Behavior of knock-in mice with a cocaine-insensitive dopamine transporter after virogenetic restoration of cocaine sensitivity in the striatum

Brian O'Neill, Michael R. Tilley, Dawn D. Han, Keerthi Thirtamara-Rajamani, Erik R. Hill, Georgia A. Bishop, Fu Ming Zhou, Matthew J. During, Howard H. Gu

Research output: Contribution to journalArticlepeer-review

15 Scopus citations

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.

Original languageEnglish
Pages (from-to)626-633
Number of pages8
JournalNeuropharmacology
Volume79
DOIs
StatePublished - Apr 2014
Externally publishedYes

Keywords

  • Addiction
  • Cocaine
  • Dopamine
  • Locomotion
  • Reward
  • Transporter

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