Aberrant dopamine system function in a rodent model of perimenopause: relevance to psychosis

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Project Summary/Abstract: The transition to menopause (or perimenopause) is a period of unique vulnerability for a woman, in which there is an increased risk of developing a psychotic disorder or the exacerbation of a pre-existing condition, such as first onset schizophrenia/psychosis or bipolar disorder. Antipsychotics used to treat symptoms of psychosis, are not always effective and are often discontinued due to adverse side effects. Further, when given to perimenopausal women, antipsychotics can worsen common symptoms of this period (i.e., weight gain and hyperprolactinemia). This is important to note because psychotic symptoms are debilitating and can severely affect a woman’s quality of life. In the present proposal we will provide a mechanistic understanding into how aberrant regulation of the mesolimbic dopamine system, by the ventral hippocampus, contributes to symptoms of psychosis during perimenopause. We will address this using in vivo electrophysiology, chemogenetics, and behavior with three specific aims: 1) Examine vHipp regulation of VTA dopamine neurons and dopamine- dependent behaviors associated with psychosis in the VCD rodent model of perimenopause. 2) Evaluate the impact of age on the psychosis-like effects of VCD. 3) Determine the utility of α5-GABAAR PAMs as a therapeutic intervention for restoring dopamine system function and dopamine-dependent behaviors associated with perimenopause in the VCD model. Our overarching hypothesis is that aberrant vHipp regulation of the mesolimbic dopamine system during perimenopause underlies behavioral changes associated with psychosis. Furthermore, we posit that α5-GABAAR modulators may have therapeutic utility during the menopausal transition.