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1.  Cocaine produces conditioned place aversion in mice with a cocaine insensitive dopamine transporter 
Genes, brain, and behavior  2012;12(1):34-38.
Cocaine is an inhibitor of the dopamine, norepinephrine, and serotonin reuptake transporters. Because its administration would therefore elevate signaling of all these three neurotransmitters, many studies have been aimed at attributing individual effects of cocaine to specific transmitter systems. Using mice with a cocaine insensitive dopamine transporter (DAT-CI mice), we previously showed that cocaine-induced dopamine elevations were necessary for its rewarding and stimulating effects. In this study, we observe that DAT-CI mice exhibit cocaine-conditioned place aversion, and that its expression depends on their genetic background. Specifically, DAT-CI mice backcrossed to the C57Bl/6J strain background did not display a preference or an aversion to cocaine, whereas DAT-CI mice that were on a mixed 129S1/SvImJ × C57Bl/6J (129B6) background had a robust conditioned place aversion to cocaine. These results indicate that while inhibition of the dopamine transporter (DAT) is necessary for cocaine reward, other cocaine targets and neurotransmitter systems may mediate the aversive properties of cocaine. Furthermore, the aversive effect of cocaine can be observed in the absence of a DAT-mediated rewarding effect, and it is affected by genomic differences between these two mouse strains.
doi:10.1111/j.1601-183X.2012.00872.x
PMCID: PMC3553275  PMID: 23083326
Aversion; Addiction; Cocaine; Dopamine; Reward
2.  Dopamine transporter inhibition is required for cocaine-induced stereotypy 
Neuroreport  2008;19(11):1137-1140.
The primary mechanism by which cocaine induces stereotypy has been difficult to discern because cocaine has three high affinity targets, the reuptake transporters for dopamine (DAT), norepinephrine, and serotonin. To dissect out the role of DAT in cocaine effects, we generated a knock-in mouse line with a cocaine insensitive DAT (DAT-CI mice). DAT-CI mice provide a powerful tool that can directly test whether DAT inhibition is important for cocaine-induced stereotypy. We found that acute cocaine failed to produce stereotypy in DAT-CI mice. In fact, 40 mg/kg cocaine suppressed stereotypy in DAT-CI mice but produced profound stereotypy in wild-type mice. These findings suggest that DAT inhibition is necessary for cocaine-induced stereotypy. Furthermore, mechanisms independent of DAT inhibition appear to inhibit stereotypy.
doi:10.1097/WNR.0b013e3283063183
PMCID: PMC3222591  PMID: 18596615
Cocaine; dopamine transporter; knock-in mice; stereotypy
3.  Potencies of Cocaine Methiodide on Major Cocaine Targets in Mice 
PLoS ONE  2009;4(10):e7578.
Cocaine methiodide (CM), a charged cocaine analog, cannot pass the blood brain barrier. It has been assumed the effects of systemic CM represent cocaine actions in peripheral tissues. However, the IC50 values of CM have not been clearly determined for the major cocaine targets: dopamine, norepinephrine, and serotonin transporters, and sodium channels. Using cells transfected with individual transporters from mice and synaptosomes from mouse striatum tissues, we observed that the inhibition IC50 values for monoamine uptake by CM were 31-fold to 184-fold higher compared to cocaine at each of the transporters. In dorsal root ganglion neurons, cocaine inhibited sodium channels with an apparent IC50 of 75 µM, while CM showed no observable effect at concentrations up to 3 mM. These results indicate that an equal dose of CM will not produce an equivalent peripheral effect of cocaine.
doi:10.1371/journal.pone.0007578
PMCID: PMC2762027  PMID: 19855831
4.  Financial and Psychological Risk Attitudes Associated with Two Single Nucleotide Polymorphisms in the Nicotine Receptor (CHRNA4) Gene 
PLoS ONE  2009;4(8):e6704.
With recent advances in understanding of the neuroscience of risk taking, attention is now turning to genetic factors that may contribute to individual heterogeneity in risk attitudes. In this paper we test for genetic associations with risk attitude measures derived from both the psychology and economics literature. To develop a long-term prospective study, we first evaluate both types of risk attitudes and find that the economic and psychological measures are poorly correlated, suggesting that different genetic factors may underlie human response to risk faced in different behavioral domains. We then examine polymorphisms in a spectrum of candidate genes that affect neurotransmitter systems influencing dopamine regulation or are thought to be associated with risk attitudes or impulsive disorders. Analysis of the genotyping data identified two single nucleotide polymorphisms (SNPs) in the gene encoding the alpha 4 nicotine receptor (CHRNA4, rs4603829 and rs4522666) that are significantly associated with harm avoidance, a risk attitude measurement drawn from the psychology literature. Novelty seeking, another risk attitude measure from the psychology literature, is associated with several COMT (catechol-O-methyl transferase) SNPs while economic risk attitude measures are associated with several VMAT2 (vesicular monoamine transporter) SNPs, but the significance of these associations did not withstand statistical adjustment for multiple testing and requires larger cohorts. These exploratory results provide a starting point for understanding the genetic basis of risk attitudes by considering the range of methods available for measuring risk attitudes and by searching beyond the traditional direct focus on dopamine and serotonin receptor and transporter genes.
doi:10.1371/journal.pone.0006704
PMCID: PMC2724734  PMID: 19693267
5.  Cocaine reward and locomotion stimulation in mice with reduced dopamine transporter expression 
BMC Neuroscience  2007;8:42.
Background
The dopamine transporter (DAT) plays a critical role in regulating dopamine neurotransmission. Variations in DAT or changes in basal dopaminergic tone have been shown to alter behavior and drug responses. DAT is one of the three known high affinity targets for cocaine, a powerful psychostimulant that produces reward and stimulates locomotor activity in humans and animals. We have shown that cocaine no longer produces reward in knock-in mice with a cocaine insensitive mutant DAT (DAT-CI), suggesting that cocaine inhibition of DAT is critical for its rewarding effect. However, in DAT-CI mice, the mutant DAT has significantly reduced uptake activity resulting in elevated basal dopaminergic tone, which might cause adaptive changes that alter responses to cocaine. Therefore, the objective of this study is to determine how elevated dopaminergic tone affects how mice respond to cocaine.
Results
We examined the cocaine induced behavior of DAT knockdown mice that have DAT expression reduced by 90% when compared to the wild type mice. Despite a dramatic reduction of DAT expression and marked elevation in basal dopamine tone, cocaine produced reward, as measured by conditioned place preference, and stimulated locomotor activity in these mice.
Conclusion
A reduction in DAT expression and elevation of dopaminergic tone do not lead to adaptive changes that abolish the rewarding and stimulating effects of cocaine. Therefore, the lack of reward to cocaine observed in DAT-CI mice is unlikely to have resulted from the reduced DAT activity but instead is likely due to the inability of cocaine to block the mutated DAT and increase extracellular dopamine. This study supports the conclusion that the blockade of DAT is required for cocaine reward and locomotor stimulation.
doi:10.1186/1471-2202-8-42
PMCID: PMC1914080  PMID: 17584943

Results 1-5 (5)