Ouyang Jiangyong, Carcea Ioana, Schiavo Jennifer K, Jones Kymry T, Rabinowitsch Ariana, Kolaric Rhonda, Cabeza de Vaca Soledad, Froemke Robert C, Carr Kenneth D
Department of Psychiatry, New York University School of Medicine, New York, NY, USA.
Skirball Institute of Biomolecular Medicine, New York University School of Medicine, New York, NY, USA.
Eur J Neurosci. 2017 Mar;45(6):826-836. doi: 10.1111/ejn.13528. Epub 2017 Feb 15.
Chronic food restriction potentiates behavioral and cellular responses to drugs of abuse and D-1 dopamine receptor agonists administered systemically or locally in the nucleus accumbens (NAc). However, the alterations in NAc synaptic transmission underlying these effects are incompletely understood. AMPA receptor trafficking is a major mechanism for regulating synaptic strength, and previous studies have shown that both sucrose and d-amphetamine rapidly alter the abundance of AMPA receptor subunits in the NAc postsynaptic density (PSD) in a manner that differs between food-restricted and ad libitum fed rats. In this study we examined whether food restriction, in the absence of reward stimulus challenge, alters AMPAR subunit abundance in the NAc PSD. Food restriction was found to increase surface expression and, specifically, PSD abundance, of GluA1 but not GluA2, suggesting synaptic incorporation of GluA2-lacking Ca2+-permeable AMPARs (CP-AMPARs). Naspm, an antagonist of CP-AMPARs, decreased the amplitude of evoked EPSCs in NAc shell, and blocked the enhanced locomotor response to local microinjection of the D-1 receptor agonist, SKF-82958, in food-restricted, but not ad libitum fed, subjects. Although microinjection of the D-2 receptor agonist, quinpirole, also induced greater locomotor activation in food-restricted than ad libitum fed rats, this effect was not decreased by Naspm. Taken together, the present findings are consistent with the synaptic incorporation of CP-AMPARs in D-1 receptor-expressing medium spiny neurons in NAc as a mechanistic underpinning of the enhanced responsiveness of food-restricted rats to natural rewards and drugs of abuse.
长期食物限制会增强对滥用药物以及全身或局部注射到伏隔核（NAc）的D-1多巴胺受体激动剂的行为和细胞反应。然而，这些效应背后的NAc突触传递变化尚未完全明确。AMPA受体转运是调节突触强度的主要机制，先前的研究表明，蔗糖和d-苯丙胺都会迅速改变NAc突触后密度（PSD）中AMPA受体亚基的丰度，且食物限制组和自由进食组大鼠的变化方式有所不同。在本研究中，我们探究了在没有奖励刺激挑战的情况下，食物限制是否会改变NAc PSD中AMPA受体亚基的丰度。结果发现，食物限制会增加GluA1而非GluA2的表面表达，特别是PSD丰度，这表明缺乏GluA2的Ca2+通透型AMPA受体（CP-AMPARs）会整合到突触中。CP-AMPARs的拮抗剂Naspm降低了NAc壳中诱发的兴奋性突触后电流（EPSCs）的幅度，并阻断了食物限制组（而非自由进食组）对局部微量注射D-1受体激动剂SKF-82958的增强运动反应。尽管微量注射D-2受体激动剂喹吡罗在食物限制组大鼠中也比自由进食组大鼠诱导出更大的运动激活，但Naspm并未降低这种效应。综上所述，目前的研究结果与CP-AMPARs在NAc中表达D-1受体的中等棘状神经元中的突触整合一致，这是食物限制大鼠对自然奖励和滥用药物反应增强的机制基础。
