# Role of TPH2 and 5HT Neuronal Loss in Non-motor Symptoms of Parkinson's

> **NIH VA I01** · JOHN D DINGELL VA MEDICAL CENTER · 2020 · —

## Abstract

Project Summary/Abstract
Parkinson's disease (PD) is the second most common neurodegenerative disorder after Alzheimer's disease and
affects about 1% of the population aged 65 and older. It is often thought of as a condition that selectively targets
the dopamine (DA) neuronal system for destruction, giving rise to the well-known motor deficits of tremor,
bradykinesia, rigidity and postural instability. The first-line pharmacological treatment for PD is L-DOPA,
which is intended to replenish brain DA levels and thereby provide significant relief from these movement
problems. It is not widely appreciated but the serotonin (5HT) and norepinephrine (NE) neuronal systems are
also severely degraded in PD. While it is appropriate that so much attention is focused on the motor
symptomatology of PD, increased interest in non-motor manifestations of PD is called for in light of the fact
that approximately 80% of PD patients suffer from co-morbid neuropsychiatric conditions such as sleep
disorders, anxiety and dementia. The most prevalent affective disorder is depression. The non-motor symptoms
(NMS) of PD, whether related to the disease process or induced by L-DOPA, are not trivial and contribute to
worsened disability, impaired quality of life and shortened life expectancy. In fact, it has been determined that
NMS of PD have a greater impact on health-related quality of life than motor symptoms. It is also clear that
affective disorders in PD are not simply a consequence of psychological distress due to the development of a
chronic debilitating disease. Many of the NMS of PD can be rationally linked to reductions in function of the
5HT and NE neuronal systems and this is reinforced by the strategy usually followed when treating the NMS of
PD- use of drugs that increase the synaptic levels of these monoamines or that activate their receptors. These
treatments (i.e. blockers of the 5HT and NE transporters, receptor agonists) have not been that effective and in
some cases, they even oppose the therapeutic efficacy of L-DOPA. The rationale for studies in this application
starts with the recognition that 5HT and NE deficits, in the face of extensive losses of DA neurons, likely
contribute to the NMS of PD. The appearance of NMS cannot be accounted for by the singular loss of DA
neurons in PD. The proposed work in this application will take advantage of the availability in our laboratory of
an innovative mouse model that lacks the gene for tryptophan hydroxylase 2 (TPH2). This new model was
created using a Cre-ERT2-Lox recombination approach to induce the loss of TPH2 and 5HT after tamoxifen
treatment of adult mice. Mice with 5HT deficits will be treated with 1-methyl-4-phenyl-1,2,3,6-
tetrahydropyridine (MPTP), a neurotoxin that targets dopamine neurons for destruction, and/or with N-(2-
chloroethyl)-N-ethyl-2-bromobenzylamine (DSP-4), a highly selective toxin that targets NE neurons. The
emergence of NMS will be assessed using a battery of behavioral, neurolo...

## Key facts

- **NIH application ID:** 10174721
- **Project number:** 5I01RX000458-09
- **Recipient organization:** JOHN D DINGELL VA MEDICAL CENTER
- **Principal Investigator:** Donald M Kuhn
- **Activity code:** I01 (R01, R21, SBIR, etc.)
- **Funding institute:** VA
- **Fiscal year:** 2020
- **Award amount:** —
- **Award type:** 5
- **Project period:** 2012-10-01 → 2020-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10174721

## Citation

> US National Institutes of Health, RePORTER application 10174721, Role of TPH2 and 5HT Neuronal Loss in Non-motor Symptoms of Parkinson's (5I01RX000458-09). Retrieved via AI Analytics 2026-05-27 from https://api.ai-analytics.org/grant/nih/10174721. Licensed CC0.

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