Clinical observations have suggested that ovarian hormones modulate the symptomology of schizophrenia.. Because the mesolimbic dopamine (DA) system has been implicated in the facilitation of emotional, motivational and cognitive behaviors associated with this disorder; it has been suggested that ovarian steroids may act on dopaminergic neurons to produce alterations in neuronal activity and ultimately changes in behavioral expression. While modulation of neuronal activity by steroid hormones is well documented; very little is known about the precise site(s) of action. We hypothesize that the ovarian steroid hormone estrogen regulates DA availability within the nucleus accumbens through a modulation of D2 DA receptor sensitivity and that this modulation is important in maintaining normal neuronal activity in pathological conditions associated with subcortical dopaminergic hyperactivity such as schizophrenia. Activation of the presynaptic D2 receptor results in a decrease in extracellular DA though an activation of the DA transporter and an inhibition of DA release and synthesis. While the mechanisms responsible for autoreceptor mediated inhibition of DA release and synthesis have been extensively investigated, it is not known how the autoreceptor regulates transporter activity. We propose that DA autoreceptor activation potentiates DA uptake through a change in second messenger mediated phosphorylation of the transporter and that examination of this mechanism will provide a tool by which estrogen modulation of DA availability can be investigated. Autoreceptor mediated changes in 3H-DA uptake and transporter phosphorylation will be examined in a synaptosomal preparation prepared from the nucleus accumbens of ovariectomized (OVX) female rats. Steroid mediated changes in DA transport will be determined following administration of a physiologically relevant dose of estradiol benzoate (EB-primed). Three main questions will be addressed. 1) Is the D2 class of dopamine autoreceptors responsible for potentiation of DA transport? 2) Does autoreceptor mediated activation of DA transport proceed by a mechanism which involves alterations in second messenger cascades and/or protein phosphorylation? 3) Does EB-priming produce a functional modulation of DA receptor sensitivity which results in an alteration in the ability to regulate dopamine availability? The answers to these questions will provide detailed information on the ability of dopamine released from the presynaptic terminal to regulate its own extracellular availability through an action at the presynaptic autoreceptor. In addition, they will clarify the ability of estrogen to modulate the functional sensitivity of the DA autoreceptor. These types of studies are critical for elucidating how estrogen may provide physiological protection under pathological conditions of increased DAergic activity.
| Thompson, Tina L; Certain, Matthew E (2005) Estrogen mediated inhibition of dopamine transport in the striatum: regulation by G alpha i/o. Eur J Pharmacol 511:121-6 |
| Thompson, T L; Bridges, S; Miller, C (2001) Modulation of dopamine uptake in rat nucleus accumbens: effect of specific dopamine receptor antagonists and sigma ligands. Neurosci Lett 312:169-72 |
| Thompson, T L; Bridges, S R; Weirs, W J (2001) Alteration of dopamine transport in the striatum and nucleus accumbens of ovariectomized and estrogen-primed rats following N-(p-isothiocyanatophenethyl) spiperone (NIPS) treatment. Brain Res Bull 54:631-8 |
| Thompson, T L; Moore, C C; Smith, B (2000) Estrogen priming modulates autoreceptor-mediated potentiation of dopamine uptake. Eur J Pharmacol 401:357-63 |
