Drugs of abuse, including amphetamine and cocaine, produce long-lasting behavioral sensitization to subsequent exposures to drug. This is manifested as increased locomotion in animals, and in humans, may underlie a progressive augmentation in the rewarding properties of the drug related to drug craving. Sensitization is initiated in the ventral tegmental area (VTA) of the midbrain, because direct injection of psychostimulants into the VTA causes behavioral sensitization like that seen with systemically administered drug, and because sensitization to peripherally administered stimulant is prevented when specific antagonists are delivered directly into the VTA. Several lines of evidence support the idea that modification of glutamatergic synapses on dopamine neurons in the VTA is required to initiate sensitization. Most compelling is the finding that sensitization is blocked by antagonists of the NMDA subclass of glutamate receptor, delivered either systemically or directly into the VTA. Given the established role of NMDA receptors in synaptic plasticity elsewhere in the brain, these data suggest the hypothesis that during behavioral sensitization an NMDA receptor-dependent form of synaptic plasticity occurs in VTA dopamine neurons that results in strengthened glutamatergic synaptic transmission. This application will test the hypothesis that synaptic plasticity in the VTA is modified by psychostimulants, and that this modification represents the onset of sensitization. We will continue using electrophysiological methods to examine the effects of amphetamine on neurons in the VTA slice preparation.

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Research Project (R01)
Project #
5R01DA011289-05
Application #
6378707
Study Section
Special Emphasis Panel (ZRG1-MDCN-5 (01))
Program Officer
Volman, Susan
Project Start
1997-07-15
Project End
2005-03-31
Budget Start
2001-04-01
Budget End
2002-03-31
Support Year
5
Fiscal Year
2001
Total Cost
$275,188
Indirect Cost
Name
Brown University
Department
Pharmacology
Type
Schools of Medicine
DUNS #
001785542
City
Providence
State
RI
Country
United States
Zip Code
02912
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Polter, Abigail M; Barcomb, Kelsey; Chen, Rudy W et al. (2017) Constitutive activation of kappa opioid receptors at ventral tegmental area inhibitory synapses following acute stress. Elife 6:
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Niehaus, Jason L; Murali, Manjari; Kauer, Julie A (2010) Drugs of abuse and stress impair LTP at inhibitory synapses in the ventral tegmental area. Eur J Neurosci 32:108-17

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