Relapse to drug use following periods of abstinence is a significant impediment in the long-term treatment ofcocaine dependence. Environmental stimuli or contexts previously associated with drug use or primingdoses of the abused drug can initiate relapse to compulsive drug-seeking and drug-taking behaviors.Project 4 will take intervention strategies identified through the NARC projects aimed at reducing relapse tococaine-seeking and systematically test compounds that will hopefully show significant and selectiveattenuation of cocaine-seeking in the relapse model. The advantages of having such a project within theNARC include: a) the ability to use standardized procedures through the NARC Animal Core of cocaine selfadministrationand reinstatement, b) testing acute and chronic drug treatment protocols that inhibit cocaineseekingthat can be further used in other NARC projects to assess the validity of cocaine-inducedneuroplasticity for drug target development, and c) integrating the NARC preclinical animal model of relapsewith potential clinical projects in the NARC Pilot Core as a transition to clinical assessment of promisingpharmacotherapies. Project 4 will initially focus on a few selected strategies of drug intervention bytargeting dopaminergic activity via a partial DA receptor agonist, enhancement of glutamatergichomeostasis, and antagonism of the orexin receptor. The proposed experiments will assess the effects ofdrug intervention after varied periods of cocaine-taking history, during and after extinction training, followingabstinence in the absence of extinction, and in response to both conditioned cues and cocaine priminginjections. Additional experiments will determine the effects of test compounds on ongoing cocaine-takingand responding for non-drug reinforcement (i.e., food). Since the focus of Project 4 will be the assessmentof compounds that can be quickly applied in a clinical environment, we will initially focus on systemicallyavailable, approved drugs for use in humans. However, in years 4-5 of the proposed NARC renewal, weintend to take identified compounds from other NARC Projects that can be thoroughly assessed using therelapse model.In summary, Project 4 will provide for the systematic examination of testable drug interventions derived fromstudies within the NARC. Other projects within the NARC, in particular Project 1, will identify future targetsof intervention as anti-relapse medications. By applying a seamless model of testing in conjunction with theNARC Animal Core, we will establish a template for the testing of putative medications as they are derivedfrom NARC projects to serve as a bridge to clinical testing of such agents through the NARC Pilot Core.The results from these integrated studies will hopefully lead to useful pharmacotherapeutic agents for the
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