# Dysregulation of dopamine receptors in the basal ganglia in OCD and tic disorders: Positron Emission Tomography with [11C]-PHNO

> **NIH NIH R01** · YALE UNIVERSITY · 2023 · $762,520

## Abstract

ABSTRACT
Disordered repetitive patterns of behavior and thought characterize numerous neuropsychiatric conditions,
including obsessive-compulsive disorder (OCD) and Tourette syndrome (TS) and other tic disorders.
Obsessions, compulsions, and tics are associated with dysregulation of the cortico-basal ganglia circuitry, but
the underlying pathophysiological details remain poorly understood.
Several lines of evidence implicate dysregulation of dopamine (DA) and its receptors in TS and OCD, but much
remains unclear, especially in OCD. New insight has arisen from our recent studies in a mouse model of the
pathophysiology of a rare genetic form of TS and OCD associated with a mutation in the Hdc gene. Parallel
studies in these mice (ex vivo 3H raclopride binding) and in a small number of adult carriers of the Hdc
mutation with TS (11C-PHNO PET imaging) revealed upregulation of D2/D3 receptors in the substantia nigra,
where previous work suggests that D3 upregulation may represent a response to chronic DA excess, and in
the globus pallidus (GP). In unrelated subjects with OCD, 11C-PHNO PET imaging revealed a distinct pattern:
increased binding to D2/D3 receptors in the SN but not in the GP, and a previously uncharacterized increase in
the ventral striatum/nucleus accumbens. We speculate that dysregulated DA signaling in the accumbens may
contribute to abnormal reward processing, which we have recently characterized in individuals with OCD.
These pilot data are not sufficient powered for definitive conclusions; they require confirmation, which the
current proposal seeks to achieve. Our tentative finding of overlapping but distinct patterns of DA receptor
abnormality in two related neuropsychiatric conditions sets the stage for an important comparative study.
We will perform 11C-PHNO PET imaging in 60 adult subjects: 15 with OCD, 15 with TS/tics, 15 with both OCD
and tics (which are frequently comorbid), and 15 healthy controls. This will permit us to perform several
analyses, all firmly grounded in our pilot data. First, we will compare individuals with and without tics; we
expect to find increased D2/D3 binding in the SN and GP, which would extend our findings in carriers of the
rare TS-associated Hdc mutation to tic patients more generally and thus constitute a rare instance of true
translation from an animal model of pathophysiology to new insight in humans. Second, we will compare
individuals with and without OCD; we expect receptor abnormalities in the ventral striatum to be related to
OCD symptomatology, while binding in the GP will be associated with tic comorbidity. Finally, we will use
continuous symptom measures across the full dataset, characterizing patterns of D2/D3 abnormality that may
cut across traditional diagnostic categories.
These studies bring together new findings with state-of-the-art methodologies to advance our understanding of
how dysregulation in DA and its receptors contributes to disordered repetitive patterns of behavior an...

## Key facts

- **NIH application ID:** 10672999
- **Project number:** 5R01MH130609-02
- **Recipient organization:** YALE UNIVERSITY
- **Principal Investigator:** Christopher John Pittenger
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2023
- **Award amount:** $762,520
- **Award type:** 5
- **Project period:** 2022-08-01 → 2027-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10672999

## Citation

> US National Institutes of Health, RePORTER application 10672999, Dysregulation of dopamine receptors in the basal ganglia in OCD and tic disorders: Positron Emission Tomography with [11C]-PHNO (5R01MH130609-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10672999. Licensed CC0.

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