A major component of the neural circuit that is thought to mediate """"""""incentive-motivation"""""""" and """"""""reinforcement"""""""" is the mesolimbic dopamine (DA) system, which consists of the ventral tegmental area (VTA) and the nucleus accumbens (Nac) along with their afferent and efferent connections. The great clinical importance of developing a sophisticated understanding of this brain system has been emphasized because of is importance in mediating many of the behavioral actions of drugs of abuse as well as is role in mental illnesses such as schizophrenia. Although much is known about the anatomy of the NAc and VTA and some of the cellular and molecular changes that occur within these structures following exposure to therapeutic drugs as well as drugs of abuse, surprisingly little is known about basic synaptic processes in these structures and how they might be modified by normal and pathological experience. A well characterized behavioral response that involves modifications within the mesolimbic DA system is the behavioral sensitization that occurs in response to psychomotor stimulants as well as other drugs of abuse. The overriding hypothesis underlying this proposal is that synaptic plasticity at excitatory inputs to both the NAc and VTA is critically important for mediating both behavioral sensitizaton to psychomotor stimultants and for the functioning of the mesolimbic DA system during normal behavior. The major goals of the proposed experiments re to elucidate the basic properties and mechanism of synaptic plasticity at excitator synapses in the NAc an TA. This will be accomplished using whole cell patch clamp recording techniques and in vitro brain slice preparations. Specific studies will include detailed analysis of long-term depression (LTD) in the Nac and long-term potentiation (LTP) in the VTA. The effects of dopamine (DA) and psychomotor stimulants (cocaine and amphetamine) on these phenomena will also be examined. Finally whether prolonged in vivo exposure to amphetamine modifies excitatory synaptic transmission in the NAc and VTA will be determined. These experiments will provide important information about the mechanisms by which synaptic transmission in the mesolimbic DA system is modified both during normal behavior and following prolonged exposure to psychomotor stimulants. Such information is critical for a detailed understanding of the neural mechanism which contribute to the development of drug addiction as well as the development of severe mental illness such as schizophrenia.
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