. B. & Koob, G. F. D1 dopamine receptors in the nucleus accumbens modulate cocaine self-administration in the rat. Pharmacol. Biochem. Behav. 45, 239–242 (1993).
Howell, L. L., Wilcox, K. M., Lindsey, K. P. & Kimmel, H. L. Olanzapine-induced suppression of cocaine self-administration in rhesus monkeys. Neuropsychopharmacology 31, 585–593 (2006).
Meil, W. M. & Schechter, M. D. Olanzapine attenuates the reinforcing effects of cocaine. Eur. J. Pharmacol. 340, 17–26 (1997).
Kampman, K. M., Pettinati, H., Lynch, K. G., Sparkman, T. & O’Brien, C. P. A pilot trial of olanzapine for the treatment of cocaine dependence. Drug Alcohol Depend. 70, 265–273 (2003).
Hamilton, J. D., Nguyen, Q. X., Gerber, R. M. & Rubio, N. B. Olanzapine in cocaine dependence: a double-blind, placebo-controlled trial. Am. J. Addict. 18, 48–52 (2009).
Glick, S. D., Maisonneuve, I. M., Raucci, J. & Archer, S. Kappa opioid inhibition of morphine and cocaine self-administration in rats. Brain Res. 681, 147–152 (1995).
Mello, N. K. & Negus, S. S. Effects of kappa opioid agonists on cocaine- and food-maintained responding by rhesus monkeys. J. Pharmacol. Exp. Ther. 286, 812–824 (1998).
Walsh, S. L., Geter-Douglas, B., Strain, E. C. & Bigelow, G. E. Enadoline and butorphanol: evaluation of kappa-agonists on cocaine pharmacodynamics and cocaine self-administration in humans. J. Pharmacol. Exp. Ther. 299, 147–158 (2001).
Fotio, Y. et al. Activation of peroxisome proliferator-activated receptor gamma reduces alcohol drinking and seeking by modulating multiple mesocorticolimbic regions in rats. Neuropsychopharmacology https://doi.org/10.1038/s41386-020-0754-4 (2020).
Schwandt, M. L. et al. PPARgamma activation by pioglitazone does not suppress cravings for alcohol, and is associated with a risk of myopathy in treatment seeking alcohol dependent patients: a randomized controlled proof of principle study. Psychopharmacology 237, 2367–2380 (2020).
Schroeder, J. R. et al. Assessment of pioglitazone and proinflammatory cytokines during buprenorphine taper in patients with opioid use disorder. Psychopharmacology 235, 2957–2966 (2018).
Scofield, M. D. et al. The nucleus accumbens: mechanisms of addiction across drug classes reflect the importance of glutamate homeostasis. Pharmacol. Rev. 68, 816–871 (2016).
LaRowe, S. D. et al. A double-blind placebo-controlled trial of N-acetylcysteine in the treatment of cocaine dependence. Am. J. Addict. 22, 443–452 (2013).
Anker, J. J. et al. Cocaine hydrolase encoded in viral vector blocks the reinstatement of cocaine seeking in rats for 6 months. Biol. Psychiatry 71, 700–705 (2012).
Simpson, T. L. et al. Double-blind randomized clinical trial of prazosin for alcohol use disorder. Am. J. Psychiatry 175, 1216–1224 (2018).
Fox, H. C. et al. Prazosin effects on stress- and cue-induced craving and stress response in alcohol-dependent individuals: preliminary findings. Alcohol Clin. Exp. Res. 36, 351–360 (2012).
Kowalczyk, W. J. et al. Clonidine maintenance prolongs opioid abstinence and decouples stress from craving in daily life: A randomized controlled trial With ecological momentary assessment. Am. J. Psychiatry 172, 760–767 (2015).
Jobes, M. L. et al. Clonidine blocks stress-induced craving in cocaine users. Psychopharmacology 218, 83–88 (2011).
Caprioli, D., Justinova, Z., Venniro, M. & Shaham, Y. Effect of novel allosteric modulators of metabotropic glutamate receptors on drug self-administration and relapse: a review of preclinical atudies and their clinical implications. Biol. Psychiatry 84, 180–192 (2018).
Shwe, G. US National Library of Medicine. ClinicalTrials.gov https://clinicaltrials.gov/ct2/show/NCT02401022 (2017).
Shelton, K. L., Hendrick, E. S. & Beardsley, P. M. Efficacy of buspirone for attenuating cocaine and methamphetamine reinstatement in rats. Drug Alcohol Depend. 129, 210–216 (2013).
Stopponi, S. et al. Activation of nuclear PPARgamma receptors by the antidiabetic agent pioglitazone suppresses alcohol drinking and relapse to alcohol seeking. Biol. Psychiatry 69, 642–649 (2011).
Negus, S. S. & Rice, K. C. Mechanisms of withdrawal-associated increases in heroin self-administration: pharmacologic modulation of heroin vs food choice in heroin-dependent rhesus monkeys. Neuropsychopharmacology 34, 899–911 (2009).
Jones, J. D. et al. A randomized, double-blind, placebo-controlled study of the kappa opioid receptor antagonist, CERC-501, in a human laboratory model of smoking behavior. Addict. Biol. 25, e12799 (2020).
Czoty, P. W., Stoops, W. W. & Rush, C. R. Evaluation of the “pipeline” for dvelopment of medications for cocaine use disorder: a review of translational preclinical, human laboratory, and clinical trial research. Pharmacol. Rev. 68, 533–562 (2016).
Nuijten, M. et al. Sustained-release dexamfetamine in the treatment of chronic cocaine-dependent patients on heroin-assisted treatment: a randomised, double-blind, placebo-controlled trial. Lancet 387, 2226–2234 (2016).
Kohut, S. J., Fivel, P. A. & Mello, N. K. Differential effects of acute and chronic treatment with the alpha2-adrenergic agonist, lofexidine, on cocaine self-administration in rhesus monkeys. Drug Alcohol Depend. 133, 593–599 (2013).
Wee, S., Mandyam, C. D., Lekic, D. M. & Koob, G. F. Alpha 1-noradrenergic system role in increased motivation for cocaine intake in rats with prolonged access. Eur. Neuropsychopharmacol. 18, 303–311 (2008).
Czoty, P. W. & Nader, M. A. Effects of the alpha-2 adrenergic receptor agonist lofexidine on food-cocaine choice in socially housed cynomolgus monkeys. J. Pharmacol. Exp. Ther. https://doi.org/10.1124/jpet.120.266007 (2020).
Jin, X. et al. The mGluR2 positive allosteric modulator BINA decreases cocaine self-administration and cue-induced cocaine-seeking and counteracts cocaine-induced enhancement of brain reward function in rats. Neuropsychopharmacology 35, 2021–2036 (2010).
Bauzo, R. M., Kimmel, H. L. & Howell, L. L. Interactions between the mGluR2/3 agonist, LY379268, and cocaine on in vivo neurochemistry and behavior in squirrel monkeys. Pharmacol. Biochem. Behav. 94, 204–210 (2009).
Czoty, P. W., Blough, B. E., Landavazo, A. & Nader, M. A. Effects of the mGluR2/3 receptor agonist LY379268 on the reinforcing strength of cocaine in rhesus monkeys. Psychopharmacology 237, 409–417 (2020).
Evans, S. M. et al. Efficacy of an adenovirus-based anti-cocaine vaccine to reduce cocaine self-administration and reacqusition using a choice procedure in rhesus macaques. Pharmacol. Biochem. Behav. 150–151, 76–86 (2016).
Thomsen, M. et al. Effects of acute and chronic aripiprazole treatment on choice between cocaine self-administration and food under a concurrent schedule of reinforcement in rats. Psychopharmacology 201, 43–53 (2008).
Haney, M., Rubin, E. & Foltin, R. W. Aripiprazole maintenance increases smoked cocaine self-administration in humans. Psychopharmacology 216, 379–387 (2011).
Lofwall, M. R., Nuzzo, P. A., Campbell, C. & Walsh, S. L. Aripiprazole effects on self-administration and pharmacodynamics of intravenous cocaine and cigarette smoking in humans. Exp. Clin. Psychopharmacol. 22, 238–247 (2014).
Moran, L. M. et al. Aripiprazole for cocaine abstinence: a randomized-controlled trial with ecological momentary assessment. Behav. Pharmacol. 28, 63–73 (2017).
Wee, S., Wang, Z., Woolverton, W. L., Pulvirenti, L. & Koob, G. F. Effect of aripiprazole, a partial dopamine D2 receptor agonist, on increased rate of methamphetamine self-administration in rats with prolonged session duration. Neuropsychopharmacology 32, 2238–2247 (2007).
John, W. S., Banala, A. K., Newman, A. H. & Nader, M. A. Effects of buspirone and the dopamine D3 receptor compound PG619 on cocaine and methamphetamine self-administration in rhesus monkeys using a food-drug choice paradigm. Psychopharmacology 232, 1279–1289 (2015).
Negus, S. S. Effects of the kappa opioid agonist U50,488 and the kappa opioid antagonist nor-binaltorphimine on choice between cocaine and food in rhesus monkeys. Psychopharmacology 176, 204–213 (2004).
Negus, S. S., Mello, N. K., Portoghese, P. S. & Lin, C. E. Effects of kappa opioids on cocaine self-administration by rhesus monkeys. J. Pharmacol. Exp. Ther. 282, 44–55 (1997).
Banks, M. L. & Blough, B. E. Effects of environmental manipulations and treatment with bupropion and risperidone on choice between methamphetamine and food in rhesus monkeys. Neuropsychopharmacology 40, 2198–2206 (2015).
Shoptaw, S. et al. Bupropion hydrochloride versus placebo, in combination with cognitive behavioral therapy, for the treatment of cocaine abuse/dependence. J. Addict. Dis. 27, 13–23 (2008).
Stoops, W. W., Pike, E., Hays, L. R., Glaser, P. E. & Rush, C. R. Naltrexone and bupropion, alone or combined, do not alter the reinforcing effects of intranasal methamphetamine. Pharmacol. Biochem. Behav. 129, 45–50 (2015).
Elkashef, A. M. et al. Bupropion for the treatment of methamphetamine dependence. Neuropsychopharmacology 33, 1162–1170 (2008).
de Moura, F. B. et al. Effects of chronic treatment with bupropion on self-administration of nicotine+cocaine mixtures in nonhuman primates. Exp. Clin. Psychopharmacol. https://doi.org/10.1037/pha0000333 (2019).
Foltin, R. W. & Fischman, M. W. Effects of buprenorphine on the self-administration of cocaine by humans. Behav. Pharmacol. 5, 79–89 (1994).
Schottenfeld, R. S., Pakes, J. R., Oliveto, A., Ziedonis, D. & Kosten, T. R. Buprenorphine vs methadone maintenance treatment for concurrent opioid dependence and cocaine abuse. Arch. Gen. Psychiatry 54, 713–720 (1997).
Wee, S., Vendruscolo, L. F., Misra, K. K., Schlosburg, J. E. & Koob, G. F. A combination of buprenorphine and naltrexone blocks compulsive cocaine intake in rodents without producing dependence. Sci. Transl. Med. 4, 146ra110 (2012).
Banks, M. L., Blough, B. E., Fennell, T. R., Snyder, R. W. & Negus, S. S. Effects of phendimetrazine treatment on cocaine vs food choice and extended-access cocaine consumption in rhesus monkeys. Neuropsychopharmacology 38, 2698–2707 (2013).
Banks, M. L., Blough, B. E. & Negus, S. S. Effects of 14-day treatment with the schedule III anorectic phendimetrazine on choice between cocaine and food in rhesus monkeys. Drug Alcohol Depend. 131, 204–213 (2013).
Stoops, W. W. et al. Influence of phendimetrazine maintenance on the reinforcing, subjective, performance, and physiological effects of intranasal cocaine. Psychopharmacology 236, 2569–2577 (2019).
Mooney, M. E. et al. Pilot study of the effects of lisdexamfetamine on cocaine use: a randomized, double-blind, placebo-controlled trial. Drug Alcohol Depend. 153, 94–103 (2015).
Johnson, A. R. et al. Development of a translational model to screen medications for cocaine use disorder I: choice between cocaine and food in rhesus monkeys. Drug Alcohol Depend. 165, 103–110 (2016).
Negus, S. S. & Banks, M. L. Modulation of drug choice by extended drug access and withdrawal in rhesus monkeys: Implications for negative reinforcement as a driver of addiction and target for medications development. Pharmacol. Biochem. Behav. 164, 32–39 (2018).
Morgan, D. et al. Social dominance in monkeys: dopamine D2 receptors and cocaine self-administration. Nat. Neurosci. 5, 169–174 (2002).
Nader, M. A. et al. Social dominance in female monkeys: dopamine receptor function and cocaine reinforcement. Biol. Psychiatry 72, 414–421 (2012).
Nader, M. A. et al. PET imaging of dopamine D2 receptors during chronic cocaine self-administration in monkeys. Nat. Neurosci. 9, 1050–1056 (2006).
The writing of this Review was supported by a grant from the US NIDA (K99DA047976 to M.V.), the Intramural Research Program of the NIH, NIDA (D.H.E. and Y.S.), UG3DA050311, R01DA026946 and UH3DA041146 from NIDA (M.L.B.), and the Swedish Research Council (M.H.). The authors thank S. Negus for helpful comments on the Review.
The authors declare no competing interests.
Peer review information
Nature Reviews Neuroscience thanks Robert Gould, who co-reviewed with Kimberly Holter; Paul Kenny and the other anonymous reviewers for their contribution to the peer review of this work.
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Resumption of drug-taking behaviour during self-imposed (voluntary) or forced abstinence in humans and laboratory animals.
- Compulsive drug use
Continued use of a drug despite (known) adverse consequences.
- Drug craving
An affective state described as an urge for drug; it can be induced in human drug users by exposure to the self-administered drug, drug cues or stress.
- Predictive validity
The extent to which laboratory-animal behaviour induced by an experimental manipulation predicts human behaviour induced by a similar event in the modelled condition; it often refers to a model’s ability to prospectively identify treatments that are effective in humans.
- Postdictive validity
The ability of a laboratory model to retrospectively demonstrate an established human phenomenon.
- Forward translation
The process of using mechanistic discoveries from animal models to develop new treatments for the modelled human condition.
- Contingency management
A learning-based treatment in which abstinence is maintained by providing non-drug rewards (monetary vouchers, prizes or other incentives, usually tangible/material and given promptly and predictably) in exchange for negative drug test results.
- The community-reinforcement approach
A learning-based treatment developed for alcohol addiction in the 1970s, where the goal is to replace drug use with non-drug social rewards (family support and employment) contingent on decrease or cessation of drug use.
- Binge self-administration
Self-administration characterized by irregular (variable) interinfusion intervals, with alternating periods of high responding and no responding.
- Progressive ratio reinforcement schedule
A schedule of reinforcement in which a reinforcer is presented only on the completion of a set number of responses. The number of required responses progressively increases after each presented reinforcement.
A consequence that follows an operant response that decreases the likelihood that the response will occur in the future.
- Q 0
A measure, in behavioural economics, of maximal consumption when the ‘price’ of a commodity is zero or at the lowest price possible (that is, FR1 reinforcement schedule in self-administration studies).
- P max
A measure, in behavioural economics, of the maximum ‘price’ that maintains maximal responding and represents the inflection point (that is, slope of −1) between inelastic and elastic demand (in other words, the price at which a proportional change in price results in an equal proportional change in consumption of the commodity).
A measure, in behavioural economics, of the elasticity of a demand curve or how quickly consumption of a commodity falls with increases in ‘price’ (response requirement divided by unit drug dose in self-administration studies).
- Demand elasticity
In behavioural economics, how quickly demand falls with increases in ‘price’ (response requirements in self-administration studies).
- Second-order reinforcement schedules
Reinforcement schedules in which completion of the response requirements of one schedule (the unit schedule) is treated as a unitary response that is reinforced according to another schedule.
- Disconnection procedure
A procedure in which a role of a neuronal pathway or projection in a given behaviour is inferred when behaviour is disrupted by the contralateral, but not ipsilateral, inactivation of two anatomically connected brain regions.
- Opioid maintenance therapy
Pharmacological treatment method in which long-acting opioid agonists such as methadone or buprenorphine are administered orally or via depot formulation, producing few or no acute subjective effects in tolerant patients but reducing craving for, and use of, other opioids.
- ABA renewal
The resumption of a conditioned response in the original training context after extinction in a different context (also called ‘context-induced reinstatement’).
- Sign tracking
Behaviour directed towards a stimulus as a result of a learned association between the stimulus and the reward. Sign-tracking responses develop even though reward delivery is not contingent on a response.
- Reverse translation
The use of data from humans (for example, that a treatment is effective for a condition) to develop animal models whose goals are to uncover underlying mechanisms and identify new treatments.
- G-protein-biased MOR agonist
An agonist of µ opioid receptor (MOR) that preferentially activates the G-protein-coupled intracellular pathway over the β-arrestin pathway.
- Daun02 inactivation procedure
A pharmacogenetic lesion approach (conversion of Daun02 into cytotoxic daunorubicin by β-galactosidase) to determine the behavioural relevance of FOS-expressing neuronal ensembles in FOS–lacZ rats that express FOS and β-galactosidase in activated neurons.
Also known as intermediate phenotype, a quantitative trait unseen by the unaided eye, located along the pathway between a genomic locus that contributes to the heritability of a complex disease phenotype and the disease itself.
About this article
Cite this article
Venniro, M., Banks, M.L., Heilig, M. et al. Improving translation of animal models of addiction and relapse by reverse translation. Nat Rev Neurosci 21, 625–643 (2020). https://doi.org/10.1038/s41583-020-0378-z
Learning from lorcaserin: lessons from the negative clinical trial of lorcaserin to treat cocaine use disorder