Oxytocin attenuates the retrieval of methamphetamine-associated reward memories by enhancing adult hippocampal neurogenesis in mice

The present study was designated to investigate the effect of oxytocin (OXT) on the retrieval of methamphetamine (METH)-associated reward memories induced by drugs in mice and its underlying mechanisms related to adult hippocampal neurogenesis (AHN) and memory engrams. The data showed that repeated hippocampal microinjections of OXT (1.25 and 2.5 μg) for 8 consecutive days significantly prevented the retrieval of METH-associated reward memories induced by drugs in a time-, dose- and receptor-dependent manner in mice. At the meanwhile, OXT was found to markedly elevate AHN levels, enhancing the proliferation, survival and maturation of newborn neurons by using NestinCreER^T2::Rosa26-tdTomato mice and BrdU labeling. Notably, reduction or depletion of AHN by temozolomide (TMZ) or NestinCreER^T2 mice combined with adeno-associated viruses (AAVs) (AAV-CAG-DIO-rtTA-EGFP and AAV-TRE-DTA) could attenuate the inhibition of OXT on the retrieval of METH-associated reward memories in mice. By using activity-dependent labeling strategy in mice, it was observed that the retrieval of METH-associated reward memories was mediated by activation of METH-associated memory engrams in the dentate gyrus (DG) region of the hippocampus. Repeated hippocampal microinjections of OXT effectively prevented the activation of these memory engrams, which could be abolished after reducing AHN by TMZ. In summary, this study revealed that OXT effectively prevented the retrieval of METH-associated reward memories induced by drugs in mice, which may be related to its enhancement on AHN as well as inhibition on METH-associated memory engrams in DG.