Accumulating evidence suggests that the corticotropin releasing factor (CRF) neurotransmitter system may play a prominent role in the mediation of motivational aspects of drug dependence and that CRF receptors participate in the arousal-enhancing properties of psychostimulants and in behavioral sensitization. The objective of the proposed research is to define the membrane mechanism of action of the CRF neuro- transmitter system in control and after chronic cocaine administration in two limbic areas, the septum and the amygdala. This project will test the hypothesis that the effects of CRF agonists and antagonists in control neurons are mediated through different receptors in the septum and amygdala and that the altered effects of CRF after chronic cocaine are due to modulation of specific CRF receptors. In these studies, CRF, urocortin - an endogenous CRF-like peptide, CRF (9-33) - a CRF binding protein inhibitor, and peptide and non-peptide CRF receptor antagonists will be analyzed using whole patch and intracellular sharp electrode recording. Electrophysiological data will be compared in naive control, saline control, and chronic cocaine animals. The following specific aims will be addressed: 1. Define the effect of CRF, urocortin, the CRF binding protein inhibitor, and CRF receptor antagonists on synaptic transmission and on membrane conductance in septal and amygdala neurons, 2. Determine receptors mediating CRF actions by analyzing the effect of the specific CRF-R1 receptor and non-specific antagonists on the agonists' responses, 3. Analyze effects of CRF, urocortin, the CRF binding protein inhibitor, and CRF receptor antagonists, on synaptic transmission and membrane conductance in the septum and amygdala in saline control and chronic cocaine treated animals, and 4. Determine the time course of the development of CRF receptor-mediated changes and the persistence of these changes. The proposed studies will contribute valuable insight into the mechanisms of CRF actions in chronic cocaine addiction and its possible motivational role in drug dependence. These results may also provide critical information regarding non-peptide and peptide antagonists of CRF as potentially effective pharmacotherapies in the treatment of chronic cocaine dependence.
