Chicora F Oliver1, Steven J Simmons2, Sunil U Nayak2, Garry R Smith3, Allen B Reitz3, Scott M Rawls4. 1. Department of Psychology, College of Liberal Arts, Temple University, Philadelphia, PA, USA; Center for Substance Abuse Research, Lewis Katz School of Medicine, Temple University Philadelphia, PA, USA. 2. Center for Substance Abuse Research, Lewis Katz School of Medicine, Temple University Philadelphia, PA, USA. 3. Fox Chase Chemical Diversity Center Inc., Doylestown, PA, USA. 4. Center for Substance Abuse Research, Lewis Katz School of Medicine, Temple University Philadelphia, PA, USA; Department of Pharmacology, Lewis Katz School of Medicine, Temple University, Philadelphia, PA, USA. Electronic address: scott.rawls@temple.edu.
Abstract
BACKGROUND AND PURPOSE: Little is known about how chemokine systems influence the behavioral effects of designer cathinones and psychostimulants. The chemokine CXCL12 and its principal receptor target, CXCR4, are of particular interest because CXCR4 activation enhances mesolimbic dopamine output that facilitates psychostimulant reward, reinforcement, and locomotor activation. Repeated cocaine enhances CXCL12 gene expression in the midbrain and produces conditioned place preference (CPP) that is inhibited by a CXCR4 antagonist. Yet, interactions between chemokines and synthetic cathinones remain elusive. METHODS: We tested the hypothesis that an FDA-approved CXCR4 antagonist (AMD3100) inhibits MDPV-induced reward, locomotor activation and positive affective state in rats using a triad of behavioral assays (CPP, open field, and 50-kHz ultrasonic vocalizations [USVs]). KEY RESULTS: AMD3100 (1, 2.5, 5, 10 mg/kg, ip) significantly reduced MDPV (2 mg/kg, ip)-evoked hyper-locomotion in a dose-related manner. AMD3100 (1, 5, 10 mg/kg) administered during CPP conditioning caused a significant, dose-dependent reduction of MDPV (2 mg/kg x 4 days) place preference. MDPV injection elicited significantly greater 50 kHz USVs in vehicle-pretreated rats but not in AMD3100-pretreated rats. CONCLUSION AND IMPLICATION: A CXCR4 antagonist reduced the rewarding and locomotor-activating effects of MDPV. Our results identify the existence of chemokine/cathinone interactions and suggest the rewarding and stimulant effects of MDPV, similar to cocaine, require an active CXCL12/CXCR4 system.
BACKGROUND AND PURPOSE: Little is known about how chemokine systems influence the behavioral effects of designer cathinones and psychostimulants. The chemokine CXCL12 and its principal receptor target, CXCR4, are of particular interest because CXCR4 activation enhances mesolimbic dopamine output that facilitates psychostimulant reward, reinforcement, and locomotor activation. Repeated cocaine enhances CXCL12 gene expression in the midbrain and produces conditioned place preference (CPP) that is inhibited by a CXCR4 antagonist. Yet, interactions between chemokines and synthetic cathinones remain elusive. METHODS: We tested the hypothesis that an FDA-approved CXCR4 antagonist (AMD3100) inhibits MDPV-induced reward, locomotor activation and positive affective state in rats using a triad of behavioral assays (CPP, open field, and 50-kHz ultrasonic vocalizations [USVs]). KEY RESULTS:AMD3100 (1, 2.5, 5, 10 mg/kg, ip) significantly reduced MDPV (2 mg/kg, ip)-evoked hyper-locomotion in a dose-related manner. AMD3100 (1, 5, 10 mg/kg) administered during CPP conditioning caused a significant, dose-dependent reduction of MDPV (2 mg/kg x 4 days) place preference. MDPV injection elicited significantly greater 50 kHz USVs in vehicle-pretreated rats but not in AMD3100-pretreated rats. CONCLUSION AND IMPLICATION: A CXCR4 antagonist reduced the rewarding and locomotor-activating effects of MDPV. Our results identify the existence of chemokine/cathinone interactions and suggest the rewarding and stimulant effects of MDPV, similar to cocaine, require an active CXCL12/CXCR4 system.
Authors: Steven J Simmons; Rose Martorana; Helene Philogene-Khalid; Fionya H Tran; Taylor A Gentile; Xinyan Xu; Shu Su; Scott M Rawls; John W Muschamp Journal: Psychopharmacology (Berl) Date: 2017-08-07 Impact factor: 4.530
Authors: L D Simmler; T A Buser; M Donzelli; Y Schramm; L-H Dieu; J Huwyler; S Chaboz; M C Hoener; M E Liechti Journal: Br J Pharmacol Date: 2013-01 Impact factor: 8.739
Authors: Callum Hicks; Ryan A Gregg; Sunil U Nayak; Lee Anne Cannella; Giana J Schena; Christopher S Tallarida; Allen B Reitz; Garry R Smith; Scott M Rawls Journal: Psychopharmacology (Berl) Date: 2017-03-01 Impact factor: 4.530
Authors: Steven J Simmons; Ryan A Gregg; Fionya H Tran; Lili Mo; Eva von Weltin; David J Barker; Taylor A Gentile; Lucas R Watterson; Scott M Rawls; John W Muschamp Journal: Addict Biol Date: 2016-12-01 Impact factor: 4.280
Authors: Sunil U Nayak; Stephanie Cicalese; Chris Tallarida; Chicora F Oliver; Scott M Rawls Journal: Brain Behav Immun Date: 2019-09-23 Impact factor: 7.217
Authors: Steven J Simmons; Jonna M Leyrer-Jackson; Chicora F Oliver; Callum Hicks; John W Muschamp; Scott M Rawls; M Foster Olive Journal: ACS Chem Neurosci Date: 2018-05-11 Impact factor: 4.418
Authors: Steven J Simmons; Chicora F Oliver; Nicholas S McCloskey; Allen B Reitz; Sunil U Nayak; Mia N Watson; Scott M Rawls Journal: Drug Alcohol Depend Date: 2021-11-27 Impact factor: 4.492