Cortical and Striatal Dopamine Dysfunction in Addiction and Schizophrenia

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DESCRIPTION (provided by applicant): This is the first resubmission of a proposal for the competitive renewal of a K02 grant to support the career development plan of the candidate. The candidate research career is directed toward developing and using novel brain imaging methods to better characterize neurochemical alterations associated with substance abuse disorders and schizophrenia, their clinical correlates, and their relevance to treatment strategies. The first cycle of this K02 (2002 to 2007) was focused on imaging cortical dopamine transmission in schizophrenia. This K02 application will expand in a new direction, which is that of comorbidity between schizophrenia and substance abuse, and will continue the work of developing new methodology to directly assess dopamine (DA) release in the cortex, a measurement relevant to both schizophrenia and addiction. A great proportion of patients with schizophrenia use substances, which complicates their treatment and prognosis. Yet, little is known about the neural substrates underlying comorbidity. The applicant has designed a program to assess DA release in cannabis dependent patients with schizophrenia, with a particular model of striatal alterations to explain a negative interactivity between the two conditions. The applicant chose to focus on cannabis dependence and its comorbidity with schizophrenia because of the wealth of data suggesting a particularly negative effect of this drug on schizophrenia's symptomatology and course. In order to address the comorbidity, studies of stimulated DA release within the striatal substructures, in dual diagnosis patients, cannabis dependent patients, and matched healthy controls will be undertaken, in addition to the already ongoing studies in patients with schizophrenia. Studies will use the high-resolution Positron Emission Tomography (PET) camera ECAT EXACT HR+, D2 radiotracers, [11C]raclopride (SA1 and 2) and the amphetamine paradigm to measure stimulated dopamine release in three groups of subjects: Dual Diagnosis patients (DD), Cannabis Dependent patients (CD), and Healthy Controls (HC). In addition she will continue her studies in schizophrenia to assess cortical DA transmission by using [11 C]FLB457 with the amphetamine paradigm (SA3). This comprehensive research plan will allow the candidate to develop expertise in a new area that of substance abuse, dependence and comorbidity, as well as continue to establish herself as a senior PET investigator. PUBLIC HEALTH RELEVANCE: This proposal will address important areas relevant to the fields of addiction and schizophrenia: 1) the comorbidity of these two disorders, 2) the alterations of DA transmission in cannabis dependence, 3) cortical DA transmission in schizophrenia. All these have great public health impact because comorbidity leads to non adherence and relapse, marijuana's use is widespread, and cortical dysfunction is associated with difficult to treat symptoms. Understanding the pathophysiology will lead to better treatment strategies.