The GLT-1 expression is reduced in the reward-related regions of alcohol-dependent rodents ( Abulseoud et al., 2014 Alhaddad et al., 2014). Maladaptation of GLT-1 has been suggested as a contributor to pathological conditions related to alcohol withdrawal. Besides its well-known function as a scavenger to prevent glutamate spillover into the extrasynaptic space ( Danbolt, 2001 Ginsberg et al., 1995 Mitani and Tanaka, 2003), the GLT-1 also acts as an important regulator of synaptic glutamatergic transmission ( Ayers-Ringler et al., 2016 Murphy-Royal et al., 2015 Trantham-Davidson et al., 2012 Weng et al., 2007), thereby neuronal activity ( Cui et al., 2014). The glial excitatory amino acid transporter 2 (EAAT2/GLT-1) is particularly important in reducing synaptic glutamate overflow ( Rothstein et al., 2005). In the tripartite synaptic architecture, astrocytic processes minimize glutamate overflow by rapidly uptaking glutamate, thereby permitting efficient synaptic signaling ( Perea et al., 2009 Rusakov et al., 2011). The evidence from genetic modification further supports this with findings associating depressive-like behaviors with hyperexcitability of LHb neurons ( Cui et al., 2014 Li et al., 2011a Shabel et al., 2014).Īddiction has been linked to the imbalance between synaptic and non-synaptic glutamate, termed glutamate homeostasis ( Kalivas, 2009). The LHb has been considered a key structure in the pathophysiology of depression ( Kiening and Sartorius, 2013 Sartorius and Henn, 2007).

The lateral habenula (LHb), a small epithalamic brain region, reciprocally interacts with several brain regions that are important for motivation and reward, including the serotonergic raphe nuclei, the noradrenergic locus coeruleus, and the dopaminergic ventral tegmental area ( Geisler and Trimble, 2008 Hikosaka et al., 2008). Thus, GLT-1 in the LHb could serve as a therapeutic target for psychiatric disorders comorbid with ethanol withdrawal.Īlcohol abuse disorders (AUDs) and psychiatric disorders such as depression and anxiety are common comorbid conditions ( Driessen et al., 2001 Hasin and Grant, 2002 Haver and Dahlgren, 1995 Kessler et al., 1997 Schuckit et al., 1997), yet the mechanisms underlying this comorbidity have not been fully explored. These findings highlight the significant role of LHb astrocytic GLT-1 in the hyperactivity of LHb neurons, and in depressive- and anxiety-like behaviors during ethanol withdrawal. Finally, systemic administration of ceftriaxone alleviated depression- and anxiety-like behaviors, which was fully blocked by intra-LHb administrations of DHK, suggesting that GLT-1’s function in the LHb is critical. Systemic ceftriaxone treatment also normalized the hyperactivity of LHb neurons in slices from withdrawn rats, which was reversed by bath-applied DHK. This reduction was restored by systemic administration of ceftriaxone, a β-lactam antibiotic known to increase GLT-1 expression.

Furthermore, GLT-1 protein expression was reduced in the LHb of withdrawn rats. Here we show that dihydrokainic acid (DHK), a GLT-1 blocker, potentiated glutamatergic transmission to LHb neurons in slices from ethanol naïve rats this potentiation, though, was not observed in slices from rats withdrawn from repeated in vivo ethanol administration, suggesting reduced GLT-1 function. The relationship between GLT-1 maladaptation, LHb activity, and abnormal behaviors related to alcohol withdrawal, however, remains unknown. Findings from animal and human studies have linked aversive states, including those related to drugs of abuse and depression, to aberrant activity in the lateral habenula (LHb). Although the mechanisms underlying this comorbidity are unclear, emerging evidence suggests that maladaptation of the glial glutamate transporter GLT-1 may play a role. Alcoholism and psychiatric disorders like depression and anxiety are often comorbid.

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