The mesolimbic system, particularly the dopaminergic neurons of the ventral tegmental area (VTA) play an essential role in endogenous reward. Activation of the reward pathway is associated with increased dopamine release brought about by an increase in the activity of VTA dopaminergic neurons. The reinforcing actions of drugs of abuse such as opioids and psychostimulants are mediated by increasing the activity of dopamine neurons. A grasp of the mechanisms that regulate the excitability of these cells, therefore, is essential for a better understanding of the cellular mechanisms involved in endogenous reward and in drug addiction. Recently, it has been shown that stimulation of glutametergic synaptic inputs result in a slow hyperpolarization of VTA dopamine cells that requires the activation of glutamate metabotropic receptors (mGluRs). It has been proposed that these inhibitory postsynaptic potentials (IPSPs) are produced by activation of small conductance calcium-dependent potassium channels (SK) by calcium release from intracellular stores. Both of the two calcium release channels, the inositol triphosphate (InsP3) and ryanodine receptors, have been implicated in this process. The main goal of this proposal is to test the hypothesis that InsP3-evoked calcium release, augmented by calcium-induced calcium release (CICR), mediates the mGluR-dependent IPSPs in VTA dopaminergic cells. These experiments will be done by combining whole-cell recordings from VTA dopaminergic neurons in acutely prepared midbrain slices with calcium imaging. To mobilize calcium, all second messenger cascades will be bypassed and InsP3 will be photoreleased into the cytosol by flash photolysis of caged InsP3. The extent to which CICR contributes to InsP3-evoked calcium transients will be evaluated by inhibition of ryanodine receptors with selective antagonists. In addition, the extent to which, and the mechanism by which, prior neuronal activity modulates the mGluR-mediated IPSPs will be delineated.

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Research Project (R01)
Project #
5R01DA015033-04
Application #
6785391
Study Section
Special Emphasis Panel (ZRG1-MDCN-4 (01))
Program Officer
Lin, Yu
Project Start
2001-08-01
Project End
2006-05-31
Budget Start
2004-06-01
Budget End
2005-05-31
Support Year
4
Fiscal Year
2004
Total Cost
$292,250
Indirect Cost
Name
Albert Einstein College of Medicine
Department
Neurosciences
Type
Schools of Medicine
DUNS #
110521739
City
Bronx
State
NY
Country
United States
Zip Code
10461