Changes in the glutamate biomarker expression in rats vulnerable or resistant to the rewarding effects of cocaine and their reversal by ceftriaxone

Abstract

Literature data show diverse vulnerability to the rewarding effects of cocaine in human as well as in laboratory animals. The molecular mechanisms of these differences have not been discovered yet. While the initial effects of cocaine depend primarily on the dopamine system, numerous studies have shown that adaptation within the glutamatergic system is responsible for the development of addiction. In this paper, we used the unbiased conditioned place preference (CPP) to identify rats showing a vulnerable or resistant phenotype to the rewarding effects of cocaine. Next, we investigated the expression of membrane glutamate transporter proteins: GLT-1 and xCT in selected brain structures in the above-mentioned groups of rats. Moreover, we determined the nuclear level of NF-κB and Nrf2 to verify whether changes in GLT-1 and xCT expression correlate with NF-κB and Nrf2 levels, respectively. In addition, we determined GLT-1, NF-κB, xCT and Nrf2 mRNA levels to verify the involvement of transcriptional mechanisms. We also analyzed the ability of the β-lactam antibiotic, ceftriaxone, to attenuate the persistence of CPP after a cocaine-free period in animals showing vulnerability to cocaine rewarding effects, and furthermore we determined GLT-1, xCT, NF-κB and Nrf2 protein expression. Our findings demonstrated molecular and neurochemical differences in the response to cocaine administration that are characteristic of the phenotype vulnerable or resistant to the rewarding effects of cocaine. Moreover, repeated administrations of ceftriaxone during cocaine-free perios attenuated CPP persistence and normalized GLT-1 level in the NAc. The results suggest the a lack of NF-κB involvement in the regulation of GLT-1 expression by ceftriaxone in the NAc. Additionally, we are the first to report that ceftriaxone strongly upregulates the GLT-1 in the HIP in a transcriptional mechanism involving the Nf-κB transcription factor. Future experiments may resolve the question concerning whether modulation exclusively of the GLT-1 expression in the HIP may attenuate cocaine-induced place preference or relapse.

Keywords: Ceftriaxone; Cocaine addiction; GLT-1; Glutamate; Nf-κB; Nrf2; xCT.