# Development of dopamine D2 receptor-targeted DARTs

> **NIH NIH R21** · NEW YORK STATE PSYCHIATRIC INSTITUTE DBA RESEARCH FOUNDATION FOR MENTAL HYGIENE, INC · 2022 · $188,104

## Abstract

Alterations in dopamine neurotransmission have been implicated in various neuropsychiatric and
neurodegenerative disorders, including schizophrenia, depression, attention-deficit hyperactivity disorder, Parkinson’s disease, and substance use disorder. Distortions in timing and anticipation are symptoms, as well
as a source of additional complications, in many of these disorders. Neuroimaging studies in humans, as well as
a wide range of animal studies, have shown that dopaminergic modulation o f cortico-striatal-thalamic circuits
alters timing and that both D2 and D1 receptor signaling are important for accurate and precise temporal control.
 A major barrier to understanding the intricacies of drug action in vivo relates to the complex and manifold
localization of the same receptor throughout the brain. For example, in the striatum, dopamine D2 receptors
(D2Rs), are located on indirect pathway medium spiny neurons (iMSNs), cholinergic interneurons, the terminals
of dopaminergic projections from the midbrain, as well as on glutamatergic corticostriatal terminals. Given this
complexity, it can be impossible to infer the precise action of dopamine at specific D2Rs, or the consequences
of blocking this action by antagonists, as the same type of receptor can have complementary or opposing effects
on circuit function when present in different neurons, or even in different locations within the same neuron. Local
intracranial injections of drugs have been used as a strategy to differentiate the local actio ns of drugs from their
systemic effects, but in a complex region such as the striatum, this is not adequate to differentiate actions of
D2Rs expressed on different neuronal subtypes. While Cre-dependent knockout of D2R can begin to address
these issues, limitations of this approach include developmental effects, compensation, and the fact that D2Rs
outside of the striatum are also deleted, making the effects complex to interpret.
 Drugs Acutely Restricted by Tethering (DARTs) is a new approach that allows targeting of endogenous
receptors with cell-type specificity using direct pharmacological treatment. This strategy has been used
successfully to target ionotropic glutamate receptors in specific neuronal populations in vivo and has also been
debuted in vitro for a muscarinic acetylcholine GPCR but has not yet been developed for studying GPCRs in
vivo. Importantly, the DART approach has the advantage that the activity of unmodified, natively expressed
receptors can be controlled. Leveraging collaborative expertise in chemistry, protein engineering, genetic
engineering of mice, and behavioral analysis, we propose to use this method to interrogate D2R function in
vivo, with an initial focus on identifying the neuronal cell types in the striatum in which D2Rs regulate timing.
We have had initial success in developing D2R-targeted DARTs, which we have validated both in vitro and in
vivo and thus propose the following aims: Aim 1: Optimize DARTs for cell-ty...

## Key facts

- **NIH application ID:** 10376835
- **Project number:** 5R21MH126499-02
- **Recipient organization:** NEW YORK STATE PSYCHIATRIC INSTITUTE DBA RESEARCH FOUNDATION FOR MENTAL HYGIENE, INC
- **Principal Investigator:** Jonathan A Javitch
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $188,104
- **Award type:** 5
- **Project period:** 2021-04-01 → 2024-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10376835

## Citation

> US National Institutes of Health, RePORTER application 10376835, Development of dopamine D2 receptor-targeted DARTs (5R21MH126499-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10376835. Licensed CC0.

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