Alcohol 6.indd

Introduction Evidence has demonstrated that deficits in glutamate transmission impair neurocircuits involved in drug abuse or drug-seeking behaviour and affect many aspects of neuroplasticity associated with alcohol and drug addiction. Alcohol-seeking behaviour is promoted by increased glutamate transmission in key regions of the mesocorticolimbic reward circuit, including the nucleus accumbens and prefrontal cortex. Glutamate transmission or glutamate uptake is regulated by a number of glutamate transporters in the brain regions. Among these glutamate transporters, glutamate transporter 1 (GLT1; its human homolog is the excitatory amino acid transporter 2, EAAT2) regulates the removal of majority of the extracellular glutamate. The role of GLT1 has been tested in alcohol and other drugs of abuse models with dysfunction in glutamate transmission. We recently reported that treatment of alcohol-preferring rats with compounds ceftriaxone and GPI-1046, known to upregulate GLT1 levels, showed reduction in alcohol intake and attenuation of relapselike ethanol-drinking behaviour. Furthermore, we demonstrated that upregulation of GLT1 was associated in part with attenuation of cueinduced cocaine relapse. Together, we suggest that GLT1 is considered as a potential therapeutic target for the treatment of drug dependence, including alcohol. The aim of this critical review was to discuss the potential therapeutic role of GLT1 for the treatment of alcohol dependence. Conclusion Dysfunction of glutamate transmission has been suggested to impair neurocircuits involved in alcohol dependence, which affect neuroplasticity that is associated with ethanol intake. Introduction Alcohol abuse and dependence continue to be significant public health problems. A better understanding of their neurobiology will facilitate the development of interventions targeting prevention and/ or treatment of these major health issues. Evidence has suggested that several neurotransmitters are involved in the development of drug abuse and dependence, including alcohol. While it is established that dopaminergic neurotransmission plays an important role in alcohol addiction, increasing evidence suggests that many aspects of neuroplasticity in drug addiction involve changes in glutamatergic neurotransmission as well. Neuroadaptations of the glutamatergic system play a key role in alcohol tolerance, dependence and withdrawal1. The selective effects of alcohol include inhibition of glutamatergic neurotransmission by alteration of N-methyl-D-aspartate (NMDA) receptors1. One of the effects of chronic alcohol exposure is the upregulation of NMDA receptors that are part of the compensatory mechanism, which results from chronic inhibition of glutamatergic neurotransmission2,3. In addition, the effects of alcohol withdrawal are associated with increased extracellular glutamate levels in the striatum of alcohol dependent rats4 and enhanced NMDA sensitivity in the nucleus accumbens (NAc)5. Importantly, drugs that have the potential to target NMDA receptors and metabotropic glutamate receptor subtype 5 (mGluR5) have indicated the important role of the glutamatergic system in alcohol dependence and seekingbehaviour6. In addition, a marked increase in the levels of extracellular glutamate was found in the NAc of animals exposed chronically to ethanol7. Extracellular glutamate levels and glutamate neurotransmission are regulated by several glutamate transporters in the brain8,9. Among these glutamate transporters, glutamate transporter 1 (GLT1, termed also as excitatory amino acid transporter 2, EAAT2) is a key player in the removal of the majority of extracellular glutamate10,11. Similar to disease models in which there is dysfunction of the glutamatergic excitatory system, the role of GLT1 has been tested in drug abuse models that show dysfunction of glutamate transmission. It is noteworthy that the activation of GLT1 by MS-153, a cerebroprotective agent, was effective in reducing the induction of conditioned place preference to methamphetamine, cocaine and morphine12. Moreover, we have recently found that ceftriaxone, a β-lactam antibiotic, known to upregulate GLT1 levels13-15, attenuates cue-induced cocaine relapse in a dose-dependent manner in a rat model16. In accordance with this data, Knackstedt et al.17 have found similar effects with ceftriaxone in cocaine relapse-like behaviour. Focussing on the role of GLT1 in alcohol-drinking behaviour, we have previously reported that male alcohol-preferring (P) rats treated Bi om ed ic al * Corresponding author Email: [email protected] 1 University of Toledo, College of Pharmacy and Pharmaceutical Sciences, Department of Pharmacology, Toledo, Ohio, USA