title: Absence of NMDA receptors in dopamine neurons attenuates dopamine release but not conditioned approach during Pavlovian conditioning.
abstract: During Pavlovian conditioning, phasic dopamine (DA) responses emerge to reward-predictive stimuli as the subject learns to anticipate reward delivery. This observation has led to the hypothesis that phasic dopamine signaling is important for learning. To assess the ability of mice to develop anticipatory behavior and to characterize the contribution of dopamine, we used a food-reinforced Pavlovian conditioning paradigm. As mice learned the cue-reward association, they increased their head entries to the food receptacle in a pattern that was consistent with conditioned anticipatory behavior. D1-receptor knockout (D1R-KO) mice had impaired acquisition, and systemic administration of a D1R antagonist blocked both the acquisition and expression of conditioned approach in wild-type mice. To assess the specific contribution of phasic dopamine transmission, we tested mice lacking NMDA-type glutamate receptors (NMDARs) exclusively in dopamine neurons (NR1-KO mice). Surprisingly, NR1-KO mice learned at the same rate as their littermate controls. To evaluate the contribution of NMDARs to phasic dopamine release in this paradigm, we performed fast-scan cyclic voltammetry in the nucleus accumbens of awake mice. Despite having significantly attenuated phasic dopamine release following reward delivery, KO mice developed cue-evoked dopamine release at the same rate as controls. We conclude that NMDARs in dopamine neurons enhance but are not critical for phasic dopamine release to behaviorally relevant stimuli; furthermore, their contribution to phasic dopamine signaling is not necessary for the development of cue-evoked dopamine or anticipatory activity in a D1R-dependent Pavlovian conditioning paradigm.
authors.affiliation: Howard Hughes Medical Institute and Department of Biochemistry, University of Washington, Seattle WA 98195, USA.
authors.forename: Jones G
authors.initials: JG
authors.lastname: Parker
authors.forename: Larry S
authors.initials: LS
authors.lastname: Zweifel
authors.forename: Jeremy J
authors.initials: JJ
authors.lastname: Clark
authors.forename: Scott B
authors.initials: SB
authors.lastname: Evans
authors.forename: Paul E M
authors.initials: PE
authors.lastname: Phillips
authors.forename: Richard D
authors.initials: RD
authors.lastname: Palmiter
mesh_terms: D000818:Animals; D001552:Benzazepines / Q000494:pharmacology; D003214:Conditioning, Classical / Q000187:drug effects / Q000502:physiology*; D003463:Cues; D004298:Dopamine / Q000378:metabolism*; D005260:Female; D007858:Learning / Q000502:physiology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009043:Motor Activity / Q000187:drug effects; D009474:Neurons / Q000166:cytology / Q000378:metabolism*; D009714:Nucleus Accumbens / Q000166:cytology / Q000378:metabolism; D017447:Receptors, Dopamine D1 / Q000235:genetics / Q000378:metabolism / Q000502:physiology; D016194:Receptors, N-Methyl-D-Aspartate / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D012201:Reward; D013997:Time Factors
chemical_list: D001552:Benzazepines; C409466:NR1 NMDA receptor; D017447:Receptors, Dopamine D1; D016194:Receptors, N-Methyl-D-Aspartate; C534628:SCH 23390; D004298:Dopamine