Current first-line mood-stabilizer and atypical antipsychotic drugs used in the treatment of bipolar disorder and schizophrenia have limited long-term prophylactic efficacy in 30-40 percent of patients, and several adverse side-effects which frequently lead to additional health-related problems and/or patient noncompliance and relapse. There is therefore an urgent need for the development and validation of new treatments with improved long-term efficacy, safety, and tolerability. Chronic, but not acute, treatment with mood-stabilizer and antipsychotic drugs at therapeutically-relevant concentrations down-regulate protein kinase C (PKC) activity and isozyme expression in rat brain. The principle omega-3 fatty acid found in brain, docosahexaenoic acid (DHA), is derived exclusively from the diet, is specifically enriched in neuronal synaptic membranes, and inhibits PKC in vitro. However, there currently exists a significant knowledge gap in our understanding of the consequences of altering synaptic DHA composition on PKC activity/expression in brain. The primary objective of this proposal is to determine if systematic alterations (increases and decreases) in brain DHA concentrations through dietary manipulations can modulate PKC activity/expression in brain. Our primary HYPOTHESIS is that reductions or elevations in brain DHA concentrations will increase and decrease, respectively, PKC activity/expression. We will also determine if alterations in brain DHA concentrations can modulate the dopamine D2 receptor, a clinically-relevant substrate of PKC. We anticipate that the proposed studies will provide 'proof-of-concept' data demonstrating that dietary-induced reductions/elevations in brain DHA concentrations will increase/decrease PKC activity (SA1) and decrease/increase D2 receptor binding (SA2) in a DHA-concentration-dependent manner. Predicative validity will be evaluated by determining if dietary-induced elevations in PKC activity and reductions in D2 receptor binding can be reversed (normalized) by chronic, but not acute, treatment with haloperidol, olanzapine, lithium, or DHA-rich diets (SA3). The anticipated results will provide a strong scientific foundation and rationale to perform analogous studies in human subjects using in vivo imaging. The proposed experiments are innovative and exploratory in that the effect of altered DHA concentrations on PKC and dopamine D2 receptor expression have not been systematically examined in brain. ? ? ?
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