Synthetic cathinone MDPV downregulates glutamate transporter subtype I (GLT-1) and produces rewarding and locomotor-activating effects that are reduced by a GLT-1 activator

Abstract

Synthetic cathinones produce dysregulation of monoamine systems, but their effects on the glutamate system and the influence of glutamate on behavioral effects related to cathinone abuse are unknown. A principal regulator of glutamate homeostasis is glutamate transporter subtype 1 (GLT-1), an astrocytic protein that clears glutamate from the extracellular space and influences behavioral effects of established psychostimulants. We hypothesized that repeated administration of the synthetic cathinone, MDPV (3,4-methylenedioxypyrovalerone), would affect GLT-1 expression in the corticolimbic circuit, and that a GLT-1 activator (ceftriaxone, CTX) would reduce rewarding and locomotor-stimulant effects of MDPV in rats. GLT-1 protein expression in the nucleus accumbens (NAcc), but not prefrontal cortex (PFC), was decreased following withdrawal (2, 5 and 10 days) from repeated MDPV treatment, but not immediately after the last MDPV injection. CTX (200 mg/kg) pretreatment did not affect acute locomotor activation produced by MDPV (0.5, 1, 3 mg/kg). However, CTX (200 mg/kg) administered during a 7-day MDPV treatment paradigm attenuated the development of MDPV-induced sensitization of repetitive movements in rats challenged with MDPV following 11 days of drug abstinence. Pretreatment with CTX (200 mg/kg) during a 4-day MDPV (2 mg/kg) conditioned place preference (CPP) paradigm reduced the development of place preference produced by MDPV. The present data demonstrate dysregulation of corticolimbic glutamate transport systems during withdrawal from chronic MDPV exposure, and show that a GLT-1 transporter activator disrupts behavioral effects of MDPV that are related to synthetic cathinone abuse.

Glutamate carboxypeptidase II (GCPII) inhibitor 2-PMPA reduces rewarding effects of the synthetic cathinone MDPV in rats: a role for N-acetylaspartylglutamate (NAAG)

“…The general procedure for Western blot protein analysis has been described previously (Gregg et al 2016). After tissue sample preparation, equal amounts of protein (20 μg per loading sample, as determined using a Thermo Scientific NanoDrop 2000 spectrometer) were loaded onto 7.5% Mini Protean Precast gels (Bio-Rad, Hercules, CA) for separation and transferred onto nitrocellulose membranes (Life Technologies, Carlsbad, CA).…”

“…CPP experiments were performed according to previously published methods described in detail elsewhere (Lisek et al 2012; Gregg et al 2015, 2016). The apparatus consisted of two equal-sized environmentally distinguishable compartments separated by a removable door.…”

“…All treatment groups were administered saline in the second conditioning session and placed in their initially preferred compartment. We selected a dose of 2 mg/kg MDPV for all CPP experiments based on our recently published dose-response experiment (Gregg et al 2016), and from previous work using a similar CPP paradigm (King et al 2015a). …”

“…This lack of research is particularly pertinent since a central role for GLU dysregulation in psychostimulant reinforcement and relapse is well documented (for review, see Kalivas 2009; D’Souza 2015; Spencer et al 2016). We recently showed that withdrawal following repeated MDPV administration disrupts GLU homeostasis by reducing glutamate transporter subtype 1 (GLT-1) levels in the nucleus accumbens (NAc) (Gregg et al 2016). Furthermore, chronic treatment with the β-lactam antibiotic ceftriaxone (CTX), which upregulates GLT-1 expression, attenuates MDPV-induced locomotor sensitization and place preference (Gregg et al 2016).…”

“…We recently showed that withdrawal following repeated MDPV administration disrupts GLU homeostasis by reducing glutamate transporter subtype 1 (GLT-1) levels in the nucleus accumbens (NAc) (Gregg et al 2016). Furthermore, chronic treatment with the β-lactam antibiotic ceftriaxone (CTX), which upregulates GLT-1 expression, attenuates MDPV-induced locomotor sensitization and place preference (Gregg et al 2016). …”