Drugs of abuse (amphetamine, cocaine, morphine) produce a long- lasting sensitization to subsequent drug exposures that may underlie a progressive enhancement in the rewarding properties of the drug (craving) in humans. In rats, sensitization can be observed as progressively enhanced locomotion in response to repeated drug. Injection of psychostimulants directly into the VTA causes behavioral sensitization to peripherally administered drugs. These data demonstrate that the sensitizing effects of psychostimulants are mediated within the VTA itself. Several lines of recent evidence indicate that modification of glutamatergic synapses within the VTA is required to initiate sensitization. First, antagonists of the NMDA subtype of glutamate receptor block sensitization, either delivered systemically or locally into the VTA. Secondly, behavioral sensitization does not develop when glutamatergic fibers from the prefrontal cortex are transsected. Third, electrical stimulation of prefrontal afferents sensitizes animals to subsequent cocaine, mimicking behavioral sensitization. Finally, in animals that exhibit behavioral sensitization following psychostimulant administration, single dopamine neurons in the VTA become abnormally responsive to glutamate. Taken together, these data suggest the hypothesis that during sensitization an NMDA-receptor dependent form of synaptic plasticity occurs in VTA dopamine neurons that results in strengthened glutamatergic synaptic transmission. The vast majority of work on sensitization has been done in vivo. I propose to use electrophysiogical recordings from dopamine neurons in a VTA slice preparation in vitro to investigate the cellular basis of sensitization in this brain area. The goals of this proposal are: 1) to test for synaptic plasticity at glutamate synapses in brain slices through the VTA, 2) to examine the direct effects of amphetamine on excitatory synaptic transmission onto VTA neurons, and 3) to examine glutamatergic synaptic transmission in vitro in VTA slices from animals treated chronically with amphetamine. This studies will provide evidence for the mechanisms that contribute to behavioral sensitization, and thus to drug craving in human drug abuse.
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