The adenosine A2A receptor offers a novel and compelling target for the modulation of addictive behaviors. Its expression in brain is largely restricted to the nucleus accumbens and straitum, where dopamine, glutamate and other neurotransmitters contribute to the sensitizing and reinforcing effects of psychostimulants. The striatal A2A receptor can modulate the release of these neurotransmitters as well as their postsynaptic effects. In addition, it influences both the acute behavioral effects of psychostimulants, and (based on our preliminary studies) the behavioral sensitization induced by repeated psychostimulant exposure. These discrete anatomical, neuromodulatory and behavioral features point to an underappreciated role of A2A receptors in basal ganglia physiology and addiction biology. We propose (in response to NIDA PA-99-033) to investigate the role of the A2A receptor in behavioral sensitization and self-administration models of psychostimulant addiction. Our core hypothesis that A2A receptor inactivation attenuates the behavioral and biochemical changes induced by repeated psychostimulant administration will be systematically tested using complementary genetic and classic pharmacological approaches to A2A receptor inactivation.
Specific Aim 1 will characterize the attenuation of amphetamine-induced locomotor sensitization and cocaine self-administration observed in A2A receptor knockout (A2A KO) mice. The effects of A2A receptor antagonists on the development and expression of psychostimulant-induced sensitization will then be correlated with the A2A KO phenotype.
Specific Aim 2 a will explore A2A receptor-facilitated neurotransmitter release as potential presynaptic mechanism of behavioral sensitization. In vivo microdialysis studies will focus on how A2A receptor inactivation affects the enhanced release of dopamine, glutamate and acetylcholine that contributes to behavioral sensitization.
Specific Aim 2 b seeks to identify postsynaptic mechanisms involved in A2A receptor regulation of behavioral sensitization. We will examine the effects of A2A receptor deficiency on a potential mediator (deltaFosB) and modulator (NAC-1) of the postsynaptic adaptations sustaining behavioral sensitization. Together these studies will clarify the role of A2A receptors in psychostimulant-induced addictive behaviors, and thus may encourage the development of novel, specific strategies for treating psychostimulant abuse and related addiction disorders

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Research Project (R01)
Project #
5R01DA013508-03
Application #
6644200
Study Section
Integrative, Functional and Cognitive Neuroscience 8 (IFCN)
Program Officer
Lin, Yu
Project Start
2001-07-25
Project End
2006-05-31
Budget Start
2003-06-01
Budget End
2004-05-31
Support Year
3
Fiscal Year
2003
Total Cost
$291,800
Indirect Cost
Name
Massachusetts General Hospital
Department
Type
DUNS #
073130411
City
Boston
State
MA
Country
United States
Zip Code
02199
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