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Background: Clinical and experimental studies have shown that single morphine could induce tolerance and addiction.The underlying neurobiological mechanism,however,is unknown.The mesocorticolimbic dopamine(DA)system,projecting from ventral tegmental area(VTA)to the medial prefrontal cortex(mPFC)and nucleus accumbens(NAc),plays an essential role in mediating the effect of abuse drug.Although the importance of the mPFC-VTA circuit in regulating the activity of VTA DA neurons has been suggested,how mPFC-modulating DA neuron activities in response to acute morphine treatment that may contribute to neurobiology of single morphine exposure remains elusive.Methods: In vivo single-unit recording of VTA DA neurons and microdialysis analysis of DA transmission in the nucleus accumbens(NAc)were used.Results: Local application of μ opioid receptor antagonist into the mPFC significantly attenuated the systemic morphine-induced excitation on VTA DA neurons.However,local infusion of morphine into the mPFC was unable to excite the DA neurons,indicating that the μ-receptor activation in the mPFC is necessary but not sufficient to activate VTA DA neurons.After local application of tetrodotoxin(TTX)to suppression the mPFC,systemic morphine failed to excite DA neurons,indicating the gating role of mPFC on acute morphine –excited DA neuron.Moreover,microdialysis study demonstrated that the mPFC specifically regulated the morphine-stimulated phasic but not tonic DA release in the NAc.Intriguingly,a singe morphine exposure resulted in the failure of mPFC-gating function in response to subsequent morphine challenge which lasted at least one week.Furthermore,we found that a single morphine pretreatment did not alter the tonic firing activity of mPFC pyramidal neurons,but dramatically altered the sensitivity of these neurons to subsequent morphine challenge.Conclusions: The mPFC gates the effects of systemic morphine on the firing of VTA DA neurons and the phasic DA release in the NAc.Single morphine exposure disrupted the gating function and produced long-lasting remodeling in the PFC-VTA circuits that may contribute to the neuroplasticity of morphine addiction.