My laboratory has been funded by NIDA since 1992 (FIRST Award, 1992-1997; RO1, 1996-2000) to study the role of glutamate in behavioral sensitization to amphetamine. Sensitization is an animal model for the intensification of craving that underlies drug dependency in human addicts. Work supported by my FIRST Award demonstrated that glutamate transmission is required for the development of sensitization and that sensitized rats show dramatic alterations in glutamate neurotransmission. The goal of my R01 is to characterize such alterations and determine how drugs of abuse, which initially target the dopamine (DA) transporter, ultimately produce adaptations in glutamate systems. This is important because it is likely that glutamate mediates the plasticity that underlies the transition from drug experimentation to drug dependency. An understanding of glutamate's role in drug-induced neuroadaptations may lead to the development of pharmacotherapies for the costly and tragic epidemic of addiction. My R01 has the following Aims: 1) To characterize amphetamine's effects on glutamate transmission in the ventral tegmental area (VTA), where sensitization is initiated. 2) To characterize amphetamine's effects on glutamate transmission in the nucleus accumbens (NAc), where sensitization is expressed. 3) To determine if repeated amphetamine administration leads to persistent changes in basal glutamate levels or turnover in VTA or NAc. 4) To determine if amphetamine-induced changes in glutamate transmission in VTA and NAc reflect disinhibition of glutamate-containing projections originating in prefrontal cortex. 5) To characterize effects of repeated amphetamine administration on expression of AMPA and NMDA receptor subunits in these circuits, both at mRNA and protein levels. While studies supported by my R01 have already led to novel hypotheses for glutamate's role in sensitization, we have reached a point where continued progress will require new experimental approaches. I am applying for this K02 Award to obtain relief from administrative and teaching responsibilities that now consume over 60 percent of my time. Under the plan described herein, these responsibilities will be significantly reduced, enabling me to devote 80 percent effort to implementing new approaches and integrating them with my existing research plan. There are 4 specific directions in which I plan to expand our research capabilities: 1) Improving methods for quantifying receptor expression, which is essential for identifying the phenotype(s) of neurons that exhibit amphetamine-induced changes in glutamate receptor expression. 2) Developing primary cultures of NAc neurons as a model system to study dopamine/glutamate receptor interactions. 3) Investigating glutamate involvement in conditioned locomotion, so as to begin to address the crucial role of environmental stimuli in eliciting craving. 4) Developing electrochemical methods for in vivo monitoring of glutamate levels. I have consulted with internationally recognized experts in the development of these new directions, all of whom will continue to provide training and consultation during the period of this Award.
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