# Functionally selective D2Rs, striatal circuit function and motivation

> **NIH NIH R01** · NEW YORK STATE PSYCHIATRIC INSTITUTE DBA RESEARCH FOUNDATION FOR MENTAL HYGIENE, INC · 2020 · $612,525

## Abstract

Brain imaging studies have found alterations in striatal dopamine D2R binding in several mental disorders
associated with altered motivation including schizophrenia, ADHD and drug addiction. In spite of these
observations it is still unclear how changes in D2R levels alter striatal circuit function and motivation.
In the first 4.5 years of this RO1 project we have found that D2R overexpression in the ventral striatum
(Nucleus accumbens core; NAcc) of the mouse enhances motivation. We further identified a new mechanism
by which D2Rs could regulate motivation: Like presynaptic D2Rs in dopamine neurons inhibit dopamine
release, we found that D2Rs inhibit collateral transmission from indirect to direct pathway neurons. The direct
pathway is one of the two functionally opposing output pathways of the striatum. It promotes thalamo-cortical
activity, thereby relaying a “go” signal, whereas the indirect pathway inhibits thalamo-cortical activity, thus
relaying a “no go” signal. We hypothesize that decreased collateral inhibition will enhance direct pathway
activity thereby promoting motivated behavior. The same mechanism that regulates synaptic transmission at
intrastriatal collaterals should also affect transmission at the main indirect output terminals in the ventral
pallidum (VP). We therefore hypothesize that D2Rs in the NAcc enhance motivation via two mechanisms, dis-
inhibition of direct pathway activity and inhibition of indirect pathway output.
To develop new therapeutic strategies for disorders of motivation it will be crucial to understand how
ventral-striatal D2Rs regulate motivation at the molecular level. D2Rs signal via two downstream
pathways one that is G-protein dependent and one is G-protein independent and involves arrestin. Here, we
will compare the efficiencies of functionally selective D2Rs in their ability to enhance motivation and to inhibit
indirect pathway transmission. Since G-protein signaling is required for D2R-mediated inhibition of dopamine
release we hypothesize that G-protein but not arrestin signaling is necessary for inhibiting indirect pathway
transmission leading to enhanced motivation.
Whether decreased indirect pathway transmission disinhibits direct pathway and downstream VP activity is
unknown but essential for understanding how D2Rs regulate motivation. We will therefore measure neuronal
activity selectively in the VP as well as in the direct or the indirect pathway during motivated behavior. We will
use the Cre/loxP system in combination with Cre-dependent viruses to selectively overexpress wild-type or
mutated functionally selective D2Rs in the indirect-pathway of the NAcc and employ patch clamp slice
physiology, in vivo calcium imaging and a behavioral analysis to address the following aims:
Aim 1: To determine the function of NAcc D2Rs in VP inhibition and motivation
Aim 2: To identify the signaling pathway(s) by which NAcc D2Rs regulate motivation

## Key facts

- **NIH application ID:** 9914328
- **Project number:** 5R01MH093672-10
- **Recipient organization:** NEW YORK STATE PSYCHIATRIC INSTITUTE DBA RESEARCH FOUNDATION FOR MENTAL HYGIENE, INC
- **Principal Investigator:** Christoph Kellendonk
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $612,525
- **Award type:** 5
- **Project period:** 2011-05-20 → 2022-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9914328

## Citation

> US National Institutes of Health, RePORTER application 9914328, Functionally selective D2Rs, striatal circuit function and motivation (5R01MH093672-10). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/9914328. Licensed CC0.

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