Insulin resistance, a primary component of the metabolic syndrome, is an escalating phenomenon in the United States, and confers an increased risk of depression and mood disorder, particularly in women. The relationship between metabolic and mood disorders may be mediated by endogenous opioid activity in limbic brain regions. We propose to examine affective state and μ- opioid system function in insulin resistant women, and change in response to insulin sensitizing treatment, through the following specific aims and hypotheses: Establish relationship between insulin resistance, affective state, and μ-opioid receptor function. 1. Insulin resistant women will have greater μ-opioid receptor availability at baseline, and a larger response to stress challenge than non-insulin resistant women 2. Insulin resistant women will have greater negative affective state at baseline, and a greater emotional response to stress challenge than non-insulin resistant women. 3. Mediational analyses will reveal that the relationship between insulin resistance and negative affect is mediated by μ-opioid receptor function and neural activation in the amygdala and nucleus accumbens affect-regulating regions. Examine effects of insulin regulation on μ-opioid receptor function and affective state. 1. Improved insulin sensitivity will be accompanied by decreased μ-opioid receptor availability at baseline and a reduced response to stress challenge. Degree of change in baseline receptor availability and response to stress challenge after treatment will correlate with degree of insulin regulation. 2. Improved insulin sensitivity will be associated with improved affective state at baseline, and with a reduced emotional response to stress challenge. Degree of change in affective state and emotional response to stress challenge after treatment will correlate with degree of insulin regulation. 3. Mediational analyses will reveal that the change in affective state after insulin regulation is mediated by change in μ-opioid receptor function and neural activation in the amygdala and nucleus accumbens. The expected results would suggest a role for the endogenous μ-opioid system in mediating the relationship between metabolic function and emotional processes.
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Mu-opioid Receptor Binding Potential in Left Nucleus Accumbens, Resting State
Timeframe: Baseline, 20 weeks, 40 weeks
Mu-opioid Receptor Binding Potential in Right Nucleus Accumbens, Resting State
Timeframe: Baseline, 20 weeks, 40 weeks
Mu-opioid Receptor Binding Potential in Left Amygdala, Resting State
Timeframe: Baseline, 20 weeks, 40 weeks
Mu-opioid Receptor Binding Potential in Right Amygdala, Resting State
Timeframe: Baseline, 20 weeks, 40 weeks