The objective of this proposal is to establish causal relationships between the function of the glutamatergic synapses of the amygdala, a key brain structure in learning and memory associated with emotional responses both in humans and animals, and cocaine addiction. To accomplish this goal we plan to study in rodent brain slices the, effects of cocaine on the basic cellular and molecular mechanisms of synaptic transmission and different forms of plasticity in different major pathways transmitting behaviorally important information to the amygdala and within the amygdala. Here we ask two specific questions: What are the synaptic effects of cocaine in the lateral amygdala? How does repeated cocaine administration affect mechanisms of synaptic plasticity in the amygdala? Both the compound and unitary postsynaptic responses will be recorded and analyzed to estimate quantal parameters of synaptic transmission during different forms of synaptic plasticity in the amygdala under control conditions and in slices from cocaine treated rats. As a working hypothesis we suggest that the ability of cocaine to establish addictive behaviors is likely to affect molecular mechanisms of synaptic transmission in the amygdala. We suggest that the persistent synaptic rearrangements resulting from cocaine use will affect the mechanisms of induction and expression of different forms of synaptic plasticity in the amygdala. These exploratory studies are important to our understanding of the mechanisms of cocaine addiction. They will determine whether the ability of cocaine to establish addictive behaviors engages molecular mechanisms of synaptic transmission and plasticity in the amygdala, one of the main elements of the brain reward circuitry. These experiments will provide a framework for our future grant applications in which we will use additional electrophysiological, behavioral and imaging techniques in an attempt to relate the long-term synaptic modifications induced by exposure to cocaine to changes in synaptic structure and eventually to changes in the amygdala-based associative learning. A better understanding of the effects of cocaine on synaptic functions in amygdala will permit the development of better therapeutics treatments for cocaine addiction and craving.
