The aim of this proposal is to understand the cellular and synaptic modifications that underlie the induction of addiction to drugs of abuse. Behavioral sensitization is an animal model for the development of paranoid ideation, psychosis, and the intensification of drug-craving and seeking that accompanies human drug addiction. Pharmacological and lesion studies have implicated a critical role for glutamate and the dopamine cells of the VTA in the development of these changes. This proposal will test the hypothesis that synaptic modifications underlie the induction of behavioral sensitization. The proposed model predicts that repeated drug presentations drive a persistent increase in VTA glutamatergic synaptic strength, such that further increases are no longer possible. This model will be tested to vitro by first characterizing the types and mechanisms of the synaptic plasticity which exist within the VTA slices from drug-naive animals, and then observing how they are affected by acute application of amphetamine, a psychomotor stimulant. The relationship between the VTA synaptic plasticity and the induction of behavioral sensitization will then be tested by characterizing the nature of the synaptic plasticity that exists in slices from drug-sensitized animals, and observing how this plasticity is affected by acute amphetamine exposure. Finally, synaptic plasticity will be blocked pharmacologically to see whether this also blocks the induction of behavioral sensitization.
