Dopamine (DA) is a monoaminergic neurotransmitter that has been implicated in multiple disorders such as Parkinson's disease, schizophrenia, attention deficit hyperactivity disorder, Tourette syndrome, addiction and affective disorders. At the cellular level the various actions of DA on target neurons are mediated via a family of 5 distinct G protein-coupled receptors. The D1-like (D1 and D5) receptors are mostly coupled to activation of the cAMP signaling cascade through the G protein Gs whereas the D2-like receptors (D2, D3 and D4) signal through Gi/Go and can inhibit the cAMP cascade. D2-like receptors also modulate Ca2+ and K + channels and can engage other signals such as MAP kinase pathways. Whereas most classical animal and cellular studies have focused on cAMP mediating the actions of DA, the applicability or potential contribution of other signaling pathways is still not fully understood. Recent investigations in mice have revealed that behavioral manifestations of elevated DA tone in the brain in response to genetic or pharmacological manipulations and the ability of lithium to antagonize these behaviors correlate with modulation of the Akt/GSK-3 signaling pathway in a cAMP-independent fashion. The overall objective of the proposed research is to define the molecular and cellular mechanisms that contribute to these processes with the goal of better understanding physiological and pathological conditions. Studies will be conducted both in cellular systems as well as in normal and genetically modified animal models.
Aim 1 : We will attempt to characterize the mechanisms by which dopamine regulate Akt/GSK-3 signaling. This will include determining which of the DA receptors and molecular signaling intermediates engage the Akt pathway and reconstitution of those interactions in cellular systems.
Aim 2 : We will address characterization of the molecular targets of GSK-3 that mediate responses to DA.
Aim 3 : These proposed experiments will examine the role of Akt/GSK-3 in DA-associated behaviors, such as those modeling affective and psychotic disorders, in animals carrying tissue-specific genetic deletion of various GSK-3 isoforms. Results from these studies should broaden our understanding of the cellular and molecular mechanisms mediating the actions of DA in normal and pathophysiological conditions and provide insight into potential novel therapeutic approaches for various psychiatric conditions.
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