Role of glutamate transporter 1 in the attenuation of alcohol intake

Evidence demonstrated that many aspects of drug abuse and dependence involve changes in glutamate neurotransmission. Neuroadaptations of the glutamatergic system are critical in alcohol dependence, tolerance and withdrawal (Krystal et al., 2003; Backstrom and Hyytia, 2005; Cowen et al., 2005; Olive et al., 2005; Hodge et al., 2006; Bird et al., 2008; Kapasova and Szumlinski, 2008; Besheer et al., 2010). One of the selective effects of alcohol has been determined to be the inhibition of glutamatergic neurotransmission by antagonizing N-methyl-D-aspartate (NMDA) receptors (Grant et al., 1990; Chen et al., 1997). Furthermore, one of the effects of chronic alcohol exposure is the upregulation of NMDA receptors that results from chronic inhibition of glutamate transmission as a compensatory mechanism (Grant et al., 1990; Sanna et al., 1993; Snell et al., 1996; Chen et al., 1997). In addition, the effects of alcohol withdrawal have been found to be associated with increased extracellular glutamate levels in the striatum (Rossetti and Carboni, 1995), and enhanced NMDA sensitivity in the nucleus accumbens (NAc) of alcohol dependent rats (Siggins et al., 2003). Importantly, studies have reported that alcohol exposure affects glutamate transport and glutamate transmission (Smith, 1997; Smith and Weiss, 1999; Othman et al., 2002). Although the neurocircuitry of the glutamatergic system is not fully defined, it has been suggested that the prefrontal cortex (PFC) (Goldstein and Volkow, 2002) and the NAc (Childress et al., 1999) play a critical role in drug reinforcement. These brain regions receive input from midbrain dopaminergic neurons, and all major drugs of abuse, including alcohol, increase forebrain dopamine transmission (Berridge and Robinson, 1998; Kalivas, 2004). The important roles of these glutamatergic projections from the PFC to the NAc and the ventral tegmental area (VTA) have been observed in neuroimaging studies performed during craving periods in several paradigms for commonly abused drugs such as alcohol, cocaine, methamphetamine, heroin and nicotine (Childress et al., 1999; Goldstein and Volkow, 2002). Moreover, glutamatergic projections from the PFC to the NAc are also important in the expression of addictive behaviors, and are the primary driver of drug abuse, including alcohol (for review see Kalivas, 2004; Rao and Sari, 2012). Glutamate neurotransmission is regulated by several glutamate transporters. Among them, glutamate transporter 1 (GLT1, its human homolog is excitatory amino acid transporter 2, EAAT2) regulates the majority of extracellular glutamate (Robinson, 1998; Danbolt, 2001). GLT1 is present in the brain in two splice variant isoforms such as GLT1a and GLT1b (Chen et al., 2002, 2004; Berger et al., 2005). It has been reported that GLT1a is predominantly localized in neurons and astrocytes, and GLT1b is localized in astrocytes (Berger et al., 2005; Holmseth et al., 2009). Both isoforms regulate extracellular glutamate at the synaptic clefts. Our central question in our laboratory was whether we could increase the expression of GLT1 level in rat brains exposed to alcohol, and further determine the effects of this increase in alcohol intake. The increase in the expression of GLT1 can lead to the reduction of the amount of glutamate available to activate neurons in central reward brain regions, and thus decrease the craving initiated by it. Studies have tested more than 1040 FDA-approved drugs to determine target compounds that may have effects in upregulating the expression of GLT1 (Rothstein et al., 2005). Rothstein et al. (2005) have found that among several β-lactam antibiotics, ceftriaxone was the potent drug that has an upregulatory effect in the expression of GLT1. This drug has been used to treat meningitis and is in phase III clinical trials for the treatment of Amyotrophic Lateral Sclerosis. We further examined the ability of this drug to increase the level of GLT1 and thereby decrease the amount of extracellular glutamate available to activate addictive behaviors. Thus, elevation of the expression of GLT1 might be associated with reduction in alcohol consumption as well as attenuation of relapse to alcohol intake. We have used the animal model of alcohol-preferring (P) rats to measure the effectiveness of ceftriaxone in reducing alcohol consumption. These rats naturally prefer drink alcohol to plain water. After 5 weeks of a constant free choice of alcohol, the rats develop alcohol dependence. We administered ceftriaxone to the rats each day for 5 days and measured their alcohol consumption. P rats treated with ceftriaxone reduced their alcohol intake as compared to rats treated with physiological saline solution (Sari et al., 2011). This reduction in alcohol drinking was associated with increased GLT1 level in central reward brain regions, including the PFC and NAc. As shown in Figure 1 (Upper