title: Behavior of knock-in mice with a cocaine-insensitive dopamine transporter after virogenetic restoration of cocaine sensitivity in the striatum.
abstract: Cocaine's main pharmacological actions are the inhibition of the dopamine, serotonin, and norepinephrine transporters. Its main behavioral effects are reward and locomotor stimulation, potentially leading to addiction. Using knock-in mice with a cocaine-insensitive dopamine transporter (DAT-CI mice) we have shown previously that inhibition of the dopamine transporter (DAT) is necessary for both of these behaviors. In this study, we sought to determine brain regions in which DAT inhibition by cocaine stimulates locomotor activity and/or produces reward. We used adeno-associated viral vectors to re-introduce the cocaine-sensitive wild-type DAT in specific brain regions of DAT-CI mice, which otherwise only express a cocaine-insensitive DAT globally. Viral-mediated expression of wild-type DAT in the rostrolateral striatum restored cocaine-induced locomotor stimulation and sensitization in DAT-CI mice. In contrast, the expression of wild-type DAT in the dorsal striatum, or in the medial nucleus accumbens, did not restore cocaine-induced locomotor stimulation. These data help to determine cocaine's molecular actions and anatomical loci that cause hyperlocomotion. Interestingly, cocaine did not produce significant reward - as measured by conditioned place-preference - in any of the three cohorts of DAT-CI mice with the virus injections. Therefore, the locus or loci underlying cocaine-induced reward remain underdetermined. It is possible that multiple dopamine-related brain regions are involved in producing the robust rewarding effect of cocaine.
authors.affiliation: Department of Pharmacology, The Ohio State University, 333 West 10th Avenue, 5184B Graves Hall, Columbus, OH 43210, USA; Neuroscience Graduate Studies Program, The Ohio State University, Columbus, OH 43210, USA.
authors.forename: Brian
authors.initials: B
authors.lastname: O'Neill
authors.affiliation: Department of Pharmacology, The Ohio State University, 333 West 10th Avenue, 5184B Graves Hall, Columbus, OH 43210, USA.
authors.forename: Michael R
authors.initials: MR
authors.lastname: Tilley
authors.affiliation: Department of Pharmacology, The Ohio State University, 333 West 10th Avenue, 5184B Graves Hall, Columbus, OH 43210, USA.
authors.forename: Dawn D
authors.initials: DD
authors.lastname: Han
authors.affiliation: Department of Pharmacology, The Ohio State University, 333 West 10th Avenue, 5184B Graves Hall, Columbus, OH 43210, USA; Neuroscience Graduate Studies Program, The Ohio State University, Columbus, OH 43210, USA.
authors.forename: Keerthi
authors.initials: K
authors.lastname: Thirtamara-Rajamani
authors.affiliation: Department of Pharmacology, The Ohio State University, 333 West 10th Avenue, 5184B Graves Hall, Columbus, OH 43210, USA; Ohio State Biochemistry Graduate Program, The Ohio State University, Columbus, OH 43210, USA.
authors.forename: Erik R
authors.initials: ER
authors.lastname: Hill
authors.affiliation: Department of Neuroscience, The Ohio State University, Columbus, OH 43210, USA.
authors.forename: Georgia A
authors.initials: GA
authors.lastname: Bishop
authors.affiliation: Department of Pharmacology, The University of Tennessee, Memphis, TN 38163, USA.
authors.forename: Fu-Ming
authors.initials: FM
authors.lastname: Zhou
authors.affiliation: Molecular Virology, Immunology & Medical Genetics, The Ohio State University, Columbus, OH 43210, USA.
authors.forename: Matthew J
authors.initials: MJ
authors.lastname: During
authors.affiliation: Department of Pharmacology, The Ohio State University, 333 West 10th Avenue, 5184B Graves Hall, Columbus, OH 43210, USA. Electronic address: gu.37@osu.edu.
authors.forename: Howard H
authors.initials: HH
authors.lastname: Gu
mesh_terms: D000818:Animals; D003042:Cocaine / Q000494:pharmacology*; D019970:Cocaine-Related Disorders / Q000503:physiopathology; D003214:Conditioning, Classical / Q000187:drug effects* / Q000502:physiology; D003342:Corpus Striatum / Q000187:drug effects* / Q000503:physiopathology; D004298:Dopamine / Q000378:metabolism; D050483:Dopamine Plasma Membrane Transport Proteins / Q000235:genetics / Q000378:metabolism*; D018765:Dopamine Uptake Inhibitors / Q000494:pharmacology*; D055879:Gene Knock-In Techniques; D057809:HEK293 Cells; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D009714:Nucleus Accumbens / Q000187:drug effects / Q000503:physiopathology; D011595:Psychomotor Agitation / Q000503:physiopathology*; D012201:Reward; D013028:Space Perception / Q000187:drug effects / Q000502:physiology
chemical_list: D050483:Dopamine Plasma Membrane Transport Proteins; D018765:Dopamine Uptake Inhibitors; D003042:Cocaine; D004298:Dopamine
keywords: Addiction; Cocaine; Dopamine; Locomotion; Reward; Transporter