Abstract
Methamphetamine (METH) is one of the psychostimulants that is co-abused with ethanol. Repeated exposure to high dose of METH has been shown to cause increases in extracellular glutamate concentration. We have recently reported that ethanol exposure can also increase the extracellular glutamate concentration and downregulate the expression of glutamate transporter subtype 1 (GLT-1). GLT-1 is a glial transporter that regulates the majority of extracellular glutamate. A Wistar rat model of METH and ethanol co-abuse was used to examine the expression of GLT-1 as well as other glutamate transporters such as cystine/glutamate exchanger (xCT) and glutamate aspartate transporter (GLAST). We also examined the body temperature in rats administered METH, ethanol or both drugs. We further investigated the effects of ceftriaxone (CEF), a β-lactam antibiotic known to upregulate GLT-1, in this METH/ethanol co-abuse rat model. After 7 days of either ethanol (6 g/kg) or water oral gavage, Wistar rats received either saline or METH (10 mg/kg i.p. every 2 h × 4), followed by either saline or CEF (200 mg/kg) posttreatment. METH administered alone decreased GLT-1 expression in the nucleus accumbens (NAc) and prefrontal cortex (PFC) and increased body temperature, but did not reduce either xCT or GLAST expression in ethanol and water-pretreated rats. Interestingly, ethanol and METH were found to have an additive effect on the downregulation of GLT-1 expression in the NAc but not in the PFC. Moreover, ethanol alone caused GLT-1 downregulation in the NAc and elevated body temperature compared to control. Finally, CEF posttreatment significantly reversed METH-induced hyperthermia, restored GLT-1 expression, and increased xCT expression. These findings suggest the potential therapeutic role of CEF against METH- or ethanol/METH-induced hyperglutamatergic state and hyperthermia.
Highlights
Methamphetamine (METH) abusers frequently use alcohol with a higher risk of reaching alcohol intoxication (Furr et al, 2000)
Since repeated exposure to high dose of METH can increase extracellular glutamate concentration (Halpin et al, 2014), we investigated in this study for any potential additive effect of ethanol and METH exposure on glutamate transporter 1 (GLT-1) expression as well as other glial glutamate transporters such as cystine/glutamate transporter and glutamate aspartate transporter (GLAST) in the nucleus accumbens (NAc) and prefrontal cortex (PFC)
We examined the effect of ceftriaxone (CEF) posttreatment on GLT-1, xCT, and GLAST expression in the NAc and PFC in rats that were exposed to repeated high-dose METH
Summary
Methamphetamine (METH) abusers frequently use alcohol with a higher risk of reaching alcohol intoxication (Furr et al, 2000). Since repeated exposure to high dose of METH can increase extracellular glutamate concentration (Halpin et al, 2014), we investigated in this study for any potential additive effect of ethanol and METH exposure on GLT-1 expression as well as other glial glutamate transporters such as cystine/glutamate transporter (xCT) and glutamate aspartate transporter (GLAST) in the NAc and PFC. CEF is known to increase GLT1 expression in several brain regions (Miller et al, 2008; Sari et al, 2009, 2013) and can normalize extracellular glutamate concentration in the NAc in cocaine and ethanol-seeking rat models (Trantham-Davidson et al, 2012; Das et al, 2015). We administered CEF after ethanol and METH exposure for clinical relevance
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