Characterization of conditioned place preference to cocaine in congenic dopamine transporter knockout female mice
ABSTRACT The dopamine transporter (DAT) is thought to play a major role in the rewarding effects of cocaine. Therefore, it is surprising that cocaine reveals conditioned effects in DAT knockout (DAT-KO) mice.
To examine these findings further, we obtained complete dose-effect curves for DAT-KO and DAT wild-type (DAT-WT) mice in a cocaine conditioned place preference (CPP) procedure.
Congenic C57BL6 background female DAT-KO and DAT-WT mice were conditioned in a three-compartment place preference apparatus. Conditioning consisted of three 30-min sessions with cocaine (2.5, 5.0, 10.0, 20.0, or 40.0 mg/kg) and three 30-min sessions with saline. The distribution of time in each choice compartment was determined after each pair of conditioning sessions (one cocaine and one saline session).
DAT-WT mice revealed CPP over a wide range of cocaine doses (5.0-40 mg/kg), whereas DAT-KO mice revealed CPP over a more restricted range of doses, with consistent CPP only occurring with 10 mg/kg of cocaine.
CPP for cocaine develops in both DAT-KO and DAT-WT mice; however, the dose range at which CPP develops is much more restricted in DAT-KO mice than in DAT-WT mice. These observations corroborate the significant role of DAT inhibition in cocaine's conditioned effects.
SourceAvailable from: hopkinsmedicine.org
Article: NOTE: The Biographical Sketch may not exceed four pages. Items A and B (together) may not exceed two of the four-page limit. Follow the formats and instructions on the attached sample. A. Positions and Honors. List in chronological order previous positions, concluding with your present position. List any honors. Include present membership on any Federal Government public advisory committee
[Show abstract] [Hide abstract]
ABSTRACT: ABSTRACT Although both cocaine and amphetamine mainly target the dopamine transporter (DAT) and cause psychomotor effects, they have very different mechanisms of actions. We examined whether responses to cocaine and amphetamine were affected differentially by changes in DAT expression levels using transgenic mice with different DAT expression levels. In the constitutive DAT knockdown mice, reduced DAT expression enhanced cocaine's locomotor stimulatory effects and at the same time diminished amphetamine's locomotor stimulatory effects. Similar effects were observed in the inducible DAT knockdown mice, ruling out the contribution of developmental compensations in DAT knockdown mice. Extracellular dopamine levels in response to psychostimulants were assessed by in vivo microdialysis. While amphetamine-induced increase in extracellular dopamine was drastically diminished in constitutive DAT knockdown mice, cocaine-induced increase in extracellular dopamine had a faster onset in knockdown mice compared to wild-type controls. Postsynaptically, D1 agonist stimulated c-fos expression was significantly attenuated in constitutive DAT knockdown mice compared to wild-type controls. We propose that responses to cocaine and amphetamine depend on psychostimulant drug type, drug dose as well as DAT expression level. DAT expression level affects presynaptic responses to psychostimulants directly and postsynaptic responses to psychostimulants indirectly via changes in receptor signaling. Our data implies that individual differences in DAT expression (either genetically or pharmacologically-induced) may affect susceptibility to addiction of different types of psychostimulants.Journal of neurogenetics 03/2014; 28(1-2). DOI:10.3109/01677063.2014.908191 · 1.38 Impact Factor
Radiotherapy and Oncology 05/2011; 99. DOI:10.1016/S0167-8140(11)70954-9 · 4.86 Impact Factor