학술논문
Presynaptic and postsynaptic mesolimbic dopamine D 3 receptors play distinct roles in cocaine versus opioid reward in mice.
Document Type
Academic Journal
Author
Xi ZX; Medicinal Chemistry Section, Molecular Targets and Medications Discovery Branch, National Institute on Drug Abuse, Intramural Research Program, Baltimore, MD 21224, USA.; Bocarsly ME; Laboratory on Neurobiology of Compulsive Behaviors, National Institute on Alcohol Abuse and Alcoholism, Intramural Research Program, Bethesda, MD, USA.; Galaj E; Medicinal Chemistry Section, Molecular Targets and Medications Discovery Branch, National Institute on Drug Abuse, Intramural Research Program, Baltimore, MD 21224, USA.; Hempel B; Medicinal Chemistry Section, Molecular Targets and Medications Discovery Branch, National Institute on Drug Abuse, Intramural Research Program, Baltimore, MD 21224, USA.; Teresi C; Laboratory on Neurobiology of Compulsive Behaviors, National Institute on Alcohol Abuse and Alcoholism, Intramural Research Program, Bethesda, MD, USA.; Shaw M; Laboratory on Neurobiology of Compulsive Behaviors, National Institute on Alcohol Abuse and Alcoholism, Intramural Research Program, Bethesda, MD, USA.; Bi GH; Medicinal Chemistry Section, Molecular Targets and Medications Discovery Branch, National Institute on Drug Abuse, Intramural Research Program, Baltimore, MD 21224, USA; Medication Development Program, Molecular Targets and Medications Discovery Branch, National Institute on Drug Abuse, Intramural Research Program, Baltimore, MD 21224, USA.; Jordan C; Medicinal Chemistry Section, Molecular Targets and Medications Discovery Branch, National Institute on Drug Abuse, Intramural Research Program, Baltimore, MD 21224, USA.; Linz E; Medicinal Chemistry Section, Molecular Targets and Medications Discovery Branch, National Institute on Drug Abuse, Intramural Research Program, Baltimore, MD 21224, USA; Medication Development Program, Molecular Targets and Medications Discovery Branch, National Institute on Drug Abuse, Intramural Research Program, Baltimore, MD 21224, USA.; Alton H; Medicinal Chemistry Section, Molecular Targets and Medications Discovery Branch, National Institute on Drug Abuse, Intramural Research Program, Baltimore, MD 21224, USA; Medication Development Program, Molecular Targets and Medications Discovery Branch, National Institute on Drug Abuse, Intramural Research Program, Baltimore, MD 21224, USA.; Tanda G; Medication Development Program, Molecular Targets and Medications Discovery Branch, National Institute on Drug Abuse, Intramural Research Program, Baltimore, MD 21224, USA.; Freyberg Z; Department of Psychiatry, University of Pittsburgh, Pittsburgh, PA, 15213, USA; Department of Cell Biology, University of Pittsburgh, Pittsburgh, PA, 15213, USA.; Alvarez VA; Laboratory on Neurobiology of Compulsive Behaviors, National Institute on Alcohol Abuse and Alcoholism, Intramural Research Program, Bethesda, MD, USA; National Institute of Mental Health, Center on Compulsive Behaviors, Intramural Research Program, Bethesda, MD, 20892 USA.; Newman AH; Medicinal Chemistry Section, Molecular Targets and Medications Discovery Branch, National Institute on Drug Abuse, Intramural Research Program, Baltimore, MD 21224, USA. Electronic address: anewman@intra.nida.nih.gov.
Source
Publisher: Elsevier Country of Publication: United States NLM ID: 0213264 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1873-2402 (Electronic) Linking ISSN: 00063223 NLM ISO Abbreviation: Biol Psychiatry Subsets: MEDLINE
Subject
Language
English
Abstract
Background: Past research illuminated pivotal roles of dopamine D 3 receptors (D3Rs) in the rewarding effects of cocaine and opioids. However, the cellular and neural circuit mechanisms underlying these actions remain unclear.
Methods: We employed Cre-LoxP techniques to selectively delete D3R from presynaptic dopamine neurons or postsynaptic dopamine D1R-expressing neurons in male and female mice. We utilized RNAscope in situ hybridization, immunohistochemistry, RT-PCR, voltammetry, optogenetics, microdialysis, and behavioral assays (n≥8) to functionally characterize the roles of presynaptic versus postsynaptic D3Rs in cocaine and opioid actions.
Results: Our results revealed D3R expression in ∼20% of midbrain dopamine neurons and ∼70% of D1R-expressing neurons in the nucleus accumbens. While D2R was expressed in ∼80% dopamine neurons, we found no D2R and D3R colocalization among these cells. Selective deletion of D3Rs from dopamine neurons increased exploratory behavior in novel environments and enhanced pulse-evoked NAc dopamine release. Conversely, D3R deletion from D1R-expressing neurons attenuated locomotor responses to D1 -like and D 2 -like agonists. Strikingly, D3R deletion from either cell type reduced oxycodone self-administration and oxycodone-enhanced brain-stimulation reward. In contrast, neither of these D3R deletions impacted cocaine self-administration, cocaine-enhanced brain-stimulation reward, or cocaine-induced hyperlocomotion. Furthermore, D3R knockout in dopamine neurons reduced oxycodone-induced hyperactivity and analgesia, while deletion from D1R-expressing neurons potentiated opioid-induced hyperactivity without affecting analgesia.
Conclusions: We dissected presynaptic versus postsynaptic D3R function in the mesolimbic dopamine system. D2R and D3R are expressed in different populations of midbrain dopamine neurons, regulating dopamine release. The mesolimbic D3Rs are critically involved in the actions of opioids but not cocaine.
(Copyright © 2024. Published by Elsevier Inc.)
Methods: We employed Cre-LoxP techniques to selectively delete D3R from presynaptic dopamine neurons or postsynaptic dopamine D1R-expressing neurons in male and female mice. We utilized RNAscope in situ hybridization, immunohistochemistry, RT-PCR, voltammetry, optogenetics, microdialysis, and behavioral assays (n≥8) to functionally characterize the roles of presynaptic versus postsynaptic D3Rs in cocaine and opioid actions.
Results: Our results revealed D3R expression in ∼20% of midbrain dopamine neurons and ∼70% of D1R-expressing neurons in the nucleus accumbens. While D2R was expressed in ∼80% dopamine neurons, we found no D2R and D3R colocalization among these cells. Selective deletion of D3Rs from dopamine neurons increased exploratory behavior in novel environments and enhanced pulse-evoked NAc dopamine release. Conversely, D3R deletion from D1R-expressing neurons attenuated locomotor responses to D
Conclusions: We dissected presynaptic versus postsynaptic D3R function in the mesolimbic dopamine system. D2R and D3R are expressed in different populations of midbrain dopamine neurons, regulating dopamine release. The mesolimbic D3Rs are critically involved in the actions of opioids but not cocaine.
(Copyright © 2024. Published by Elsevier Inc.)