Oxytocin Acts in Nucleus Accumbens to Attenuate Methamphetamine Seeking and Demand

Abstract

Background Evidence indicates that oxytocin, an endogenous peptide well known for its role in social behaviors, childbirth and lactation, is a promising addiction pharmacotherapy. We employed a within-session behavioral-economic (BE) procedure in rats to examine oxytocin as a pharmacotherapy for methamphetamine (meth) addiction. The BE paradigm was modeled after BE procedures used to assess motivation for drugs in human addicts. Importantly, the same BE variables assessed across species have been shown to predict later relapse behavior. Thus, the translational potential of preclinical BE studies is particularly strong. Methods We tested the effects of systemic and microinfused oxytocin on demand for self-administered i.v. meth and reinstatement of extinguished meth-seeking in male and female rats using a behavioral economics paradigm. Correlations between meth demand and meth seeking were assessed. Results Females showed greater demand (i.e., motivation) for meth compared to males. In both males and females, meth demand predicted reinstatement of meth-seeking, and systemic oxytocin decreased demand for meth and attenuated reinstatement to meth seeking. Oxytocin was most effective at decreasing meth demand and seeking in rats with the strongest motivation for drug. Finally, we found that these effects of systemic oxytocin were mediated by actions in the nucleus accumbens (NAc). Discussion Oxytocin decreases meth demand and seeking in both sexes, and these effects depend on oxytocin signaling in the NAc. Overall, these data indicate that development of oxytocin-based therapies may be a promising treatment approach for meth addiction in humans.

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

“…For systemic injections oxytocin was administered at 1 mg/kg (Cox et al, 2013, Zhou et al, 2015; Leong et al, 2016) and LY341495 was injected at 1 mg/kg (Scofield et al, 2015; Li et al, 2010). For intracranial administration, oxytocin was infused at a concentration of 0.6nmol/0.25µl/side (Baracz et al, 2012; Cox et al., 2017). LY341495 was infused at a concentration of 1.3nmol/0.25µl/side based on a range of two efficient doses (Kim et al , 2015; Richard and Berridge, 2011).…”

“…Oxytocin infusion into the NAcore decreased heroin self-administration in heroin tolerant rats (Ibragimov et al, 1987) and reduced cocaine-induced sniffing behavior (Sarnyai et al, 1991). More recently, our laboratory (Cox et al, 2017) and others (Baracz et al, 2012, 2014, 2015) have shown that oxytocin acts in the NAcore to decrease meth taking and seeking. Specifically, oxytocin infused directly into the NAcore decreased cued meth seeking, and co-treatment with an oxytocin receptor antagonist blocked this effect (Cox et al, 2017).…”

“…More recently, our laboratory (Cox et al, 2017) and others (Baracz et al, 2012, 2014, 2015) have shown that oxytocin acts in the NAcore to decrease meth taking and seeking. Specifically, oxytocin infused directly into the NAcore decreased cued meth seeking, and co-treatment with an oxytocin receptor antagonist blocked this effect (Cox et al, 2017). …”

“…In preclinical studies using rats trained to self-administer meth, oxytocin decreased motivation for meth, decreased drug intake, and reduced drug primed reinstatement (Carson et al, 2010a; Cox et al., 2017). Consistently, our laboratory has reported that intraperitoneal (ip) oxytocin decreased lever responding for meth-associated cues using a model of self-administration, extinction, and reinstatement (Cox et al, 2017; Cox et al, 2013). The mechanisms by which oxytocin reduces responding to drug conditioned cues have not been identified within brain areas involved in the addiction circuitry.…”

The Anorexigenic Neural Pathways of Oxytocin and Their Clinical Implication

“…On the other hand, oxytocin receptors are expressed in NAc, the site where dopamine neurons project from the VTA. Furthermore, oxytocin administration to NAc reduces food, palatable sucrose and saccharin intake [110], as well as attenuates methamphetamine seeking and demand [111]. In social rewards, coordinated activity of oxytocin and serotonin in NAc is required [112].…”