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    • In conclusion we have designed

    2021-10-16

    In conclusion, we have designed and characterized a novel series of EAAT-blockers, exemplified by (-[4-(2-bromo-4,5-difluorophenoxy)phenyl]--asparagine)—a potent, selective, competitive non-substrate inhibitor of EAAT-2. As one of the most potent and selective EAAT-2 inhibitors identified to date, compound represents a unique addition to the arsenal of pharmacological tools which can be used to elucidate further the role of specific EAAT subtypes and to improve our understanding of hyperglutamatergic and neurodegenerative disorders.
    Introduction Opioids are a major class of analgesics used clinically. However, it was estimated that about 5.1million Americans in 2010 abused opioids (topics in Brief, NIDA, 2011). Activation of various rewarding pathways, such as dopamine system in ventral tegmental area (VTA), contributes to the opioid addiction (Johnson and North, 1992). However, glutamatergic system may also be involved in opioid addiction (Del Pozo et al., 1996, Popik and Wrobel, 2002). Glutamate, the major excitatory neurotransmitter, can be taken up by glutamate transporters (also called excitatory amino estrone sale transporters, EAAT) into cells after it is released from presynaptic termini. In fact, glutamate uptake via EAAT is a major mechanism to regulate extracellular glutamate levels due to the lack of extracellular enzyme to metabolize glutamate (Danbolt, 2001). Consistent with this function, it has been shown that EAAT can regulate glutamate neurotransmission (Danbolt, 2001, Sepkuty et al., 2002). Five types of EAAT have been known: EAAT1–5. EAAT1 and EAAT2 are mainly expressed in glia. EAAT3 and EAAT4 are mostly in neurons. EAAT5 exists in the retina. EAAT1–3 are expressed in many regions of the central nervous system; whereas EAAT4 is mainly in the cerebellum. Based on the amount of protein, EAAT2 and EAAT3 are considered the major glial and neuronal EAAT, respectively (Danbolt, 2001). Consistent with their functions of regulating glutamate neurotransmission, glial EAATs, especially EAAT2, have been indicated to play a role in drug addiction, such as cocaine addiction (Fujio et al., 2005, Fischer et al., 2013). Morphine, a commonly used analgesic and addicted opioid, is known to regulate the expression of EAAT. For example, morphine can reduce EAAT1 and EAAT3 expression in the dorsal horn of spinal cord (Mao et al., 2002). Morphine withdrawal increases EAAT2 expression in the hippocampus (Xu et al., 2003). However, it is not known yet whether EAATs play a role in morphine addiction behavior. Studies from our and other groups have shown that EAAT3, the major neuronal EAAT, participates in the learning and memory processes (Aoyama et al., 2006, Lee et al., 2012, Cao et al., 2014, Wang et al., 2014). Drug addiction is a pathological form of learning and memory related to rewards and cures that predict rewards (Hyman, 2005, Rosen et al., 2015). Thus, we hypothesize that EAAT3 plays a role in morphine addiction that can be considered as pathological learning and memory toward morphine use. To test this hypothesis, we exposed wild-type and EAAT3 knockout (EAAT3−/−) mice to morphine and measured their conditioned place preference (CPP). The conditioning, extinction and reinstatement behaviors of these mice were studied. In addition, we performed these tests in male and female mice to test whether there is a gender difference in these behaviors because inconsistent findings regarding gender difference of opioid addiction have been reported (Lee and Ho, 2013).
    Experimental procedures
    Results Male and female mice developed significant place preference after morphine injection. In supporting this point, they stayed more in the box where they received morphine than in the box where they received saline after the conditioning phase; whereas saline injection did not induce this place preference. Gender was not a significant factor to affect this conditioned activity for both wild-type and EAAT3−/− mice [main effect of gender: F(1,16)=1.836, P=0.194 for wild-type mice; F(1, 23)=0.313, P=0.581 for EAAT3−/− mice]. EAAT3 knockout did not affect the induction of this conditioned behavior [F(1,41)=1.797, P=0.187]. However, wild-type mice took 8–9days for the CPP to extinct; whereas the extinction occurred 6days after morphine application was stopped in the EAAT3−/− mice (Fig. 2), suggesting that EAAT3 is important for the maintenance of CPP.