Regulatory system of mGluR group II in the nucleus accumbens for methamphetamine‐induced dopamine increase by the medial prefrontal cortex

AIM: We previously reported that methamphetamine (METH)‐induced conditioned place preference was attenuated by Shati/Nat8l overexpression in the medial prefrontal cortex (mPFC). Shati/Nat8l overexpression in the mPFC expressed lower levels of both glutamate and dopamine (DA) in the nucleus accumbens (NAc) and attenuated METH‐induced DA elevation. We suggested a mechanism in which a decline of glutamate levels in the NAc decreases extracellular DA levels. However, the hypothesis has not confirmed. METHODS: We conducted a recovery experiments by pre‐microinjection of an mGluR group II antagonist, LY341495, into the NAc shell of mPFC‐Shati/Nat8l‐overexpressed mice followed by METH injection and DA levels measurement by in vivo microdialysis. RESULTS: Pretreatment with LY341495 was able to restore METH‐induced DA increase. Furthermore, mice injected with an adeno‐associated virus vector containing GFP (AAV‐GFP vector) in the mPFC expressed a colocalization of GFP with DARPP‐32 a medium spiny neuron (MSN) marker. Next, co‐immunostaining of DARPP‐32 and neuronal nitric oxide synthase (nNOS: expressed in a subtype of gamma‐Aminobutyric acid (GABA interneurons) in ventral tegmental area (VTA) showed a colocalization of nNOS and DARPP‐32. CONCLUSION: These results provided a proof that Shati/Nat8l attenuation of METH‐induced DA increase is mediated by mGluR group II in the NAc. Moreover, immunohistochemical study showed a direct connection of mPFC projection neurons with NAc MSN and a connection of MSN projection neurons with a subtype of GABA interneurons in VTA.