# Chemokine CXCL12/CXCR4 system and synthetic cathinones

> **NIH NIH R01** · TEMPLE UNIV OF THE COMMONWEALTH · 2020 · $368,513

## Abstract

PROJECT SUMMARY
We propose to investigate how the chemokine CXCL12 (SDF-1α), and its main receptor, CXCR4, are
influenced by exposure to the synthetic cathinone MDPV (methylenedioxypyrovalerone), and, in turn, how
CXCL12/CXCR4 antagonism influences behavioral and neurochemical correlates of synthetic cathinone
(ab)use. Different cathinones are found in bath salts products, but MDPV and its next-generation analogs
appear more apt to cause life-threatening medical consequences including hypertension, tachycardia,
aggression and suicide. Part of the problem with MDPV, as well as more traditional illicit psychostimulants
such as cocaine, is a highly-addictive phenotype that perpetuates ongoing drug taking and relapse to drug
taking. MDPV, similar to cocaine, blocks cellular monoamine reuptake but with enhanced potency at DAT and
NET. Little is known about how non-monoamine systems in the brain reward pathway are affected by MDPV
and contribute to its addictive effects. Since there is still no approved medication available for cocaine abuse,
let alone for synthetic cathinones, it is anticipated that a new target, a new approach or both will lead to the first
approved pharmacotherapy. Our proposed target is a chemokine, specifically CXCL12, and its receptor
CXCR4. CXL12 is one of the few chemokines found in the brain. It also has a FDA-approved, commercially-
available antagonist (AMD3100) to investigate a CXCR4-receptor mechanism. Notably, of all the chemokines,
CXCL12 is the one most linked to psychostimulant addiction. Mice exposed to acute cocaine display increased
plasma levels of CXCL12. In human cocaine abusers, CXCL12 is the only chemokine correlated to the history
of pathological cocaine use and severity of dependence. Recently, we took the critical next step of linking the
CXCL12/CXCR4 system in the mesolimbic dopamine circuit with psychostimulant reward by showing that
repeated cocaine exposure increases CXLC12 gene expression in the midbrain ventral tegmental area (VTA)
and produces place preference in rats that is reduced by a CXCR4 antagonist (AMD3100). The efficacy of
CXCR4 antagonism extends to MDPV-induced behaviors, as our data show that AMD3100 reduces MDPV
place preference, locomotor activation, and acquisition (self-administration) in rats. We propose behavioral,
cellular and neurochemical experiments to test the hypotheses that CXCL12 and CXCR4 in the mesolimbic DA
circuit are dysregulated by MDPV exposure and abstinence and that genetic or pharmacological antagonism of
CXCR4 receptors in the VTA reduces MDPV acquisition, reinforcement and relapse by decreasing mesolimbic
dopamine (DA) output. By providing information about how interplay between chemokine and mesolimbic brain
reward systems impact psychostimulant addiction, we expect to identify CXCL12/CXCR4 as a chemokine-
based therapeutic target for countering adverse effects of both new and established psychostimulant drugs.

## Key facts

- **NIH application ID:** 9913484
- **Project number:** 5R01DA045499-03
- **Recipient organization:** TEMPLE UNIV OF THE COMMONWEALTH
- **Principal Investigator:** SCOTT M. RAWLS
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $368,513
- **Award type:** 5
- **Project period:** 2018-07-01 → 2023-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9913484

## Citation

> US National Institutes of Health, RePORTER application 9913484, Chemokine CXCL12/CXCR4 system and synthetic cathinones (5R01DA045499-03). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9913484. Licensed CC0.

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