Estrogen effects on dopamine autoreceptor activity

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DESCRIPTION (provided by applicant): Schizophrenia is a catastrophic neuropsychiatric disorder that routinely presents in late adolescence or early adulthood, a time when cortical development is nearing completion and circulating gonadal hormones are approaching their adult levels. Clinical observations have suggested that estrogen provides a neuroprotective influence on the expression of schizophrenic symptoms. Because the mesolimbic dopamine (DA) system has been implicated in the facilitation of behaviors associated with this disorder and mesolimbic DAergic hyperactivity is associated with the expression of symptoms, it has been suggested that estrogen may act on DAergic neurons to produce alterations in neuronal activity and ultimately changes in behavioral expression. We have shown that estrogen regulates DA availability within the nucleus accumbens through an alteration of DA D2 autoreceptor sensitivity and DA transporter (DAT) activity. The cellular mechanisms mediating these types of regulation are not known. We hypothesize that estrogen modulates D2 receptor sensitivity through an alteration of a pertussis (PTX) toxin sensitive G-protein and that this regulation is important in maintaining normal neuronal activity in pathological conditions associated with subcortical DAergic hyperactivity. Furthermore, we propose that the developmental and hormonal changes occurring during periadolescence may influence the subsequent alteration of DA D2 receptor sensitivity observed in the adult and may account for the increased susceptibility to early onset psychiatric disorders. Functional alteration of the D2 autoreceptor activation will be investigated in the nucleus accumbens of periadolescent and adult rats. Three questions will be addressed: 1] Are there age and/or sex dependent alterations in the functional sensitivity of the D2 receptor? 2] Does activation of the D2 receptor alter phosphorylation of the DAT, and if so is this alteration age or sex dependent? 3] Are female rats more susceptible to an impaired ability to clear DA from the extracellular space following a functional loss of D2 receptors? The answers to these questions will provide specific information on the functional association between the D2 receptor and the DAT. In addition, they will clarify how developmental and sex dependent changes in sensitivity of the D2 autoreceptor may alter the responsiveness of the mesolimbic DAergic system and ultimately the symptomology associated with schizophrenia.