Abstract：
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 (PrLGlu) was significantly reduced during ORM retrieval. Chemogenetic activation of PrLGlu or glutamatergic projections from ventral CA1 to PrL (vCA1Glu-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 PrLGlu 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 PrLGlu activity, possibly due to excessive DA activity on D2R. Selective activation of PrLGlu or vCA1Glu-PrL may serve as a potential therapeutic strategy for METH-induced cognitive dysfunction.
摘要：
甲基苯丙胺（METH），被滥用的精神兴奋剂,通过长时间甚至单剂量暴露损害认知，但是动物实验显示了对记忆缺陷的矛盾影响。在这项研究中，我们研究了单剂量METH给药对小鼠物体识别记忆（ORM）检索的影响和潜在机制。我们显示单剂量METH给药（2mg/kg，i.p.）小鼠的ORM检索显着受损。在METH处理的小鼠中进行的纤维光度记录显示，在ORM检索过程中，前边缘皮质谷氨酸能神经元（PrLGlu）的活性显着降低。PrLGlu的化学遗传激活或从腹侧CA1到PrL的谷氨酸能投射（vCA1Glu-PrL）挽救了ORM恢复障碍。纤维光度记录显示，METH处理的小鼠PrL中的多巴胺（DA）水平显着增加，并将D2受体（D2R）拮抗剂舒必利（0.25μg/侧）微输注到PrL中，可挽救ORM恢复障碍。包含PrL的脑切片中的全细胞记录显示，在METH处理的小鼠中，PrLGlu的内在兴奋性和基础谷氨酸能突触传递显着降低，通过向METH治疗的小鼠的PrL中微量输注舒必利，可以逆转内在兴奋性的降低。因此，单剂量METH给药引起的ORM恢复受损可能归因于PrLGlu活性降低，可能是由于D2R上的DA活性过度。PrLGlu或vCA1Glu-PrL的选择性激活可能是METH诱导的认知功能障碍的潜在治疗策略。
