Troriluzole inhibits methamphetamine place preference in rats and normalizes methamphetamine-evoked glutamate carboxypeptidase II (GCPII) protein levels in the mesolimbic pathway

• Published in: Drug and alcohol dependence Vol. 242; p. 109719
• Main Authors: Wiah, Sonita, Roper, Abigail, Zhao, Pingwei, Shekarabi, Aryan, Watson, Mia N., Farkas, Daniel J., Potula, Raghava, Reitz, Allen B., Rawls, Scott M.
• Format: Journal Article
• Language: English
• Published: Ireland Elsevier B.V 01.01.2023; Elsevier Science Ltd
• Subjects: Amphetamine-Related Disorders - drug therapy; Amyotrophic lateral sclerosis; Animals; Ataxia; Biological markers; Biomarkers; Carboxypeptidase; Central Nervous System Stimulants - pharmacology; Cerebellar ataxia; Cerebellum; Clinical research; Clinical trials; Conditioning; Cortex; CPP; Extinction; GCPII; Glutamate; Glutamate carboxypeptidase; Glutamate Carboxypeptidase II - therapeutic use; Glutamatergic transmission; Glutamates - therapeutic use; Mesolimbic system; Methamphetamine; Methamphetamine - pharmacology; mRNA; Normalization; Pharmacokinetics; Place preference conditioning; Plasma levels; Prefrontal cortex; Proteins; Psychological extinction; Psychostimulant; Rats; Riluzole; Riluzole - therapeutic use; Substrates; Therapeutic targets; Troriluzole; Ventral tegmentum; CPP; Methamphetamine; Troriluzole; Psychostimulant; Glutamate; GCPII; Riluzole
• ISSN: 0376-8716; 1879-0046
• DOI: 10.1016/j.drugalcdep.2022.109719

Riluzole, approved to manage amyotrophic lateral sclerosis, is mechanistically unique among glutamate-based therapeutics because it reduces glutamate transmission through a dual mechanism (i.e., reduces glutamate release and enhances glutamate reuptake). The profile of riluzole is favorable for normalizing glutamatergic dysregulation that perpetuates methamphetamine (METH) dependence, but pharmacokinetic and metabolic liabilities hinder repurposing. To mitigate these limitations, we synthesized troriluzole (TRLZ), a third-generation prodrug of riluzole, and tested the hypothesis that TRLZ inhibits METH hyperlocomotion and conditioned place preference (CPP) and normalizes METH-induced changes in mesolimbic glutamate biomarkers. TRLZ (8, 16 mg/kg) reduced hyperlocomotion caused by METH (1 mg/kg) without affecting spontaneous activity. TRLZ (1, 4, 8, 16 mg/kg) administered during METH conditioning (0.5 mg/kg x 4 d) inhibited development of METH place preference, and TRLZ (16 mg/kg) administered after METH conditioning reduced expression of CPP. In rats with established METH place preference, TRLZ (16 mg/kg) accelerated extinction of CPP. In cellular studies, chronic METH enhanced mRNA levels of glutamate carboxypeptidase II (GCPII) in the ventral tegmental area (VTA) and prefrontal cortex (PFC). Repeated METH also caused enhancement of GCPII protein levels in the VTA that was prevented by TRLZ (16 mg/kg). TRLZ (16 mg/kg) administered during chronic METH did not affect brain or plasma levels of METH. These results indicate that TRLZ, already in clinical trials for cerebellar ataxia, reduces development, expression and maintenance of METH CPP. Moreover, normalization of METH-induced GCPII levels in mesolimbic substrates by TRLZ points toward studying GCPII as a therapeutic target of TRLZ. •Troriluzole (TRLZ) is a riluzole prodrug and glutamate release inhibitor/transport activator.•TRLZ was tested for the first time in animal models of addiction.•TRLZ reduced development, expression and maintenance of methamphetamine place preference.•Methamphetamine enhanced VTA levels of glutamate carboxypeptidase II (GCPII).•TRLZ normalized methamphetamine-evoked increase in mesolimbic GCPII levels.