Abstract Background Methamphetamine (METH) is a psychostimulant with strong addiction potential, yet there is no effective pharmacotherapy until now. Oxytocin (OXT), a neuropeptide has been given rise to combat various addictive drugs, including METH. However, questions remain about how METH affects the endogenous OXT system and how OXT modulates METH addiction. Aims & Objectives The present study aimed to investigate the effects of OXT on METH-induced conditioned place preference (METH-CPP) and its underlying mechanisms. Method We devloped a METH-induced conditioned place preference model. The alterations of central OXTergic system under METH treatment were evaluated by qPCR、ELISA and cFos staining. Using a comination of pharmacology, chemogenetics and optogenetics, the role of PVN OXTergic neurons and its projections to the NAc core were clarified. Results First, we found that intranasal OXT other than AVP administration was sufficient to blunt METH-CPP, which could be reversed by intra-NAc core OXTRs antagonist instead of V1aRs antagonist. Additionally, intra-NAc core microinjection of OXTRs agonist produced a similar anti-addictive effect as well. Then, we investigated the role of endogenous OXT/OXTRs system in METH-CPP. Under chronic METH exposure, OXTergic neurons within the paraventricular nucleus (PVN) were inhibited, and a significant reduction in OXT protein level was observed in the PVN. In line with this, chemogenetic activation of PVNOXT neurons was able to block METH-CPP. Furthermore, we studied the role of NAc-projecting PVN OXTergic neurons (PVNOXT-NAc circuit) in METH-CPP. Results from immunofluorescence staining indicated that PVNOXT - NAc core circuit other than PVNOXT - NAc shell circuit was inhibited during METH-CPP. Chemogenetic or optic activation of PVNOXT - NAc core circuit significantly inhibited METH-CPP, which could be reversed by the blockade of OXTRs within the NAc core. Discussion & Conclusions The current results demonstrated that hypofunction of the endogenous OXT system may be an important mechanism to modulate METH addiction, especially the projections from the PVNOXT neurons to the NAc core, which shed light on OXT as a potential agent against drug abuse.
Cheng et al. (Fri,) studied this question.