# Cellular and molecular mechanisms of vasopressin in anxiety

> **NIH NIH R01** · UNIVERSITY OF NORTH DAKOTA · 2021 · $347,500

## Abstract

Project Summary/Abstract
 Anxiety disorders are among the most common psychiatric disorders affecting ~20 million American
people. Because current medications are effective for only 50~60% of patients and have certain side effects or
problems with tolerance or dependence, exploring novel neurobiological mechanisms and therapeutic
approaches for anxiety disorders is still an arduous task. Our long-term goal is to explore novel mechanisms by
which innovative therapeutic strategies for anxiety disorders can be developed. Accumulating evidence
demonstrates that elevation of vasopressin (also known as arginine vasopressin, AVP; antidiuretic hormone)
system facilitates anxiety via activation of V1a receptors (V1aRs). However, the mechanisms whereby
activation of V1aRs increases anxiety have not been determined. The objective of this proposal is to determine
the cellular and molecular mechanisms whereby V1aR activation facilitates anxiety. Our rationale is that
determining the mechanisms whereby V1aR activation augments anxiety would stimulate the development and
uses of V1aR antagonists and drugs targeting the downstream signaling molecules of V1aRs for the treatment
of anxiety. Because elevation in glutamatergic functions underlies the generation of anxiety, we are testing the
central hypothesis that activation of V1aRs facilitates anxiety by increasing the glutamatergic functions. The
formation of the hypothesis is also based on our preliminary results demonstrating that activation of V1aRs
facilitates the excitability of principal neurons and glutamatergic transmission in the ventral hippocampus which
is closely involved in anxiety-like responses. We further showed that microinjection of AVP into the ventral
hippocampus or optogenetically stimulating endogenous AVP release induces anxiogenic effects assessed by
Elevated-Plus Maze (EPM), Open Field Test (OFT) and Light-Dark Box (LDB). Aim 1 will identify the
mechanisms underlying AVP-induced excitation of ventral hippocampal principal neurons. We will test the
hypothesis that V1aR activation increases neuronal excitability via PLCβ1-mediated depletion of PIP2,
facilitating TRPC4/5 channels function and Ca2+ influx. Aim 2 will define the mechanisms whereby AVP
facilitates glutamate release at the ventral hippocampal synapses. We will test the hypothesis that V1aR
activation increases the quantal size, the number of release site and/or multivesicular release via interaction
with PLCβ1, TRPC4/5 channels, calcium/calmodulin-dependent kinase II (CaMKII) and synapsin I. Aim 3 will
elucidate the mechanisms by which V1aR activation induces anxiogenic effects. We will test the hypothesis
that PLCβ1, TRPC4/5 channels, CaMKII and synapsin I are involved in V1aR-mediated anxiogenic effects
using EPM, OFT and LDB. We believe that determining the mechanisms underlying V1aR-mediated increases
in anxiety would provide novel approaches for anxiety therapy.

## Key facts

- **NIH application ID:** 10166945
- **Project number:** 5R01MH118258-03
- **Recipient organization:** UNIVERSITY OF NORTH DAKOTA
- **Principal Investigator:** Saobo Lei
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $347,500
- **Award type:** 5
- **Project period:** 2019-08-06 → 2024-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10166945

## Citation

> US National Institutes of Health, RePORTER application 10166945, Cellular and molecular mechanisms of vasopressin in anxiety (5R01MH118258-03). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10166945. Licensed CC0.

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