The goal of this competing continuation is to further the development of the Candidate as a translational neuroscientist. In this competing continuation, the Candidate plans to focus on the role of glutamatergic synaptic transmission in sensitization. It is well known that psychostimulants act by increasing synaptic dopamine levels, principally in the nucleus accumbens. When taken repeatedly, constant doses produce an increasing behavioral response -- known as psychostimulant sensitization. This animal model of drug dependence is mediated by neuroplastic changes both at the level of the dopamine neuron cell bodies in the ventral tegmental area and at their synapses in the nucleus accumbens. These changes require glutamatergic synaptic transmission. Recently, this laboratory has made the striking observation that dopamine neurons corelease glutamate. If so, glutamatergic synapses of dopamine neurons are likely to be important in sensitization. To test this, mice generated in this laboratory with fluorescent dopamine neurons will be used to examine the relationship between the dopaminergic and glutamatergic terminals of single dopamine neurons and to assess the plastic capabilities of the glutamatergic synapses as a basis for sensitization. To address the role of the glutamatergic cotransmission in the behaving animal, another line of mice have been made that lack glutaminase -- the enzyme principally responsible for the production of neurotransmitter glutamate. Preliminary results confirming the importance of glutaminase will be extended to test this definitively. Interestingly, mice heterozygous for glutaminase appear to be already in a sensitized state, as they show an exaggerated response to stimulants. Using tissue-specific rescue and deletion approaches, the final aim is to identify the crucial glutamatergic circuits underlying the sensitized phenotype. Finally, the role of glutamatergic cotransmission by dopamine neurons in the development of sensitization will be tested in mice lacking glutaminase in their dopamine neurons. This integrated approach should help to elucidate the crucial glutamatergic circuits underlying sensitization, and offer new targets for the pharmacological reduction of sensitization and thus of drug dependence.

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Research Scientist Development Award - Research (K02)
Project #
5K02DA000356-09
Application #
7271317
Study Section
Human Development Research Subcommittee (NIDA)
Program Officer
Frankenheim, Jerry
Project Start
1999-05-01
Project End
2009-07-31
Budget Start
2007-08-01
Budget End
2008-07-31
Support Year
9
Fiscal Year
2007
Total Cost
$122,861
Indirect Cost
Name
Columbia University (N.Y.)
Department
Psychiatry
Type
Schools of Medicine
DUNS #
621889815
City
New York
State
NY
Country
United States
Zip Code
10032
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