Neuroactive Steroids,Dopamine and Cocaine Sensitization

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DESCRIPTION (provided by applicant): The mesotelencephalic dopamine system is implicated in the etiologies of schizophrenia and Parkinson's disease as well as in the reinforcing properties of psychostimulants, including cocaine and amphetamine. Recent evidence from our laboratory indicates that a number of neuroactive steroids influence dopamine transmission in the striatum by potentiating or inhibiting ionotropic glutamate receptor function. The major objective of this project is to follow up on these findings by assessing the activity of these neuroactive steroids in the nucleus accumbens, the limbic portion of the striatal complex that is the locus for the reinforcing effects of many drugs of abuse. To that end, we will assess the modulatory influence of neuroactive steroids on the behavioral and neurochemical effects of ionotropic glutamate receptor agonists in the core and shell of the nucleus accumbens. Using microdialysis (coupled with HPLC-EC and HPLC-MS) and behavioral techniques we will determine, i) the accumulation of systemically administered neuroactive steroids in the brain, ii) the behavioral and neurochemical consequences of neuroactive steroid modulation of ionotropic glutamate receptors in the nucleus accumbens shell, iii) the influence of neuroactive steroids on the initiation of behavioral sensitization to cocaine and iv) the influence of neuroactive steroids on cocaine priming-induced reinstatement of cocaine-seeking behavior. Collectively, these experiments will provide information on the activity of neuroactive steroids in the CNS, which will be invaluable for the development of steroids as potential pharmacological treatments for disorders involving ionotropic glutamate receptors in general and the craving associated with cocaine addiction in particular.