Drug abuse and addiction are major societal problems with devastating medical and economic consequences. The development of more effective treatment regimens requires a detailed understanding of the neural mechanisms which mediate the effects of drugs of abuse. This proposal outlines an extensive series of experiments which address fundamentally important questions about the mechanism of action of the psychostimulant drugs, cocaine and amphetamine, in the nucleus accumbens. The nucleus accumbens is part of the mesolimbic dopamine system and is considered a fundamental component of the neural circuits which mediate many of the behavioral and reinforcing actions of drugs of abuse. Despite the clear importance of the nucleus accumbens in mediating many of the behavioral effects of drugs of abuse, relatively little is known about synaptic processes within this structure and how these are modified by acute and chronic exposure to such drugs. An initial goal of the proposed experiments is to examine excitatory synaptic transmission and the different forms of synaptic plasticity which can be generated at the synapse between prelimbic cortical afferents and cells in the core region of the nucleus accumbens. This will be accomplished using an in vitro rat brain slice preparation and single cell electrophysiological recording techniques. The occurrence and mechanisms of both long-term potentiation (LTP) and long-term depression (LTD) will be examined. Because a major action of psychostimulant drugs such as cocaine and amphetamine is to block the re-uptake of the neurotransmitter, dopamine (DA), a second series of experiments will examine the actions of DA on synaptic transmission and pharmacologically characterize the DA receptor subtype mediating the observed effect(s) using subtype specific agonists and antagonists. Whether endogenous DA or exogenously applied DA influences the generation of LTP or LTD will also be examined and if so, the DA receptor subtype(s) responsible for these effects will be determined. After elucidating the actions of DA on synaptic physiology and plasticity, the effects of acute application of cocaine and amphetamine will be determined. Two related questions will be addressed: (1) do these psychostimulants closely mimic the actions of DA on synaptic physiology and synaptic plasticity? and (2) do they exert their actions via the same receptor mechanisms as DA? In a final extensive series of experiments, cocaine or amphetamine will be chronically administered to animals for 2 weeks at which point the effects of DA, cocaine, and amphetamine on synaptic physiology and synaptic plasticity in the nucleus accumbens will be examined and compared to those observed in control tissue. Whether modifications in the function of DA receptors or the DA transporter contribute to any observed changes will also be examined. The experiments in this proposal should provide fundamental information about the mechanisms by which cocaine and amphetamine modify synaptic processes in the nucleus accumbens. Such information is critical for a detailed understanding of the neural mechanisms which lead to drug abuse and drug addiction and will eventually lead to the development of pharmacological agents which modify these mechanisms so as to promote abstinence and retard the development of addiction.
