Changes in the Neuronal Glutamate Transporter EAAT3 in Rat Brain after Exposure to Methamphetamine

Abstract

Methamphetamine (METH), an addictive psychostimulant, can induce glutamate release in several brain areas such as cerebral cortex, hippocampus and striatum. Excess glutamate is ordinarily removed from the synaptic cleft by glutamate transporters for maintaining homoeostasis. EAAT3, a subtype of glutamate transporter expressed mainly by neurons, is a major glutamate transporter in the hippocampus and cortex. Therefore, this study examined the effects of acute and sub-acute METH administration on the expression of the EAAT3 in the hippocampal formation, striatum and frontal cortex. Male Sprague-Dawley rats received vehicle injections (i.p.) for 13 days followed by one injection of METH (8 mg/kg, i.p.) on day 14 in acute group. Animals received METH (4 mg/kg, i.p.) or vehicle for 14 days in sub-acute and control groups, respectively. EAAT3 immunoreactivity was determined by western blotting followed by measurement of the integrated optical density. A significant increase in EAAT3 was found in the hippocampal formation after sub-acute, but not acute, METH administration. Conversely, a significant decrease in EAAT3 in striatum was observed in both acute and sub-acute groups. A trend towards a decrease in EAAT3 was also found in frontal cortex in the sub-acute group. Our results of decreased EAAT3 in striatum and frontal cortex suggest deficits of cortico-striatal glutamatergic synapses after METH exposure. Increased EAAT3 expression in the hippocampus may be a compensatory response to possible deficits of glutamatergic neurotransmission induced by METH. Moreover, our findings provide further support for glutamatergic dysfunction with abnormalities involving a transporter important in the regulation of neuronal glutamate.Methamphetamine (METH) is an addictive psychostimulant with potent effects on the central nervous system (CNS) [1,2]. METH has been reported to have a major impact on both cortical and subcortical regions of brain [3,4]. Several studies have shown neurotoxic effects of METH on dopaminergic and serotonergic systems [5,6]. Dysfunctions of dopaminergic neurotransmission such as fibre degeneration, abnormalities of dopamine transporter and tyrosine hydroxylase as well as depletion of dopamine content have been observed following METH exposure [7][8][9][10]. In addition, METH-induced dopamine depletion is blocked by glutamate N-methyl-D-aspartate (NMDA) receptor antagonism [11]. This has led to a hypothesis that the glutamatergic system may be implicated in the neurotoxic effect of METH. Glutamatergic effects of METH exposure have also been reported. METH-induced glutamate release was observed in several brain regions, such as striatum [12], cerebral cortex [13], hippocampus [14], ventral tegmental area and nucleus accumbens [15]. Excess extracellular glutamate can stimulate glutamate receptors such as NMDA and alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) receptors, potentially leading to neurotoxicity [16][17][18]. An up-regulation of NMDAR1 and AMPA GluR2 subunits after METH...

Spinal RhoA/Rho Kinase Signalling Pathway may Participate in the Development of Bone Cancer Pain

“…Protein bands were detected by enhanced chemiluminescence system (GE Healthcare, Shanghai, China). Band densities of RhoA and ROCK2 to β‐actin were calculated and normalized to the intensity of the control samples .…”

Glutamate Transport: A New Bench to Bedside Mechanism for Treating Drug Abuse

“…There is accumulating evidence for some EAAT3 involvement in amphetamine/methamphetamine addiction, but EAAT3 levels have never been measured following self-administration. In striatum, acute (8 mg/kg i.p., 1 day) and repeated (4 mg/kg i.p., 14 days) methamphetamine injections decrease EAAT3 levels, but in frontal cortex this effect is only significant with repeated injections ( Kerdsan et al, 2012 ). Conversely, repeated methamphetamine increases EAAT3 levels in hippocampus, perhaps as compensatory mechanism to counter excitotoxicity in this brain region ( Kerdsan et al, 2012 ).…”

Differential Responses of LINE-1 in the Dentate Gyrus, Striatum and Prefrontal Cortex to Chronic Neurotoxic Methamphetamine: A Study in Rat Brain

“…For example, chronic exposure to medium-dose METH (4 mg/kg/d, i.p. for 14 d) resulted in differential changes in glutamate transporter EAAT3: a 39% decrease in the striatum, 25% decrease in the prefrontal cortex and 72% increase in the hippocampus [96]. Dopamine transporter was also differentially affected by chronic METH, with dorsal striatum showing a higher deficit than the prefrontal cortex and hippocampus showing no deficit [97].…”