title: Striatal dopamine D1 receptor suppression impairs reward-associative learning.
abstract: Dopamine (DA) is required for reinforcement learning. Hence, disruptions in DA signaling may contribute to the learning deficits associated with psychiatric disorders. The DA D1 receptor (D1R) has been linked to learning and is a target for cognitive/motivational enhancement in patients with schizophrenia. Separating the striatal D1R contribution to learning vs. motivation, however, has been challenging. We suppressed striatal D1R expression in mice using a D1R-targeting short hairpin RNA (shRNA), delivered locally to the striatum via an adeno-associated virus (AAV). We then assessed reward- and punishment-associative learning using a probabilistic learning task and motivation using a progressive-ratio breakpoint procedure. We confirmed suppression of striatal D1Rs immunohistochemically and by testing locomotor activity after the administration of (+)-doxanthrine, a full D1R agonist, in control mice and those treated with the D1RshRNA. D1RshRNA-treated mice exhibited impaired reward-associative learning, while punishment-associative learning was spared. This deficit was unrelated to general learning impairments or amotivation, because the D1shRNA-treated mice exhibited normal Barnes maze learning and normal motivation in the progressive-ratio breakpoint procedure. Suppression of striatal D1Rs selectively impaired reward-associative learning whereas punishment-associative learning, aversion-motivated learning, and appetitive motivation were spared. Because patients with schizophrenia exhibit similar reward-associative learning deficits, D1R-targeted treatments should be investigated to improve reward learning in these patients.
authors.affiliation: Department of Psychiatry, University of California San Diego, 9500 Gilman Drive, La Jolla, CA 92093, United States.
authors.forename: Kerin K
authors.initials: KK
authors.lastname: Higa
authors.affiliation: Department of Psychiatry, University of California San Diego, 9500 Gilman Drive, La Jolla, CA 92093, United States; Research Service, VA San Diego Healthcare System, 3350 La Jolla Village Drive, San Diego, CA, 92037, United States. Electronic address: jaredyoung@ucsd.edu.
authors.forename: Jared W
authors.initials: JW
authors.lastname: Young
authors.affiliation: Department of Molecular Biology, The Scripps Research Institute, La Jolla, CA, 92037, United States.
authors.forename: Baohu
authors.initials: B
authors.lastname: Ji
authors.affiliation: Department of Chemical Biology and Medicinal Chemistry, University of North Carolina, Chapel Hill, NC, 27599, United States.
authors.forename: David E
authors.initials: DE
authors.lastname: Nichols
authors.affiliation: Department of Psychiatry, University of California San Diego, 9500 Gilman Drive, La Jolla, CA 92093, United States; Research Service, VA San Diego Healthcare System, 3350 La Jolla Village Drive, San Diego, CA, 92037, United States.
authors.forename: Mark A
authors.initials: MA
authors.lastname: Geyer
authors.affiliation: Department of Psychiatry, University of California San Diego, 9500 Gilman Drive, La Jolla, CA 92093, United States; Research Service, VA San Diego Healthcare System, 3350 La Jolla Village Drive, San Diego, CA, 92037, United States.
authors.forename: Xianjin
authors.initials: X
authors.lastname: Zhou
mesh_terms: D000818:Animals; D001245:Association Learning / Q000187:drug effects / Q000502:physiology*; D003342:Corpus Striatum / Q000187:drug effects / Q000502:physiology*; D008297:Male; D008810:Mice, Inbred C57BL; D009042:Motivation / Q000187:drug effects / Q000502:physiology; D010617:Phenanthridines / Q000008:administration & dosage; D011337:Probability Learning; D011678:Punishment; D017447:Receptors, Dopamine D1 / Q000819:agonists / Q000502:physiology*; D012201:Reward
chemical_list: C516224:2,3-dihydroxy-6a,7,8,12b-tetrahydro-6H-chromeno(3,4-c)isoquinoline; D010617:Phenanthridines; D017447:Receptors, Dopamine D1
keywords: D1RshRNA; Dopamine D1 receptor (D1R); Probabilistic learning; Reward-related learning; Schizophrenia; Striatum