Dopaminergic neurons in the ventral midbrain, i.e., the ventral tegmental area and the substantia nigra pars compacta, are believed to be critically involved in the perception of reward and addiction to drugs of abuse, such as psychostimulants and opioids. The firing pattern of dopamine neurons, which is controlled by excitatory and inhibitory synaptic inputs, is significantly modulated by presentation of rewards and administration of drugs of abuse. Modulation of dopamine neuron firing affects dopamine release in target structures, and hence contributes to reward-driven motivated behaviors in vivo, including drug-seeking and drug-taking behaviors. It has been shown recently that repetitive stimulation of glutamatergic inputs to dopamine neurons evokes a slow inhibitory postsynaptic potential mediated by activation of metabotropic glutamate receptors (mGluRs). This hyperpolarization results from the opening of calcium-activated potassium channels following release of calcium from intracellular stores. The overall hypothesis of the proposal is that this calcium-mediated inhibition plays a key role in controlling the excitability of dopamine neurons and in psychostimulant-induced modulation of dopamine neuronal activity.
The first aim i s to determine the intracellular signaling pathway mediating the release of calcium following the activation of mGluRs. This will be accomplished by combined whole-cell patch clamp recording and confocal calcium imaging techniques using acutely prepared midbrain slices from rats. Furthermore, flash photolysis of caged compounds will be performed to examine the effects of second messengers applied directly into the cytosol on a millisecond time scale. These methods will enable detailed examination of the intracellular events that follow the activation of plasma membrane receptors.
The second aim i s to determine the impact of this glutamate-induced hyperpolarization on the firing pattern of dopamine neurons. An effort will be made to reproduce the firing pattern observed in vivo in an in vitro slice preparation.
The third aim i s to investigate how acute administration of psychostimulants interferes with the mGluR-induced inhibition to modulate the firing pattern of dopamine neurons. The information obtained will open a new avenue toward the understanding of the neural mechanism responsible for the development of drug addiction. ? ?
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