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  • br Introduction Opioids have long

    2022-08-09


    Introduction Opioids have long been used in pain management [1]. However, their non-medical use has grown rapidly in the last few years. Hydrocodone (HYD) is one of the most widely used short-acting opioids; with over 136.7 million prescriptions in 2011 [2]. HYD is a semi-synthetic opioid used for analgesic and antitussive purposes. However, data shows that the nonmedical use of HYD was one of the most common causes of emergency medical visits between 2004 and 2008 [3]. HYD abuse liability and relative potency have been shown to be similar to those of oxycodone and hydromorphone [4]. In addition, a study suggested that HYD has similar effects to those of oxycodone and morphine when administered intravenously (i.v) [5]. Relapse after a long period of abstinence is a major problem in the treatment of drug dependence [6]. The high rate of relapse associated with opioids remains as one of the most challenging clinical problems in opioid dependence. It has been suggested that the glutamatergic system has regulatory effects on opioid dependence [7], withdrawal [8] and relapse in animals [9]. Indeed, memantine (N-methyl-d-aspartate receptor blocker) attenuated reinstatement to morphine, while dopaminergic blockers failed [10]. Studies have found an increase in extracellular glutamate concentration in the nucleus accumbens (NAc) with exposure to heroin [11], nicotine [12] and PCI-34051 cocaine [13]. The extracellular glutamate is maintained via several glutamate transporters (also called the excitatory amino PCI-34051 transporters, EAATs), including glutamate transporter 1 (GLT-1, EAAT2), glutamate/aspartate transporter (GLAST, EAAT1) and glutamate transporter (EAAT3). GLT-1 is a major glutamate transporter that regulates the uptake of the majority of glutamate [14,15]. It has been demonstrated that chronic exposure to morphine can lead to reduction of GLT-1 mRNA expression in the NAc, striatum, thalamus, and hippocampus (HIP) [7]. Relapse to heroin was shown to be associated with increase in the extracellular glutamate concentration in the NAc [16]. Thus, restoring the glutamate uptake may have beneficial therapeutic effect in attenuating opioid relapse. In regards to GLAST, this protein transports both glutamate and aspartate, and expressed mostly in the cerebellum and spinal cord [17]. Several studies have suggested that the loss of morphine analgesic effect after repeated exposure to morphine might be due to reduction in GLAST expression as well as glutamate uptake in the spinal cord [18,19]. The EAAT3 is a neuronal glutamate transporter, expressed mainly in the HIP, basal ganglia and cerebellum [20]. It has been shown that chronic exposure to morphine could downregulate the expression of EAAT3 in the HIP neuronal culture [21]. In addition, recent report suggested that EAAT3 is important in morphine-induced conditioned place preference (CPP), but not in reinstatement [22]. Furthermore, cystine/glutamate transporter (xCT) is another transporter that regulates extracellular glutamate through the exchange of cystine with glutamate [14,23,24]. Although there is less known about the role of xCT in opioid relapse, one study has demonstrated that restoring xCT function with N-acetylcysteine can attenuate heroin relapse in animals [25]. N-acetylcysteine is known to improve the function of xCT, which might attenuate heroin relapse by increasing the glutamatergic tone on the pre-synaptic metabotropic glutamate receptor (mGluR2/3) [26]. Thus, xCT might be a target candidate for the treatment of opioids dependence. Therefore, in this study, we investigated the effect of HYD reinstatement on the glial glutamate transporters such as GLT-1, xCT and GLAST. In this study, we investigated the effects of HYD in alcohol-preferring (P) rats using the CPP paradigm. We used P rats due to the fact that they have higher density of mu opioid receptors than non-preferring (NP) rats [27]. Similarly, others have found that alcohol-preferring Alko Alcohol (AA) rats express higher amount of opioid peptides and receptors as compared to alcohol-avoiding Alko Non-Alcohol (ANA) rats in several brain regions, including the NAc and ventral tegmental area (VTA) [28,29]. Also, AA rats have shown to be more susceptible to drug-induced behavioral sensitization in response to morphine than ANA rats [30]. Therefore, high ethanol drinking rats may have a potential benefit over low ethanol drinking rats in testing opioids dependence and relapse. In this study, we tested a lower dose of HYD (5 mg/kg, i.p.) in P rats as sensitive bred to induce the conditioning and the reinstatement effects of HYD.