Strong C E, Hagarty D P, Brea Guerrero A, Schoepfer K J, Cajuste S M, Kabbaj M
Program in Neuroscience, Department of Biomedical Sciences, Florida State University, Medical Science Research, Room 3300-H, 1115 W. Call St., Tallahassee, FL, 32306, USA.
Sci Rep. 2020 Nov 5;10(1):19178. doi: 10.1038/s41598-020-76183-2.
The nucleus accumbens (NAc), considered the hub of reward circuitry, is comprised of two medium spiny neuron (MSN) subtypes that are classified by their enrichment of dopamine 1 (D1) or 2 (D2) receptors. While reports indicate that alcohol increases excitatory neurotransmission exclusively on NAc D1-MSNs in male rats, it remains unknown how NAc MSNs control alcohol intake in either sex. Therefore, this study investigated how NAc MSNs mediate alcohol intake by using Drd1a-iCre and Drd2-iCre transgenic rats of both sexes. Intra-NAc infusions of Cre-inducible viral vectors containing stimulatory (hM3Dq) or inhibitory (hM4Di) designer receptors exclusively activated by designer drugs (DREADDs) were delivered after 4-weeks of alcohol intake, and clozapine-N-oxide (CNO) was administered to selectively manipulate NAc MSNs. Our results show that activation of NAc D1-MSNs increased alcohol intake 1-, 4-, and 24-h after the start of drinking while inhibition decreased it 1-h after the start of drinking, with no sex differences observed at any time point. Activation of NAc D2-MSNs had no impact on alcohol intake while inhibition increased alcohol intake in Drd2-iCre rats for 1-h in males and 4-h in females. These findings suggest opposing roles for how NAc D1- and D2-MSNs modulate alcohol intake in rats of both sexes.
伏隔核（NAc）被认为是奖赏回路的枢纽，由两种中等棘状神经元（MSN）亚型组成，这两种亚型根据多巴胺1（D1）或2（D2）受体的富集情况进行分类。虽然有报道表明酒精仅增加雄性大鼠伏隔核D1-MSNs上的兴奋性神经传递，但尚不清楚伏隔核MSNs如何控制两性的酒精摄入量。因此，本研究通过使用两性的Drd1a-iCre和Drd2-iCre转基因大鼠，研究了伏隔核MSNs如何介导酒精摄入。在酒精摄入4周后，向伏隔核内注射含有仅由设计药物（DREADDs）特异性激活的刺激性（hM3Dq）或抑制性（hM4Di）设计受体的Cre诱导型病毒载体，并给予氯氮平N-氧化物（CNO）以选择性地操纵伏隔核MSNs。我们的结果表明，伏隔核D1-MSNs的激活在开始饮酒后1小时、4小时和24小时增加了酒精摄入量，而抑制则在开始饮酒后1小时减少了酒精摄入量，在任何时间点均未观察到性别差异。伏隔核D2-MSNs的激活对酒精摄入量没有影响，而抑制则使Drd2-iCre大鼠的酒精摄入量在雄性中增加1小时，在雌性中增加4小时。这些发现表明伏隔核D1-和D2-MSNs在调节两性大鼠酒精摄入量方面具有相反的作用。
