The striatum is a subcortical brain region that is involved in the regulation of important physiological processes such as locomotion, motivation and stimulus-reward learning. The neuromodulator dopamine (DA) regulates striatal activity via its five receptors (DARs), which are distributed in a complex manner throughout a highly interconnected striatal network. The dysregulation of striatal DA and its receptors has been implicated in disorders such as Parkinson?s disease, schizophrenia and addiction, highlighting the need to better understand the mechanisms underlying DA-dependent striatal processes. However, our understanding of striatal DARs has been hampered in part due to our inability to selectively target and thereby understand the function of individual receptor subtypes. Traditional pharmacological and genetic approaches that are used to study receptor function target receptors non-selectively, in a cell-type independent manner and/or with poor temporal resolution. Recently, powerful optogenetic and pharmacogenetic tools (i.e., optoXRs and DREADDs) have been developed that address these limitations. However, because these tools lack features that are specific to individual DARs, they would likely provide incomplete representations of DAR function in vivo. I recently developed genetically- encodable, light-gated DARs (LiDARs) that can be used to control individual DARs in a cell-type specific and spatio-temporally precise manner. These near-native proteins are engineered to bind covalently to azobenzene- containing, photo-isomerizable ligands that activate/block receptors in response to light. Herein I propose to develop this toolkit further by enhancing LiDAR photo-activation and -blockade using novel azobenzene analogs. Furthermore, I propose to use these tools to better understand the role of individual DARs on striatal physiology and DA-dependent behaviors.
Dopamine (DA) is an important neuromodulator that regulates diverse physiological processes. The dysregulation of DA and its receptors (DARs) has been implicated in disorders including Parkinson?s disease, schizophrenia, addiction, Huntington?s disease, Tourette?s syndrome and ADHD. The goal of the proposed studies is to develop and use novel tools to better understand how DARs regulate brain function, which may provide insight into the development of improved therapeutic agents for treatment of DA-associated disorders.
|Marcott, Pamela F; Gong, Sheng; Donthamsetti, Prashant et al. (2018) Regional Heterogeneity of D2-Receptor Signaling in the Dorsal Striatum and Nucleus Accumbens. Neuron 98:575-587.e4|
|Donthamsetti, Prashant; Gallo, Eduardo F; Buck, David C et al. (2018) Arrestin recruitment to dopamine D2 receptor mediates locomotion but not incentive motivation. Mol Psychiatry :|
|Donthamsetti, Prashant C; Winter, Nils; Schönberger, Matthias et al. (2017) Optical Control of Dopamine Receptors Using a Photoswitchable Tethered Inverse Agonist. J Am Chem Soc 139:18522-18535|