title: Differential modulation of reinforcement learning by D2 dopamine and NMDA glutamate receptor antagonism.
abstract: The firing pattern of midbrain dopamine (DA) neurons is well known to reflect reward prediction errors (PEs), the difference between obtained and expected rewards. The PE is thought to be a crucial signal for instrumental learning, and interference with DA transmission impairs learning. Phasic increases of DA neuron firing during positive PEs are driven by activation of NMDA receptors, whereas phasic suppression of firing during negative PEs is likely mediated by inputs from the lateral habenula. We aimed to determine the contribution of DA D2-class and NMDA receptors to appetitively and aversively motivated reinforcement learning. Healthy human volunteers were scanned with functional magnetic resonance imaging while they performed an instrumental learning task under the influence of either the DA D2 receptor antagonist amisulpride (400 mg), the NMDA receptor antagonist memantine (20 mg), or placebo. Participants quickly learned to select ("approach") rewarding and to reject ("avoid") punishing options. Amisulpride impaired both approach and avoidance learning, while memantine mildly attenuated approach learning but had no effect on avoidance learning. These behavioral effects of the antagonists were paralleled by their modulation of striatal PEs. Amisulpride reduced both appetitive and aversive PEs, while memantine diminished appetitive, but not aversive PEs. These data suggest that striatal D2-class receptors contribute to both approach and avoidance learning by detecting both the phasic DA increases and decreases during appetitive and aversive PEs. NMDA receptors on the contrary appear to be required only for approach learning because phasic DA increases during positive PEs are NMDA dependent, whereas phasic decreases during negative PEs are not.
authors.affiliation: Faculty of Economics and Management, Center for Behavioral Brain Sciences, Max Planck Institute for Neurological Research, D-50931 Cologne, Germany, jocham@ovgu.de.
authors.forename: Gerhard
authors.initials: G
authors.lastname: Jocham
authors.affiliation: Max Planck Institute for Human Cognitive and Brain Sciences, D-04103 Leipzig, Germany, Day Clinic for Cognitive Neurology, University Hospital Leipzig, D-04103 Leipzig, Germany, and.
authors.forename: Tilmann A
authors.initials: TA
authors.lastname: Klein
authors.affiliation: Center for Behavioral Brain Sciences, Department of Neuropsychology, Otto-von-Guericke-University Magdeburg, D-39106 Magdeburg, Germany, Donders Institute for Brain, Cognition and Behaviour, Radboud University Nijmegen, 6525 EZ Nijmegen, The Netherlands.
authors.forename: Markus
authors.initials: M
authors.lastname: Ullsperger
mesh_terms: D000328:Adult; D000077582:Amisulpride; D001362:Avoidance Learning; D003216:Conditioning, Operant; D018492:Dopamine Antagonists / Q000494:pharmacology; D065127:Dopamine D2 Receptor Antagonists; D006801:Humans; D008297:Male; D008559:Memantine / Q000494:pharmacology; D017448:Receptors, Dopamine D2 / Q000378:metabolism*; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors*; D012201:Reward; D013469:Sulpiride / Q000031:analogs & derivatives / Q000494:pharmacology
chemical_list: D018492:Dopamine Antagonists; D065127:Dopamine D2 Receptor Antagonists; D017448:Receptors, Dopamine D2; D016194:Receptors, N-Methyl-D-Aspartate; D013469:Sulpiride; D000077582:Amisulpride; D008559:Memantine
keywords: NMDA; dopamine; glutamate; prediction error; reinforcement learning; striatum