Dysregulation of the control of extracellular dopamine concentration, and its concomitant effect on neuronal firing, is a hallmark of many addictive drugs of abuse such as cocaine and amphetamine. The control of dopamine cell firing is of critical importance for the normal function of the mesolimbic system since dopamine cell firing can control phasic changes in dopamine concentration. These phasic changes may be of substantial importance since transient, impulse-dependent release of dopamine is known to be critical in the natural processing of reward in the mesolimbic system. Phasic increases in dopamine concentration are induced by bursts of action potentials. Therefore, the timing and duration of bursts are critical in the control of dopamine release. A posited cellular mechanism for dopamine cell bursting control is the metabotropic glutamate receptor (mGluR)-mediated inhibitory response that normally follows an ionotropic glutamate receptor-mediated excitatory response. Through the combined activation of ionotropic and metabotropic receptors in response to synaptically released glutamate a burst-pause pattern would be promoted. Psychostimulants such as amphetamine reduce the mGluR response thereby increasing burst duration and dopamine levels in target loci. However, although much progress has been made toward understanding the direct effects of psychostimulants on the brain, less is known about the cellular mechanisms involved in the vulnerability of certain individuals to prefer high amounts of drugs of abuse. Since psychostimulants cause different behavioral responses in different animals, the ability of psychostimulants to reduce the amplitude of the mGluR response may also differ. Differences in susceptibility of the mGluR response, and other synaptic responses, to desensitization may be genetically predisposed. A propensity to self-administer psychostimulants may correlate with the ability of psychostimulants to affect the amplitude of synaptic responses. The experiments in this proposal are designed to investigate whether differences in propensity to self-administer psychostimulants correlate with differences in the ability of psychostimulants to decrease the amplitude of synaptic responses. In the behavioral assay, rats will be trained to lever press for cocaine under fixed and progressive ratios of reinforcement. Yoked controls, which receive an infusion of cocaine whenever the corresponding, self-administering animal chooses to take cocaine, will be used to control for any differences in systemic cocaine concentrations. In the electrophysiological assay, whole-cell recordings of dopamine neurons will be obtained. The amplitude of the synaptic response and the effect of psychostimulants on the response will be measured. Dose-response curves will be constructed and comparisons will be made between recordings of dopamine neurons taken from slices of passive exposure and self-administration rats. Recordings from yoked-controls will also be used. Intracranial microinjections will also be used to determine whether the mGluR response can control cocaine self-administration.
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| Paladini, Carlos A; Williams, John T (2004) Noradrenergic inhibition of midbrain dopamine neurons. J Neurosci 24:4568-75 |
| Paladini, Carlos A; Mitchell, Jennifer M; Williams, John T et al. (2004) Cocaine self-administration selectively decreases noradrenergic regulation of metabotropic glutamate receptor-mediated inhibition in dopamine neurons. J Neurosci 24:5209-15 |
