# Cocaine-specific phosphomimicking and phospholacking norepinephrine transporter mouse models

> **NIH NIH R21** · VIRGINIA COMMONWEALTH UNIVERSITY · 2020 · $194,063

## Abstract

Compulsive drug-seeking and drug-taking behaviors are hallmarks of drug-addiction and propensity to relapse
is a significant problem. Cocaine-addiction is a human disease, in particular, a multifaceted mental disorder
involving many neuro-adaptations and enduring changes in the neurobiology of addicted brain reflect in altered
neurochemistry and behavior. Despite the identification of several putative pharmacological targets, there are
no effective FDA approved pharmacotherapies for the treatment of cocaine addiction or relapse. Therefore,
further understanding of addiction neurobiology is necessary to develop effective treatment strategies.
Monoamine transporters are critical molecular targets that mediate abuse-related effects of psychostimulants.
Our long-standing investigations lead us to a new line of thinking that monoamine transporters, DAT, NET and
SERT are regulated neuronal targets of cocaine, dictated by signaling architecture of synapses associated with
cocaine-addiction. Our studies have demonstrated that T30-dependent NET regulation plays a critical role in
cocaine regulation of synaptic NE signaling, and interventions of this molecular event attenuate cocaine reward
(PMC3121486; PMID: 25724654). Our recent preliminary data from in vivo and in vitro studies show that brain
nuclei specific manipulation of NET-T30 phosphorylation can attenuate cocaine-reinforcing behaviors and that
NET-T30E mutation mimics cocaine-exposed-like phenotype, the NET upregulation. However, the
neurobiological consequences of in vivo NET-T30 phosphorylation are unclear, and studies using intact animal
models are crucial to a clear understanding of the role of in vivo NET-T30 phosphorylation (the molecular
mechanism) in cocaine reinforcing behaviors. As a continued effort to address this, we have developed
prototypical mutant mouse models mimicking and lacking NET-T30 phosphorylation. In this R21 exploratory
application, we propose to test an overarching hypothesis that while the NET-T30 phospho-mimicking NET-
T30E mice exhibit gain of function and cocaine-exposed like behavioral phenotypes, the phospho-lacking NET-
T30A mice exhibit normal transport function and insensitivity to cocaine-mediated effects (loss of cocaine
induced transport upregulation and behaviors). Two specific aims will test this hypothesis. Aim 1 will study the
effects of acute and chronic cocaine on animal behavior along with parallel analysis of NET functional
expression and phosphorylation in NET-T30E mice. Aim 2 will Study the effects of acute and chronic cocaine
on animal behavior along with parallel analysis of NET functional expression and phosphorylation in NET-T30A
mice. Aims 1 and 2 will implement locomotor activation and sensitization as well as conditioned place
preference (CPP) paradigms to study the behavioral response of NET-T30E and NET-T30A mice to cocaine.
These NET-T30E and T30A mutant mouse models will be powerful biomolecular tools not only for basic
neurobiological ...

## Key facts

- **NIH application ID:** 9850567
- **Project number:** 5R21DA045888-02
- **Recipient organization:** VIRGINIA COMMONWEALTH UNIVERSITY
- **Principal Investigator:** LANKUPALLE D JAYANTHI
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $194,063
- **Award type:** 5
- **Project period:** 2019-02-01 → 2022-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9850567

## Citation

> US National Institutes of Health, RePORTER application 9850567, Cocaine-specific phosphomimicking and phospholacking norepinephrine transporter mouse models (5R21DA045888-02). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9850567. Licensed CC0.

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