# Ketamine-Class Antidepressants in Vesicles

> **NIH NIH R21** · CALIFORNIA INSTITUTE OF TECHNOLOGY · 2020 · $205,625

## Abstract

The project studies ketamine, its metabolites, and related drugs [Ketamine-Class Antidepressant
Drugs (KCADs), our term]. Sub-anesthetic doses of ketamine produce antidepressant effects in
just a few hours (2 h) via unknown mechanism(s). However, higher doses have adverse effects.
Understanding the mechanism mediating KCAD antidepressant activity is an important step in the
process of drug development. This research program has the goal to fundamentally change our
understanding of how this rapid antidepressant mechanism works and holds promise for
development of more robust and safer treatments.
The molecular target(s) of KCAD action are not known. In the absence of such knowledge, one
should investigate possible actions in the compartments where KCADs are most concentrated.
We test the hypothesis that the effects of KCADs in the brain are mediated, in least in part, by the
accumulation of KCADs in various subcellular compartments (organelles), including synaptic
vesicles.
Aim 1 develops a family of next-generation genetically encoded “Intensity-based Ketamine-Sensing Fluorescent Reporters” (iKetSnFRs) for KCADs. These will dynamically image and
quantify the presence of KCADs at sub-cellular levels. Aim 1 measures the time course of KCAD
entry and exit from various organelles after the drugs appear or disappear near cells. Aim 2 tests
the hypothesis that the antidepressant mechanism of KCADs involves accumulation in the lumen
of acidic vesicles, especially in synaptic vesicles, followed by synaptic stimulation-induced release
of KCAD from presynaptic terminals. Aim 3 detects KCAD-induced neurotransmitter release from
presynaptic terminals, employing next generation genetically encoded biosensors for various
neurotransmitters. The experiments also include electrophysiological studies of membrane and
synaptic properties.
The data from Aims 1, 2 and 3 will not in themselves develop a new ~2 h antidepressant drug.
But the data from the proposed experiments can help to understand how KCADs exert their
effects. The data will also guide the development of related molecules with fewer potential side
effects as new fast-acting therapies for depression.

## Key facts

- **NIH application ID:** 9936457
- **Project number:** 5R21MH120823-02
- **Recipient organization:** CALIFORNIA INSTITUTE OF TECHNOLOGY
- **Principal Investigator:** Henry A. Lester
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $205,625
- **Award type:** 5
- **Project period:** 2019-06-01 → 2022-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9936457

## Citation

> US National Institutes of Health, RePORTER application 9936457, Ketamine-Class Antidepressants in Vesicles (5R21MH120823-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/9936457. Licensed CC0.

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