Antagonism of mGlu2/3 receptors in the nucleus accumbens prevents oxytocin from reducing cued methamphetamine seeking in male and female rats

Abstract

Methamphetamine (meth) addiction is a prevalent health concern worldwide, yet remains without approved pharmacological treatments. Preclinical evidence suggests that oxytocin may decrease relapse, but the neuronal underpinnings driving this effect remain unknown. Here we investigate whether oxytocin’s effect is dependent on presynaptic glutamatergic regulation in the nucleus accumbens core (NAcore) by blocking metabotropic glutamate receptors 2/3 (mGluR2/3). Male and female Sprague-Dawley rats self-administered meth or sucrose on an escalating fixed ratio, followed by extinction and cue-induced reinstatement sessions. Reinstatement tests consisted of systemic (Experiment 1) or site-specific application of the drugs into the NAcore (Experiments 2 and 3). Before reinstatement sessions, rats received LY341495, an mGluR2/3 antagonist, or its vehicle followed by a second infusion/injection of oxytocin or saline. As expected, both males and females reinstated lever pressing to meth associated cues, and LY341495 alone did not impact this behavior. Oxytocin injected systemically or infused into the NAcore decreased cued meth seeking. Importantly, combined LY341495 and oxytocin administration restored meth cued reinstatement. Interestingly, neither oxytocin nor LY341495 impacted sucrose-cued reinstatement, suggesting distinct mechanisms between meth and sucrose. These findings were consistent between males and females. Overall, we report that oxytocin reduced responding to meth-associated cues and blocking presynaptic mGluR2/3 reversed this effect. Further, oxytocin’s effects were specific to meth cues as NAcore oxytocin was without an effect on sucrose cued reinstatement. Results are discussed in terms of oxytocin receptor localization in the NAcore and modulation of presynaptic regulation of glutamate in response to drug associated cues.

Oxytocin and Rodent Models of Addiction

“…Another similarity with meth, a concurrent intra-NAcc infusion of an mGluR2/3 antagonist blocked the oxytocin reduction of cued reinstatement suggesting presynaptic mechanisms in the NAcc (Bernheim et al, 2017; Weber et al, 2018). Similar findings were uncovered with peripheral administration of both compounds.…”

“…In regard to cued reinstatement of meth seeking, oxytocin decreases responding in males and females (Bernheim, Leong, Berini, & Reichel, 2017; Cox et al, 2017; Cox, Young, et al, 2013). This decrease may involve additional behavioral parameters because in one study (Cox, Young, et al, 2013), rats were reinstated on an FR5 schedule of reinstatement and responding was greater female rats.…”

“…This decrease may involve additional behavioral parameters because in one study (Cox, Young, et al, 2013), rats were reinstated on an FR5 schedule of reinstatement and responding was greater female rats. When rats were reinstated on an FR1, both sexes robustly reinstated on the active lever and oxytocin decreased this reinstatement (Bernheim et al, 2017; Cox et al, 2017). Recently, we have proposed that the ability of oxytocin to reduce cued reinstatement is through interactions with the glutamatergic system in the NAcc (discussed in Section 4.1).…”

“…A recent model from our laboratory postulates that oxytocin receptors located on astrocytes (Dolen et al, 2013) within the NAc modulate drug-seeking behavior (Bernheim et al, 2017; Weber et al, 2018). More specifically, oxytocin activation of Gq-coupled oxytocin receptors on astrocytes results in astrocytic glutamate release.…”

“…Scofield et al (2015) demonstrated that chemogenetic activation of astrocytes in NAc core decreased cue reinstatement of cocaine (Scofield et al, 2015) seeking through a mGlu2/3 receptor dependent mechanism. Support for this notion, comes from work showing concurrent mGlu2/3 receptor antagonism reversed the attenuating effect of oxytocin on cocaine and meth-seeking behavior (Bernheim et al, 2017; Weber et al, 2018). …”