# Rapid and Long-Lasting Antidepressant Action by Targeting Midbrain HCN Channels

> **NIH NIH R01** · ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI · 2021 · $458,069

## Abstract

PROJECT SUMMARY
Current antidepressant medications for major depressive disorder (MDD) take several weeks to months to
achieve therapeutic effect. This inevitable delay for drug efficacy not only prolongs distress and impairment for
depressed patients, but is also life threatening for MDD patients with suicidal ideation. This delay has led to the
widely accepted theory that the therapeutic efficacy of antidepressants can only be achieved by chronic
treatments. However, an increasing body of clinical studies, including deep brain stimulation, ketamine and
scopolamine therapies, has demonstrated the ability to regulate mood states within minutes to hours. These
groundbreaking findings provide new hope in minimizing MDD disease burden. The main purpose of this
application is to explore a novel drug target, which offers the potential for rapid antidepressant efficacy. There
are early lines of evidence linking the midbrain dopamine system mechanistically in rapid depression
treatment. Consistent with this, various studies showed that optogenetically activating or inhibiting dopamine
neurons in the ventral tegmental area (VTA) circuits, a brain’s reward system, rapidly and bi-directionally
regulated depression-related behaviors in rodent models of depression. In a repeated social defeat stress
(RSDS) model of depression, we previously demonstrated that pharmacological inhibition of hyperpolarization-
activated cyclic nucleotide-gated (HCN) channels in the VTA reversed the pathophysiological hyperactivity of
VTA dopamine neurons and achieved antidepressant-like effects within one hour. In our initial follow-up
studies, we find that one single intra-VTA infusion of a HCN blocker induces rapid and long-lasting
antidepressant-like effects. The single infusion-induced antidepressant efficacy lasts ~2 weeks. Similarly, one
single systemic administration (intraperitoneal injection) of this HCN blocker also induces rapid and ~2 weeks
long antidepressant-like effects, which is evidently different from typical antidepressants such as SSRIs that
took two weeks to gain antidepressant-like efficacy in the same model. Focusing on the rapid and long-lasting
treatment effects, the overall objectives of this application are: (1) Drug Effect: to systematically define dose-
dependent effects of three selected HCN blockers on the VTA dopamine neuron activity and depression-
related behaviors; and (2) Drug Mechanism: to determine the cellular and circuit mechanisms that underlie the
long-lasting antidepressant-like efficacy induced by a single exposure to HCN blockers. Upon the completion of
this project, the proposed studies will provide highly novel HCN channel mechanisms for rapid and long-lasting
treatment effects. Additionally, we also expect novel information to improve our knowledge of dopamine circuit
mechanisms of depression.

## Key facts

- **NIH application ID:** 10201445
- **Project number:** 5R01MH120637-03
- **Recipient organization:** ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
- **Principal Investigator:** SCOTT JAMES RUSSO
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $458,069
- **Award type:** 5
- **Project period:** 2019-08-15 → 2023-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10201445

## Citation

> US National Institutes of Health, RePORTER application 10201445, Rapid and Long-Lasting Antidepressant Action by Targeting Midbrain HCN Channels (5R01MH120637-03). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10201445. Licensed CC0.

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