Abstract
Dopamine controls diverse behaviors and their dysregulation contributes to many disorders. Our ability to understand and manipulate the function of dopamine is limited by the heterogenous nature of dopaminergic projections, the diversity of neurons that are regulated by dopamine, the varying distribution of the five dopamine receptors (DARs), and the complex dynamics of dopamine release. In order to improve our ability to specifically modulate distinct DARs, here we develop a photo-pharmacological strategy using a Membrane anchored Photoswitchable orthogonal remotely tethered agonist for the Dopamine receptor (MP-D). Our design selectively targets D1R/D5R receptor subtypes, most potently D1R (MP-D1ago), as shown in HEK293T cells. In vivo, we targeted dorsal striatal medium spiny neurons where the photo-activation of MP-D1ago increased movement initiation, although further work is required to assess the effects of MP-D1ago on neuronal function. Our method combines ligand and cell type-specificity with temporally precise and reversible activation of D1R to control specific aspects of movement. Our results provide a template for analyzing dopamine receptors.
Highlights
Dopamine controls diverse behaviors and their dysregulation contributes to many disorders
This raises the question: Which of the many targets of substantia nigra compacta (SNc) DA neurons in the dorsal striatum (dStr) (Supplementary Fig. 1e) triggers movement? A compelling candidate is D1R expressed in direct pathway medium spiny neurons of the dStr
D1R agonists do not differentiate between D1R in direct pathway medium spiny neurons (dMSNs) and the terminals of glutamatergic inputs in the dStr (Supplementary Figs. 1e and 2)[1], and they bind its close homolog D5R25, which is found in the four major classes of striatal interneurons
Summary
Dopamine controls diverse behaviors and their dysregulation contributes to many disorders. SNc DA neurons become more active just before movement initiation[6,10], and the brief optogenetic stimulation of these neurons increases the probability of movement initiation[11] This raises the question: Which of the many targets of SNc DA neurons in the dStr (Supplementary Fig. 1e) triggers movement? A recent model suggests that D1R increases in activation in the dStr prior to movement initiation[10], and the systemic activation of D1R with a synthetic agonist increases the probability of movement initiation[23] For these reasons, D1R is a putative target for treatment of motor deficits in Parkinson’s disease[24], where dopaminergic inputs from the SNc to the dStr degenerate. D1R agonists do not differentiate between D1R in dMSNs and the terminals of glutamatergic inputs in the dStr (Supplementary Figs. 1e and 2)[1], and they bind its close homolog D5R25, which is found in the four major classes of striatal interneurons
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