In the present study, the effect of S-3,4-DCPG as a selective mGlu8 receptor allosteric agonist within the NAc on development of morphine-induced CPP was investigated in rats. To our best knowledge, this is the first study which has examined the role of mGlu8 receptor within the NAc on morphine-induced CPP. Main findings of the present study can be expressed as :a) bilateral intra-accumbal microinjection of S-3,4-DCPG dose-dependently reduced the acquisition of morphine-induced CPP, b) after conditioning, intra-accumbal activation of mGlu8 receptor by S-3,4-DCPG at highest dose of 3 μg / 0.5 μL, it did not affect the expression of morphine-induced CPP in the rats, c) administering the highest dose of S-3,4-DCPG into the NAc alone could not induce CPP, and d) this drug did not affect locomotor activity. Brain regions that control locomotion, such as striatum, are enriched in group III mGlu receptors (38), indicating the possible role for these receptors in locomotor activity. Our data showed that S-3,4-DCPG did not affect locomotor activity. This indicates that mGlu8 receptors does not play a chief role in locomotor activity. On the contrary, it has been shown that other group III mGlu receptors (such as mGlu4 and mGlu7 receptors) are involved in the locomotion (28, 39, 40), that could be explained receptors type specificity in the role of mGlu receptors on locomotor activity, site specificity and by the animal species used and/or by the dose of agonists.
Since two decades, glutamatergic system has been involved in drug addiction. Among the components of the glutamatergic system, the presynaptic mGlu receptors have recently received much attention because of their role in glutamate release and regulation of glutamatergic responses. Up to present day only a few studies on the role of mGlu8 receptor in morphine dependence have been reported. Numerous findings confirm that the Group III mGlu receptors family plays an important role in drug addiction, regulating transmitter release and behavioral plasticity in the limbic system (41, 42).
Previous studies have shown that mGlu receptors are involved in the acquisition and expression of morphine-induced CPP (5, 6). The NAc plays a crucial role in developing physical dependence on morphine (43). Morphine eliminates the inhibitory effects of dopamine on glutamatergic inputs to the NAc neurons and enhances glutamatergic transmission to the NAc neurons, especially from the BLA to the NAc (44). Other observations have reported that repeated exposure to opioids enhances the function of mGlu receptors and presynaptic stimulation of these receptors results in reduced glutamate release (45, 46). It has also been shown that attenuation of glutamatergic neurotransmission through presynaptic mGlu receptor agonists is effective in suppressing drug craving and substance use (27).
There is some evidences indicating the role of the NAc shell in the acquisition of CPP (Olive et al., 2002; Scofield et al., 2016). However, there are also studies showing the involvement of the NAc Core too (Alaghband et al., 2018; Miyamoto et al., 2015; Scofield et al., 2016; Zhou et al., 2020). In addition, some studies have shown the role of whole NAc in this issue including our previous studies (Alizamini et al., 2017; Baharlouei et al., 2018; Vatankhah et al., 2018). On the other hand, there is no difference in case of mGlu8 receptor density between NAc shell and core (Messenger et al., 2002). Finally, based on the stereotaxic coordination, sizes of the NAc core and shell, the volume of injected drug and the time after injection to the end of the CPP session the diameter of spatio-temporal diffusion may include both parts of the NAc (Freund et al., 2010). Therefore, we can’t consider one part effective and completely exclude the effects of drug on another part.
Findings from other studies confirm the findings of the current study regarding the inhibitory role of mGlu receptor activation in the NAc on drug induced CPP acquisition. Bahi showed that systemic injection of mGlu8 receptor agonist decreases voluntary ethanol intake and ethanol-induced CPP in C57BL/6J mice (47). Several studies have suggested that mGlu8 receptors are involved in associative learning (Boccella et al., 2019; Gerlai et al., 2002). Associative learning and synaptic long-term potentiation (LTP) depend on the same cellular mechanisms (Maren, 2005), which is consistent with our results regarding the inhibitory role of mGlu8 receptors in morphine induced CPP. It is possible that DCPG impair the formation of an association between the environmental cues in the morphine-paired compartment and the rewarding properties of the drug (Fendt and Schmid, 2002) without influencing the rewarding effects of morphine.
On the other hand, we found that mGlu8 receptor activation in the NAc has no effect on morphine reward after acquisition. Consistent with the results of the present study, findings from other studies showed that after conditioning, mGlu8 receptor activation had no effect on the expression of spatial conditioning relative to ethanol (47).
The systemic injection of cocaine decreases mGlu8 receptor protein levels in rat striatum. The decrease in mGlu8 receptor protein expression in the striatum may indicate a decrease in mGlu8 autoreceptors in corticostriatal terminals on the other hand as we know, presynaptic mGlu8 receptor inhibits glutamate release from corticostriatal terminals (48). This transient deletion of inhibitory tone by mGlu8 receptor may be necessary to stimulate increased local release of glutamate and stimulate locomotor activity. Lack of presynaptic mGlu8 receptor can disrupt glutamatergic translocation in corticostriatal synapses, that is consistent with other mechanisms involved in behavioral responses to acute stimulation by cocaine (48).
In conclusion, the results of the current study revealed that intra-accumbal injection of mGlu8 receptor agonist (S-3,4-DCPG) in a dose-dependent manner reduced the acquisition while it had no effect on the expression of morphine-induced CPP. Taken together, the available evidences indicate an important modulatory rather than necessary role for mGluR8 in NAc based morphine reward. It can be proposed that the plasticity related to mGlu8 receptor downstream proteins during CPP of morphine could account for the behavioral response found by S-3,4-DCPG. Future studies are needed to characterize the specific mechanisms of action of mGlu8 receptor in acquisition and expression of morphine-induced place preference in rats.