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  2. Positive allosteric modulation of glutamate transporter reduces cocaine-induced locomotion and expression of cocaine conditioned place preference in rats

Positive allosteric modulation of glutamate transporter reduces cocaine-induced locomotion and expression of cocaine conditioned place preference in rats

  • Eur J Pharmacol. 2024 Dec 5:984:177017. doi: 10.1016/j.ejphar.2024.177017.
Katelyn L Reeb 1 Sonita Wiah 2 Bhumiben P Patel 1 Stacia I Lewandowski 1 Ole V Mortensen 1 Joseph M Salvino 3 Scott M Rawls 4 Andréia C K Fontana 5
Affiliations

Affiliations

  • 1 Department of Pharmacology and Physiology, Drexel University College of Medicine, Philadelphia, PA, 191022, USA.
  • 2 Center for Substance Abuse Research, Lewis Katz School of Medicine, Temple University, Philadelphia, PA, 19140, USA.
  • 3 Medicinal Chemistry, Molecular and Cellular Oncogenesis (MCO) Program, The Wistar Cancer Center Molecular Screening, The Wistar Institute, Philadelphia, PA, 19104, USA.
  • 4 Center for Substance Abuse Research, Lewis Katz School of Medicine, Temple University, Philadelphia, PA, 19140, USA; Department of Neural Sciences, Lewis Katz School of Medicine, Temple University, Philadelphia, PA, 19140, USA. Electronic address: scott.rawls@temple.edu.
  • 5 Department of Pharmacology and Physiology, Drexel University College of Medicine, Philadelphia, PA, 191022, USA. Electronic address: acm83@drexel.edu.
Abstract

The glutamatergic system, located throughout the brain including the prefrontal cortex and nucleus accumbens, plays a critical role in reward and reinforcement processing, and mediates the psychotropic effects of addictive drugs such as cocaine. Glutamate transporters, including EAAT2/GLT-1, are responsible for removing glutamate from the synaptic cleft. Reduced expression of GLT-1 following chronic cocaine use and abstinence has been reported. Here, we demonstrate that targeting GLT-1 with a novel positive allosteric modulator (PAM), NA-014, results in reduction of cocaine-associated behaviors in rats. Pharmacokinetic analysis demonstrated that NA-014 is brain-penetrant and suitable for in vivo studies.We found that 15 and 30 mg/kg NA-014 significantly reduced cocaine-induced locomotion in males. Only the 15 mg/kg dose was effective in females and 60 mg/kg was ineffective in both sexes. Furthermore, 30 and 60 mg/kg NA-014 reduced expression of cocaine conditioned place preference (CPP) in males. 30 mg/kg NA-014 reduced expression of cocaine CPP in females and 15 mg/kg did not affect cocaine CPP in either sex, suggesting GLT-1 influences cocaine-associated behaviors in a sex-dependent manner. NA-014 did not elicit rewarding behavior, nor alter baseline locomotion. Twice daily/7-day administration of 100 mg/kg of NA-014 did not alter GLT-1 or GLAST expression in either sex in the prefrontal cortex (PFC). Collectively, these studies demonstrated that NA-014 reduced the locomotor stimulant and rewarding effects of cocaine in male and female rats. In the context of psychostimulant use disorders, our study suggests studying GLT-1 PAMs as alternatives to β-lactam compounds that increase GLT-1 protein levels.

Keywords

Allosteric modulation; Cocaine use disorder; EAAT2; GLT-1; Glutamate transporter.

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