Effects of ceftriaxone on hydrocodone seeking behavior and glial glutamate transporters in P rats

Hydrocodone (HYD) is one of the most widely prescribed opioid analgesic drugs. Several neurotransmitters are involved in opioids relapse. Among these neurotransmitters, glutamate is suggested to be involved in opioid dependence and relapse. Glutamate is regulated by several glutamate transporters, including glutamate transporter 1 (GLT-1) and cystine/glutamate transporter (xCT). In this study, we investigated the effects of ceftriaxone (CEF) (200 mg/kg, i.p.), known to upregulate GLT-1 and xCT, on reinstatement to HYD (5 mg/kg, i.p.) using the conditioned place preference (CPP) paradigm in alcohol-preferring (P) rats. Animals were divided into three groups: 1) saline-saline group (SAL-SAL); 2) HYD-SAL group, and 3) HYD-CEF group. The CPP was conducted as follows: habituation phase, conditioning phase with HYD (i.p.) injections every other day for four sessions, extinction phase with CEF (i.p.) injections every other day for four sessions, and reinstatement phase with one priming dose of HYD. Time spent in the HYD-paired chamber after conditioning training was increased as compared to pre-conditioning. There was an increase in time spent in the HYD-paired chamber with one priming dose of HYD in the reinstatement test. HYD exposure downregulated xCT expression m the nucleus accumbens and hippocampus, but no effects were observed in the dorsomedial prefrontal cortex and amygdala. Importantly, CEF treatment attenuated the reinstatement effect of HYD and normalized xCT expression in the affected brain regions. These findings demonstrate that the attenuating effect of HYD reinstatement with CEF might be mediated through xCT.