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  • To further implicate the role of EAAT in

    2022-06-23

    To further implicate the role of EAAT3 in morphine-induced place preference, the effects of morphine on EAAT3 nm to lb australia was determined. Interestingly, morphine increased EAAT3 protein expression in the plasma membrane of mPFC, nucleus accumbens and VTA but not in the hippocampus of wild-type mice at 24h after the last dose of morphine. Consistent with our previous studies (Lee et al., 2010, Li and Zuo, 2011), EAAT3−/− mice did not express EAAT3 in the mPFC (Fig. 3). Similar to the situation that gender did not affect morphine-induced CPP, EAAT3 abundance in the plasma membrane did not differ between male and female mice in the nucleus accumbens (ranged from 0.9 to 2.7 of control and from 1.3 to 3.7 of control for male and female mice, respectively, n=4, P>0.05) and VTA (ranged from 2.5 to 4.3 of control and from 0.9 to 5.9 of control for male and female mice, respectively, n=4, P>0.05) after morphine application. Although the initial experiment had eight animals for each experimental condition, four males and four females were included for each experimental condition. Thus, we had a sample size of 4 to determine whether there was a gender difference in EAAT3 expression after morphine application. These EAAT3 expression change patterns are consistent with the findings that EAAT3 plays a role in morphine-induced CPP that may not have a gender difference. Next, we studied the reinstatement of CPP, an important biological component of drug addiction. A small dose of morphine given after the extinction of the CPP reinstated the CPP in both wild-type and EAAT3−/− mice (Fig. 4). EAAT3 knockout did not affect this reinstatement [F(1,79)=0.401, P=0.529]. Of note, the data presented in Fig. 4, Fig. 2 were from the same mice. These results suggest that EAAT3 may not play a role in the reinstatement of morphine-induced CPP. Our study with using EAAT3 knockout mice determined the effects of EAAT3 inhibition/deletion on morphine-induced CPP. To further study the role of EAATs in this conditioned behavior, we used riluzole that can activate EAAT. An activator specifically for EAAT3 might have been more desirable than a general activator to implicate the role of EAAT3. However, such an activator has not been developed yet. We reproduced the results of morphine-induced CPP in this third experiment. Interestingly, whereas riluzole did not induce place preference; it abolished morphine-induced CPP (Fig. 5). These results suggest that inhibition of EAAT activation is important for the initiation of morphine-induced CPP. This finding is consistent with the results that morphine induced CPP in EAAT3−/− mice.
    Discussion Our results clearly showed that morphine induced CPP in both male and female mice. Gender does not appear to affect this preference and the morphine-induced increase of EAAT3 expression in the cell plasma membrane. Consistent with our study, both male and female patients can develop addiction to morphine. There is no consistent effect of gender on this addiction (Lee and Ho, 2013). Glutamatergic neurotransmission has been implicated in the morphine addiction (Del Pozo et al., 1996, Popik and Wrobel, 2002). Although EAATs that can regulate glutamatergic neurotransmission have been shown to participate in the development of addiction to drugs, such as cocaine (Fujio et al., 2005, Fischer et al., 2013), it is not clear whether EAATs play a role in morphine addiction. Our recent studies have shown that EAAT3, the major neuronal EAAT, may be an important component in the biochemical processes for learning and memory (Lee et al., 2012, Cao et al., 2014, Wang et al., 2014). Thus, EAAT3 may regulate morphine addiction. We showed here that induction of morphine-induced CPP was not affected by EAAT3 knockout. Its reinstatement was not affected by EAAT3 knockout either. However, the extinction of morphine-induced CPP was quicker in the EAAT3 knockout mice than in wild-type mice. Also, the amount of EAAT3 in the cell plasma membrane, the function site of EAATs, was increased in multiple addiction-related brain regions at 24h after the last dose of morphine. These results suggest that EAAT3 plays an important role in the extinction of morphine-induced CPP. The increase of EAAT3 may contribute to delaying this behavior.