title: Loss of feedback inhibition via D2 autoreceptors enhances acquisition of cocaine taking and reactivity to drug-paired cues.
abstract: A prominent aspect of drug addiction is the ability of drug-associated cues to elicit craving and facilitate relapse. Understanding the factors that regulate cue reactivity will be vital for improving treatment of addictive disorders. Low availability of dopamine (DA) D2 receptors (D2Rs) in the striatum is associated with high cocaine intake and compulsive use. However, the role of D2Rs of nonstriatal origin in cocaine seeking and taking behavior and cue reactivity is less understood and possibly underestimated. D2Rs expressed by midbrain DA neurons function as autoreceptors, exerting inhibitory feedback on DA synthesis and release. Here, we show that selective loss of D2 autoreceptors impairs the feedback inhibition of DA release and amplifies the effect of cocaine on DA transmission in the nucleus accumbens (NAc) in vitro. Mice lacking D2 autoreceptors acquire a cued-operant self-administration task for cocaine faster than littermate control mice but acquire similarly for a natural reward. Furthermore, although mice lacking D2 autoreceptors were able to extinguish self-administration behavior in the absence of cocaine and paired cues, they exhibited perseverative responding when cocaine-paired cues were present. This enhanced cue reactivity was selective for cocaine and was not seen during extinction of sucrose self-administration. We conclude that low levels of D2 autoreceptors enhance the salience of cocaine-paired cues and can contribute to the vulnerability for cocaine use and relapse.
authors.affiliation: Section on Neuronal Structure, National Institute on Alcohol Abuse and Alcoholism, National Institute of Health, Bethesda, MD, USA.
authors.forename: Kathryn B
authors.initials: KB
authors.lastname: Holroyd
authors.affiliation: Section on Neuronal Structure, National Institute on Alcohol Abuse and Alcoholism, National Institute of Health, Bethesda, MD, USA.
authors.forename: Martin F
authors.initials: MF
authors.lastname: Adrover
authors.affiliation: Section on Neuronal Structure, National Institute on Alcohol Abuse and Alcoholism, National Institute of Health, Bethesda, MD, USA.
authors.forename: Robert L
authors.initials: RL
authors.lastname: Fuino
authors.affiliation: Section on Neuronal Structure, National Institute on Alcohol Abuse and Alcoholism, National Institute of Health, Bethesda, MD, USA.
authors.forename: Roland
authors.initials: R
authors.lastname: Bock
authors.affiliation: Section on Neuronal Structure, National Institute on Alcohol Abuse and Alcoholism, National Institute of Health, Bethesda, MD, USA.
authors.forename: Alanna R
authors.initials: AR
authors.lastname: Kaplan
authors.affiliation: Laboratory for Integrative Neuroscience, National Institute on Alcohol Abuse and Alcoholism, National Institute of Health, Bethesda, MD, USA.
authors.forename: Christina M
authors.initials: CM
authors.lastname: Gremel
authors.affiliation: 1] Instituto de Investigaciones en Ingeniería Genética y Biología Molecular, Consejo Nacional de Investigaciones Científicas y Técnicas, Buenos Aires, Argentina [2] Facultad de Ciencias Exactas y Naturales, Universidad de Buenos Aires, Buenos Aires, Argentina.
authors.forename: Marcelo
authors.initials: M
authors.lastname: Rubinstein
authors.affiliation: Section on Neuronal Structure, National Institute on Alcohol Abuse and Alcoholism, National Institute of Health, Bethesda, MD, USA.
authors.forename: Veronica A
authors.initials: VA
authors.lastname: Alvarez
mesh_terms: D000818:Animals; D017660:Autoreceptors / Q000378:metabolism*; D003042:Cocaine / Q000008:administration & dosage; D019970:Cocaine-Related Disorders / Q000378:metabolism*; D003216:Conditioning, Operant / Q000187:drug effects / Q000502:physiology; D003463:Cues; D004195:Disease Models, Animal; D004298:Dopamine / Q000378:metabolism; D018765:Dopamine Uptake Inhibitors / Q000008:administration & dosage; D025461:Feedback, Physiological / Q000187:drug effects; D008297:Male; D008636:Mesencephalon / Q000187:drug effects / Q000378:metabolism*; D018345:Mice, Knockout; D009433:Neural Inhibition / Q000187:drug effects / Q000502:physiology*; D009474:Neurons / Q000187:drug effects / Q000378:metabolism*; D017448:Receptors, Dopamine D2 / Q000235:genetics / Q000378:metabolism*; D012646:Self Administration
chemical_list: D017660:Autoreceptors; C000600618:DRD2 protein, mouse; D018765:Dopamine Uptake Inhibitors; D017448:Receptors, Dopamine D2; D003042:Cocaine; D004298:Dopamine