The mesolimbic dopamine system, which consists of the ventral tegmental area (VTA) and the nucleus accumbens (NAc) along with their afferent and efferent connections, is thought to play a critical role in several aspects of motivated behavior. The overriding hypothesis, which provides the motivation for this proposal, is that plasticity at excitatory synapses in the VTA and NAc contributes to the normal functioning of the mesolimbic dopamine system in adaptive behavior and the drug-induced neural adaptations that lead to addiction. The major goal of this project is to use cellular electrophysiological recording techniques to further elucidate the adaptations that occur at excitatory synapses in the VTA and NAc following acute and chronic administration of several different classes of drugs of abuse. A second goal is to elucidate some of the molecular mechanisms that underlie these adaptations by using genetically modified mice that have been shown to have clear deficits in synaptic plasticity in other brain regions. These mice, which either lack the glutamate receptor subunit GluR1 or express a mutant form of the critical signaling molecule alpha-calcium/calmodulin-dependent protein kinase II (CaMKII), will also provide the opportunity to examine drug-induced behavioral correlates of the synaptic adaptations. The results of these experiments will provide important information about the neural circuit adaptations that occur in the mesolimbic dopamine system both during normal behavior and following exposure to drugs of abuse. Such information is critical for a detailed understanding of the neural mechanisms that lead to drug addiction as well as the development of severe mental illnesses such as schizophrenia.
