# Novel Molecular Mechanisms of Abusable Drugs

> **NIH NIH P50** · JOHNS HOPKINS UNIVERSITY · 2021 · $376,723

## Abstract

Project Summary – Snyder Project
Our laboratory has long focused on molecular signaling systems in the brain that underlie actions of
psychotropic drugs, especially abusable agents. The present proposal addresses two areas of current interest.
Cocaine has long been known to impair monoamine transport with modest potency. We recently discovered a
very high affinity cocaine `receptor.' As little as 0.1 nM cocaine induces autophagy in cortical cultures,
thousands of times more potent than other actions of the drug. We identified BASP-1 protein as the apparent
cocaine target. We propose studies to elucidate cocaine-BASP-1 links and their relevance to psychoactivity of
cocaine.
In a second project, we will explore how ketamine elicits its antidepressant actions via mTOR. We recently
established a relevant pathway wherein NMDA signaling triggers NO generation to nitrosylate glyceraldehyde
phosphate dehydrogenase (GAPDH) in a complex with the ubiquitin E3-ligase Siah1. In this complex, Siah1
degrades the small G protein Rheb, a physiologic stimulus for mTOR, thereby leading to diminished mTOR
activity. By blocking NMDA receptors, ketamine elicits the reverse process, mTOR enhancement. Utilizing a
variety of agents, we propose to explicate this signaling system in an effort to understand
psychotomimetic/antidepressant actions of ketamine and, hopefully, lead to more effective/safer therapies.

## Key facts

- **NIH application ID:** 10171824
- **Project number:** 5P50DA044123-04
- **Recipient organization:** JOHNS HOPKINS UNIVERSITY
- **Principal Investigator:** SOLOMON H. SNYDER
- **Activity code:** P50 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $376,723
- **Award type:** 5
- **Project period:** 2018-09-15 → 2023-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10171824

## Citation

> US National Institutes of Health, RePORTER application 10171824, Novel Molecular Mechanisms of Abusable Drugs (5P50DA044123-04). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10171824. Licensed CC0.

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