Abstract
Ketamine is a popular recreational substance of abuse that induces persistent behavioral deficits. Although disrupted oxytocinergic systems have been considered to modulate vulnerability to developing drugs of abuse, the involvement of central oxytocin in behavioral abnormalities caused by chronic ketamine has remained largely unknown. Herein, we aimed to investigate the potential role of oxytocin in the medial prefrontal cortex (mPFC) in social avoidance and cognitive impairment resulting from repeated ketamine administration in mice. We found that ketamine injection (5 mg/kg, i.p.) for 10 days followed by a 6-day withdrawal period induced behavioral disturbances in social interaction and cognitive performance, as well as reduced oxytocin levels both at the periphery and in the mPFC. Repeated ketamine exposure also inhibited mPFC neuronal activity as measured by a decrease in c-fos-positive cells. Furthermore, direct microinjection of oxytocin into the mPFC reversed the social avoidance and cognitive impairment following chronic ketamine exposure. In addition, oxytocin administration normalized ketamine-induced inflammatory cytokines including TNF-α, IL-6, and IL-1β levels. Moreover, the activation of immune markers such as neutrophils and monocytes, by ketamine was restored in oxytocin-treated mice. Finally, the reversal effects of oxytocin on behavioral performance were blocked by pre-infusion of the oxytocin receptor antagonist atosiban into the mPFC. These results demonstrate that enhancing oxytocin signaling in the mPFC is a potential pathway to reverse social avoidance and cognitive impairment caused by ketamine, partly through inhibition of inflammatory stimulation.
Highlights
Ketamine abuse has become a global issue, it was originally developed as a dissociative anesthetic for medical purposes
The counts of immune cell neutrophils and monocytes, as well as the neutrophil–lymphocyte ratio (NLR), reliable inflammatory biomarkers for systemic inflammatory response (Gibson et al, 2007; Azab et al, 2011), were found increased in ketamine and psychiatric disorders with a core symptom of impaired social behaviors (Aydin Sunbul et al, 2017; Kayhan et al, 2017; Kido et al, 2019). These findings suggest that novel pharmacotherapies targeting neuroinflammatory processes may result in improvements in behavioral dysfunctions induced by addictive drugs. Based on these previous studies, we aimed to investigate the potential role of oxytocin in the medial prefrontal cortex in the social avoidance and cognitive impairment resulting from repeated ketamine administration in mice and the possible involvement of inflammatory stimulation
We further found that exposure to ketamine after withdrawal induced a robust decrease in oxytocin levels in both the plasma (p < 0.0001, Figure 2A) and the medial prefrontal cortex (mPFC) (p < 0.0001, Figure 2B)
Summary
Ketamine abuse has become a global issue, it was originally developed as a dissociative anesthetic for medical purposes. It is important to be able to evaluate the neurobiological processes that are relevant to ketamine exposure-encoded behavioral phenotypes, including social avoidance and cognitive deficits, which are associated with an increased risk of drug relapse. As seen in decreased contacts and time with partners in the social interaction, and impaired cognitive function are characteristic behavioral changes induced by ketamine (Lipska and Weinberger, 2000; Gama et al, 2012). Addictive drug abuse and withdrawal caused impairments in the social interaction behavior through the enhancement of ketamine’s rewarding effects and deficits in social recognition (Liao et al, 2018), suggesting that behavioral changes might partially explain the increased risk of relapse in drug abusers. Disturbed oxytocin may participate in the pathophysiology of ketamineinduced neurobehavioral phenotypes
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