The intention of this project is to examine post-synaptic changes in second and third messenger systems in brain areas involved in behavioral sensitization to cocaine or kindling. The role of dopamine-regulated phosphoproteins (i.e., DARPP-32) in the striatum during behavioral sensitization is being studied. Preliminary results suggest that the increases in the phosphorylation of DARPP-32 seen with acute cocaine administration are attenuated following repeated administration of cocaine. FOS, a transcription factor that acts as a third messenger, also behaves in a similar fashion. In the striatum, the increases in FOS seen after an acute cocaine injection are diminished following repeated administration of cocaine. Because both DARPP-32 and FOS are regulated by the dopamine Dl receptor in the striatum, a common, but as yet unknown, mechanism may be responsible for the similar changes seen in both systems. With cocaine seizures, FOS is also increased in the hippocampus. This does not seem to be related to whether the cocaine was given acutely or repeatedly, but only to the incidence of the seizure. Thus, different brain regions seem to participate in cocaine sensitization and seizures. In other experiments related to fear conditioning and behavioral sensitization, rats that are given foot shocks or are reintroduced to an environment in which they have previously been given footshocks, show increased startle response. In these situations, c-fos mRNA is also dramatically increased in the amygdala. This is the first study to show that following unconditioned and conditioned fear, c-fos is increased in the amygdala, a nucleus known to be crucial for fear conditioning and sensitization.
