title: Differential roles of dopamine D1 and D2 receptor-containing neurons of the nucleus accumbens shell in behavioral sensitization.
abstract: The nucleus accumbens (Nac) mediates the reinforcing and motor stimulating properties of psychostimulants. It receives dopaminergic afferents from the ventral midbrain and is divided into two distinct subregions: shell and core. Each of these contains two subtypes of medium spiny neurons, which express either dopamine D1 (D1R) or D2 (D2R) receptors. However, functional dissociation between the two subtypes in psychostimulant response remains to be elucidated. We performed selective ablation of each subtype in the Nac shell in mice, using immunotoxin-mediated cell targeting, and examined the behavioral sensitization evoked by repeated administration of methamphetamine. The D1R cell-ablated mice exhibited delayed induction of sensitized locomotion compared to control mice, whereas the D2R cell-ablated mice showed a mildly enhanced rate of induction of sensitization. In vivo microdialysis revealed a marked blockade of the increase in extracellular dopamine in the Nac of the D1R cell-ablated animals in response to methamphetamine, indicating that the observed delay in behavioral sensitization in these mice involves an impairment in accumbal dopamine release. Our results reveal differential roles of D1R- and D2R-containing accumbal shell neurons in the development of behavioral sensitization to psychostimulants. Behavioral sensitization, enhanced motility by repetitive psychostimulant administration, is a model of drug addiction. Here, we show that the nucleus accumbens (Nac) shell neurons containing dopamine D1 receptor (D1R) or D2 receptor (D2R) play distinct roles in behavioral sensitization triggered by methamphetamine, and that D1R-containing neurons enhance the induction of behavioral sensitization at the early phase, whereas D2R-containing neurons act to suppress the rate of development of the behavior.
authors.affiliation: Department of Molecular Genetics, Institute of Biomedical Sciences, Fukushima Medical University School of Medicine, Fukushima, Japan.|Department of Histology & Neurobiology, Dokkyo Medical University School of Medicine, Tochigi, Japan.
authors.forename: Nobuyuki
authors.initials: N
authors.lastname: Kai
authors.affiliation: Department of Molecular Genetics, Institute of Biomedical Sciences, Fukushima Medical University School of Medicine, Fukushima, Japan.
authors.forename: Kayo
authors.initials: K
authors.lastname: Nishizawa
authors.affiliation: Faculty of Symbiotic Systems Science, Fukushima University, Fukushima, Japan.
authors.forename: Yuji
authors.initials: Y
authors.lastname: Tsutsui
authors.affiliation: Department of Histology & Neurobiology, Dokkyo Medical University School of Medicine, Tochigi, Japan.
authors.forename: Shuichi
authors.initials: S
authors.lastname: Ueda
authors.affiliation: Department of Molecular Genetics, Institute of Biomedical Sciences, Fukushima Medical University School of Medicine, Fukushima, Japan.
authors.forename: Kazuto
authors.initials: K
authors.lastname: Kobayashi
mesh_terms: D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D000697:Central Nervous System Stimulants / Q000494:pharmacology*; D004298:Dopamine / Q000378:metabolism; D008694:Methamphetamine / Q000494:pharmacology; D051379:Mice; D009474:Neurons / Q000378:metabolism*; D009714:Nucleus Accumbens / Q000187:drug effects / Q000378:metabolism*; D017447:Receptors, Dopamine D1 / Q000378:metabolism*; D017448:Receptors, Dopamine D2 / Q000378:metabolism*
chemical_list: D000697:Central Nervous System Stimulants; C000600618:DRD2 protein, mouse; C583261:Drd1 protein, mouse; D017447:Receptors, Dopamine D1; D017448:Receptors, Dopamine D2; D008694:Methamphetamine; D004298:Dopamine
keywords: behavioral sensitization; dopamine receptor; immunotoxin cell targeting; microdialysis; nucleus accumbens; shell