Differential Modulation of Glutamate Transporter-1 by Cocaine and Oxycodone and the Efficacy of MC-100093 to Reduce Reinstatement of Self-Administration

Introduction

Despite the widespread impact of opioid use disorder, pharmacological options for treatment remain limited. Recent studies find that cocaine exposure decreases the expression of the glutamate transporter GLT-1 in the nucleus accumbens (NAc) and that treatment with the beta-lactam antibiotic ceftriaxone rescues this loss of expression and reduces cue-induced reinstatement to cocaine self-administration. The novel beta-lactam derivative MC-100093 (093) lacks antimicrobial properties but crosses the blood-brain barrier more rapidly and retains the beneficial effects of ceftriaxone following cocaine. However, 093 effects following oxycodone exposure have not been examined.

Methods

We used intravenous self-administration (IVSA) of oxycodone in rats to test if 093 can attenuate oxycodone seeking. Membrane expression of GLT-1 in the NAc was investigated using western blots. Conditioned place preference (CPP) was used to test the effect of oxycodone and cocaine alone on GLT-1 expression.

Results

We find that 093 injections following IVSA of oxycodone in rats did not reduce cue-induced reinstatement. Interestingly, western blot analysis revealed that 093 failed to upregulate the expression of GLT-1 in the NAc of oxycodone-exposed animals. Follow-up CPP experiments suggest that oxycodone exposure alone does not decrease GLT-1 expression as cocaine does.

Conclusions

Our results indicate that drug-specific reductions in NAc GLT-1 expression may be necessary for 093's efficacy. Further investigation into 093 and other opioids is needed to fully understand their relationship with GLT-1 expression and beta-lactams.