Targeting glutamate homeostasis for potential treatment of nicotine dependence

Abstract

Several studies demonstrated that impairment in glutamatergic neurotransmission is linked to drug dependence and drug-seeking behavior. Increased extracellular glutamate concentration in mesocorticolimbic regions has been observed in animals developing nicotine dependence. Changes in glutamate release might be associated with stimulatory effect of nicotinic acetylcholine receptors (nAChRs) via nicotine exposure. We and others have shown increased extracellular glutamate concentration, which was associated with downregulation of the major glutamate transporter, glutamate transporter 1 (GLT-1), in brain reward regions of animals exposed to drug abuse, including nicotine and ethanol. Importantly, studies from our laboratory and others showed that upregulation of GLT-1 expression in the mesocorticolimbic brain regions may have potential therapeutic effects in drug dependence. In this review article, we discussed the effect of antagonizing presynaptic nAChRs in glutamate release, the upregulatory effect in GLT-1 expression and the role of glutamate receptors antagonists in the treatment of nicotine dependence.

Effects of chronic inhalation of electronic cigarettes containing nicotine on glial glutamate transporters and α-7 nicotinic acetylcholine receptor in female CD-1 mice

“…Stimulating α-7 nAChR by nicotine has been suggested to be one of the main mechanisms for nicotine-induced high extracellular glutamate concentrations in the mesocorticolimbic areas (Konradsson-Geuken et al, 2009, Cheng and Yakel, 2014). Chronic exposure to nicotine was found to be associated with upregulation of post-synaptic glutamate receptors (Wang et al, 2007, Kenny et al, 2009, Alasmari et al, 2016a) and that the effect has been suggested to be associated with altered glutamate neurotransmission in the mesocorticolimbic brain regions (Wang et al, 2007). Importantly, α-7 nAChR is expressed in glutamatergic projections from PFC to central brain reward regions such as NAc and ventral tegmental area (VTA) [For review see (Feduccia et al, 2012)].…”

“…Western blotting was used to quantify changes in the expression of α-7 nAChR, GLT-1, xCT, GLAST and GAPDH in FC, STR and HIP tissues between e-cigarette and air control groups, as described previously (Alasmari et al, 2015, Alasmari et al, 2016a, Hakami et al, 2016). Brain tissues (FC, STR and HIP) were homogenized in lysis buffer-containing protease inhibitors.…”

Peri-adolescent drinking of ethanol and/or nicotine modulates astroglial glutamate transporters and metabotropic glutamate receptor-1 in female alcohol-preferring rats

“…A prior study from our group reported that upregulating GLT-1 in the NAc and the PFC by ceftriaxone treatment led to an attenuation of EtOH and/or NIC drinking behavior in female P rats (Sari et al, 2016). This indicates that astroglial glutamate transporters, mainly GLT-1, plays a critical role in regulating EtOH or NIC seeking [For review see (Alasmari et al, 2016a, Goodwani et al, 2017]. In the present work, for the first time, we found that peri-adolescent binge-like scheduled access to SUC-NIC downregulated GLT-1 in the NAc compared to water and SUC control groups, while peri-adolescent EtOH-NIC binge-like drinking reduced GLT-1 expression in the NAc compared to the water control and EtOH groups.…”

Metabotropic and ionotropic glutamate receptors as potential targets for the treatment of alcohol use disorder

“…(Alasmari et al, 2015b; Pistillo et al, 2015)]. It is important to note that the NAc shell receives dopaminergic projections from the VTA and is responsible for motivation and reward; however, the NAc core is innervated mainly by glutamatergic projections from the HPC and AMG and is responsible for sensory motor integration, goal-directed behavior, and emotional cues (Guo et al, 2009; Suto et al, 2010).…”