Abstract
Reward-predicting cues motivate goal-directed behavior, but in unstable environments humans must also be able to flexibly update cue-reward associations. While the capacity of reward cues to trigger motivation (‘reactivity’) as well as flexibility in cue-reward associations have been linked to the neurotransmitter dopamine in humans, the specific contribution of the dopamine D1 receptor family to these behaviors remained elusive. To fill this gap, we conducted a randomized, placebo-controlled, double-blind pharmacological study testing the impact of three different doses of a novel D1 agonist (relative to placebo) on reactivity to reward-predicting cues (Pavlovian-to-instrumental transfer) and flexibility of cue-outcome associations (reversal learning). We observed that the impact of the D1 agonist crucially depended on baseline working memory functioning, which has been identified as a proxy for baseline dopamine synthesis capacity. Specifically, increasing D1 receptor stimulation strengthened Pavlovian-to-instrumental transfer in individuals with high baseline working memory capacity. In contrast, higher doses of the D1 agonist improved reversal learning only in individuals with low baseline working memory functioning. Our findings suggest a crucial and baseline-dependent role of D1 receptor activation in controlling both cue reactivity and the flexibility of cue-reward associations.
Similar content being viewed by others
Log in or create a free account to read this content
Gain free access to this article, as well as selected content from this journal and more on nature.com
or
References
Garbusow M, et al. Pavlovian-to-instrumental transfer effects in the nucleus accumbens relate to relapse in alcohol dependence. Addict Biol. 2016;21:719–31.
Reddy LF, Waltz JA, Green MF, Wynn JK, Horan WP. Probabilistic reversal learning in schizophrenia: stability of deficits and potential causal mechanisms. Schizophr Bull. 2016;42:942–51.
Timmer MHM, Sescousse G, van der Schaaf ME, Esselink RAJ, Cools R. Reward learning deficits in Parkinson’s disease depend on depression. Psychol Med. 2017;47:2302–11.
Schultz W. Neuronal reward and decision signals: from theories to data. Physiol Rev. 2015;95:853–951.
Salamone JD, Correa M. The mysterious motivational functions of mesolimbic dopamine. Neuron. 2012;76:470–85.
Ott T, Nieder A. Dopamine and cognitive control in prefrontal cortex. Trends Cogn Sci. 2019;23:213–34.
de Boer L, et al. Attenuation of dopamine-modulated prefrontal value signals underlies probabilistic reward learning deficits in old age. Elife. 2017;6:e26424.
Durstewitz D, Seamans JK. The computational role of dopamine D1 receptors in working memory. Neural Netw. 2002;15:561–72.
Collins AG, Frank MJ. Opponent actor learning (OpAL): modeling interactive effects of striatal dopamine on reinforcement learning and choice incentive. Psychol Rev. 2014;121:337–66.
Weber SC, et al. Dopamine D2/3- and mu-opioid receptor antagonists reduce cue-induced responding and reward impulsivity in humans. Transl Psychiatry. 2016;6:e850.
Swart JC, et al. Catecholaminergic challenge uncovers distinct Pavlovian and instrumental mechanisms of motivated (in)action. Elife. 2017;6:e22169.
Hebart MN, Glascher J. Serotonin and dopamine differentially affect appetitive and aversive general Pavlovian-to-instrumental transfer. Psychopharmacology. 2015;232:437–51.
van der Schaaf ME, et al. Establishing the dopamine dependency of human striatal signals during reward and punishment reversal learning. Cereb Cortex. 2014;24:633–42.
Cools R, et al. Striatal dopamine predicts outcome-specific reversal learning and its sensitivity to dopaminergic drug administration. J Neurosci. 2009;29:1538–43.
Glueck E, Ginder D, Hyde J, North K, Grimm JW. Effects of dopamine D1 and D2 receptor agonists on environmental enrichment attenuated sucrose cue reactivity in rats. Psychopharmacology. 2017;234:815–25.
Lex A, Hauber W. Dopamine D1 and D2 receptors in the nucleus accumbens core and shell mediate Pavlovian-instrumental transfer. Learn Mem. 2008;15:483–91.
Thompson JL, et al. Age-dependent D1-D2 receptor coactivation in the lateral orbitofrontal cortex potentiates NMDA receptors and facilitates cognitive flexibility. Cereb Cortex. 2016;26:4524–39.
Calaminus C, Hauber W. Guidance of instrumental behavior under reversal conditions requires dopamine D1 and D2 receptor activation in the orbitofrontal cortex. Neuroscience. 2008;154:1195–204.
Haluk DM, Floresco SB. Ventral striatal dopamine modulation of different forms of behavioral flexibility. Neuropsychopharmacology. 2009;34:2041–52.
Calaminus C, Hauber W. Intact discrimination reversal learning but slowed responding to reward-predictive cues after dopamine D1 and D2 receptor blockade in the nucleus accumbens of rats. Psychopharmacology. 2007;191:551–66.
de Boer L, et al. Dorsal striatal dopamine D1 receptor availability predicts an instrumental bias in action learning. Proc Natl Acad Sci USA. 2019;116:261–70.
Frank MJ, Fossella JA. Neurogenetics and pharmacology of learning, motivation, and cognition. Neuropsychopharmacology. 2011;36:133–52.
Cox SM, et al. Striatal D1 and D2 signaling differentially predict learning from positive and negative outcomes. Neuroimage. 2015;109:95–101.
Davoren JE, et al. Discovery and lead optimization of atropisomer D1 agonists with reduced desensitization. J Med Chem. 2018;61:11384–97.
Gray DL, et al. Impaired beta-arrestin recruitment and reduced desensitization by non-catechol agonists of the D1 dopamine receptor. Nat Commun. 2018;9:674.
Vijayraghavan S, Wang M, Birnbaum SG, Williams GV, Arnsten AF. Inverted-U dopamine D1 receptor actions on prefrontal neurons engaged in working memory. Nat Neurosci. 2007;10:376–84.
Floresco SB. Prefrontal dopamine and behavioral flexibility: shifting from an “inverted-U” toward a family of functions. Front Neurosci. 2013;7:62.
Arnsten AF. Catecholamine influences on dorsolateral prefrontal cortical networks. Biol Psychiatry. 2011;69:e89–99.
Takahashi H, Yamada M, Suhara T. Functional significance of central D1 receptors in cognition: beyond working memory. J Cereb Blood Flow Metab. 2012;32:1248–58.
Muller U, von Cramon DY, Pollmann S. D1- versus D2-receptor modulation of visuospatial working memory in humans. J Neurosci. 1998;18:2720–8.
Cools R, D’Esposito M. Inverted-U-shaped dopamine actions on human working memory and cognitive control. Biol Psychiatry. 2011;69:e113–25.
Landau SM, Lal R, O’Neil JP, Baker S, Jagust WJ. Striatal dopamine and working memory. Cereb Cortex. 2008;19:445–54.
Bäckman L, et al. Effects of working-memory training on striatal dopamine release. Science. 2011;333:718.
Kimberg DY, D’Esposito M, Farah MJ. Effects of bromocriptine on human subjects depend on working memory capacity. Neuroreport. 1997;8:3581–5.
Cools R, Gibbs SE, Miyakawa A, Jagust W, D’Esposito M. Working memory capacity predicts dopamine synthesis capacity in the human striatum. J Neurosci. 2008;28:1208–12.
Soutschek A, et al. Dopaminergic D1 receptor stimulation affects effort and risk preferences. Biol Psychiatry. 2019. Epub 2019/11/02.
Carver CS, White TL. Behavioral-inhibition, behavioral activation, and affective responses to impending reward and punishment—the Bis Bas Scales. J Pers Soc Psychol. 1994;67:319–33.
Lehrl S, Mehrfachwahl-Wortschatz-Intelligenztest: MWT-B. Spitta, Balingen, 1999.
Patton JH, Stanford MS, Barratt ES. Factor structure of the Barratt Impulsiveness Scale. J Clin Psychol. 1995;51:768–74.
Lovibond PF, Colagiuri B. Facilitation of voluntary goal-directed action by reward cues. Psychol Sci. 2013;24:2030–7.
Watson P, Wiers RW, Hommel B, de Wit S. Working for food you don’t desire: cues interfere with goal-directed food-seeking. Appetite. 2014;79:139–48.
Corbit LH, Janak PH, Balleine BW. General and outcome-specific forms of Pavlovian-instrumental transfer: the effect of shifts in motivational state and inactivation of the ventral tegmental area. Eur J Neurosci. 2007;26:3141–9.
Cools R, Altamirano L, D’Esposito M. Reversal learning in Parkinson’s disease depends on medication status and outcome valence. Neuropsychologia. 2006;44:1663–73.
Cartoni E, Puglisi-Allegra S, Baldassarre G. The three principles of action: a Pavlovian-instrumental transfer hypothesis. Front Behav Neurosci. 2013;7:153.
Corbit LH, Balleine BW. Double dissociation of basolateral and central amygdala lesions on the general and outcome-specific forms of Pavlovian-instrumental transfer. J Neurosci. 2005;25:962–70.
Corbit LH, Balleine BW. The general and outcome-specific forms of Pavlovian-instrumental transfer are differentially mediated by the nucleus accumbens core and shell. J Neurosci. 2011;31:11786–94.
Verharen JPH, Adan RAH, Vanderschuren L. Differential contributions of striatal dopamine D1 and D2 receptors to component processes of value-based decision making. Neuropsychopharmacology. https://doi.org/10.1038/s41386-019-0454-0 (2019).
Frank MJ. Dynamic dopamine modulation in the basal ganglia: a neurocomputational account of cognitive deficits in medicated and nonmedicated Parkinsonism. J Cogn Neurosci. 2005;17:51–72.
Xue G, et al. Common neural mechanisms underlying reversal learning by reward and punishment. PLoS ONE. 2013;8:e82169.
Wischnewski M, Zerr P, Schutter D. Effects of theta transcranial alternating current stimulation over the frontal cortex on reversal learning. Brain Stimul. 2016;9:705–11.
Dalton GL, Wang NY, Phillips AG, Floresco SB. Multifaceted contributions by different regions of the orbitofrontal and medial prefrontal cortex to probabilistic reversal learning. J Neurosci. 2016;36:1996–2006.
Ghods-Sharifi S, Haluk DM, Floresco SB. Differential effects of inactivation of the orbitofrontal cortex on strategy set-shifting and reversal learning. Neurobiol Learn Mem. 2008;89:567–73.
Homayoun H, Moghaddam B. Differential representation of Pavlovian-instrumental transfer by prefrontal cortex subregions and striatum. Eur J Neurosci. 2009;29:1461–76.
Keistler C, Barker JM, Taylor JR. Infralimbic prefrontal cortex interacts with nucleus accumbens shell to unmask expression of outcome-selective Pavlovian-to-instrumental transfer. Learn Mem. 2015;22:509–13.
van der Schaaf ME, Fallon SJ, Ter Huurne N, Buitelaar J, Cools R. Working memory capacity predicts effects of methylphenidate on reversal learning. Neuropsychopharmacology. 2013;38:2011–8.
Schlagenhauf F, et al. Striatal dysfunction during reversal learning in unmedicated schizophrenia patients. Neuroimage. 2014;89:171–80.
Acknowledgements
We are grateful to Poppy Watson, Sanne de Wit and Roshan Cools for providing us with versions of the PIT and reversal learning tasks that we reprogrammed in Cogent. We are also thank Barbara Fischer and Ali Sigaroudi for support with the medical examinations, Susan Mahoney for clinical operations support, Sofie Carellis, Cecilia Etterlin, Alina Frick, Geraldine Gvozdanovic, Amalia Stüssi, Karl Treiber for expert help with data collection and Nadine Enseleit for study monitoring.
Author information
Authors and Affiliations
Contributions
AS, RK, NdM, WH, CJB, EF, AJ, and PNT designed research; AS and AJ performed research; AS analyzed data; AS and PNT wrote manuscript; all authors approved final version of manuscript.
Corresponding author
Additional information
Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Supplementary information
Rights and permissions
About this article
Cite this article
Soutschek, A., Kozak, R., de Martinis, N. et al. Activation of D1 receptors affects human reactivity and flexibility to valued cues. Neuropsychopharmacol. 45, 780–785 (2020). https://doi.org/10.1038/s41386-020-0617-z
Received:
Revised:
Accepted:
Published:
Version of record:
Issue date:
DOI: https://doi.org/10.1038/s41386-020-0617-z
This article is cited by
-
Neuromodulation of prefrontal cortex cognitive function in primates: the powerful roles of monoamines and acetylcholine
Neuropsychopharmacology (2022)
