Single-dose methamphetamine administration impairs ORM retrieval in mice via excessive DA-mediated inhibition of PrL(Glu) activity.

Methamphetamine (METH), an abused psychostimulant, impairs cognition through prolonged or even single-dose exposure, but animal experiments have shown contradictory effects on memory deficits. In this study we investigated the effects and underlying mechanisms of single-dose METH administration on the retrieval of object recognition memory (ORM) in mice. We showed that single-dose METH administration (2 mg/kg, i.p.) significantly impaired ORM retrieval in mice. Fiber photometry recording in METH-treated mice revealed that the activity of prelimbic cortex glutamatergic neurons (PrL(Glu)) was significantly reduced during ORM retrieval. Chemogenetic activation of PrL(Glu) or glutamatergic projections from ventral CA1 to PrL (vCA1(Glu)-PrL) rescued ORM retrieval impairment. Fiber photometry recording revealed that dopamine (DA) levels in PrL of METH-treated mice were significantly increased, and micro-infusion of the D2 receptor (D2R) antagonist sulpiride (0.25 μg/side) into PrL rescued ORM retrieval impairment. Whole-cell recordings in brain slices containing the PrL revealed that PrL(Glu) intrinsic excitability and basal glutamatergic synaptic transmission were significantly reduced in METH-treated mice, and the decrease in intrinsic excitability was reversed by micro-infusion of Sulpiride into PrL in METH-treated mice. Thus, the impaired ORM retrieval caused by single-dose METH administration may be attributed to reduced PrL(Glu) activity, possibly due to excessive DA activity on D2R. Selective activation of PrL(Glu) or vCA1(Glu)-PrL may serve as a potential therapeutic strategy for METH-induced cognitive dysfunction.