title: Increased amphetamine-induced hyperactivity and reward in mice overexpressing the dopamine transporter.
abstract: The dopamine transporter (DAT) plays a key role in the regulation of dopaminergic signaling wherein it controls both the spatial and temporal actions of dopamine. Here we evaluated the behavioral and neurochemical consequences of increased DAT function by generating DAT transgenic mice (DAT-tg) that overexpress the transporter. These mice were generated by pronuclear injection of a bacterial artificial chromosome containing the mouse DAT locus, yielding an anatomical expression pattern of DAT-tg identical to WT. In DAT-tg mice there is a 3-fold increase in the levels of total and membrane-expressed DAT, but synaptic plasma membrane fractions of DAT-tg mice show only a 30% increase in transporter levels. Functional studies reveal that in the DAT-tg animals there is a 50% increase in the rate of dopamine (DA) uptake resulting in extracellular levels of DA that are decreased by approximately 40%. Behaviorally, DAT-tg animals display similar locomotor stimulation when treated with DAT blockers such as GBR12909, methylphenidate, and cocaine. However, these mice demonstrate markedly increased locomotor responses to amphetamine compared with WT animals. Furthermore, compared with controls, there is a 3-fold greater increase in the amount of DA released by amphetamine in DAT-tg mice that correlates with the 3-fold increase in protein expression. Finally, DAT-tg animals show reduced operant responding for natural reward while displaying preference for amphetamine at much lower doses (0.2 and 0.5 mg/kg) than WT mice (2 mg/kg). These results suggest that overexpression of DAT leads to a marked increase in sensitivity to psychomotor and rewarding properties of amphetamine.
authors.affiliation: Department of Cell Biology, Duke University Medical Center, Durham, NC 27710, USA.
authors.forename: Ali
authors.initials: A
authors.lastname: Salahpour
authors.forename: Amy J
authors.initials: AJ
authors.lastname: Ramsey
authors.forename: Ivan O
authors.initials: IO
authors.lastname: Medvedev
authors.forename: Brian
authors.initials: B
authors.lastname: Kile
authors.forename: Tatyana D
authors.initials: TD
authors.lastname: Sotnikova
authors.forename: Ericka
authors.initials: E
authors.lastname: Holmstrand
authors.forename: Valentina
authors.initials: V
authors.lastname: Ghisi
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Nicholls
authors.forename: Ling
authors.initials: L
authors.lastname: Wong
authors.forename: Karen
authors.initials: K
authors.lastname: Murphy
authors.forename: Susan R
authors.initials: SR
authors.lastname: Sesack
authors.forename: R Mark
authors.initials: RM
authors.lastname: Wightman
authors.forename: Raul R
authors.initials: RR
authors.lastname: Gainetdinov
authors.forename: Marc G
authors.initials: MG
authors.lastname: Caron
mesh_terms: D000661:Amphetamine / Q000494:pharmacology*; D000818:Animals; D050483:Dopamine Plasma Membrane Transport Proteins / Q000235:genetics / Q000378:metabolism*; D005260:Female; D005786:Gene Expression Regulation; D007150:Immunohistochemistry; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D016253:Microscopy, Immunoelectron; D009043:Motor Activity
chemical_list: D050483:Dopamine Plasma Membrane Transport Proteins; D000661:Amphetamine