毒蕈碱乙酰胆碱受体介导大鼠的饮酒和寻求。虽然M4和M5受体最近被暗示介导纹状体中的这些行为,它们在其他大脑区域的作用仍然未知。腹侧被盖区(VTA)和腹侧下膜(vSub)都密集表达M4和M5受体并调节寻求酒精,通过它们对伏隔核壳(AcbSh)的投影。
在印第安纳州酒精偏好(iP)雄性大鼠中,我们使用RT-qPCR检查了长期饮酒和禁欲后VTA和vSub中Chrm4(M4)和Chrm5(M5)的表达。使用逆行追踪和RNAscope的组合,我们检查了Chrm4和Chrm5在投射到AcbSh的vSub单元上的定位。使用选择性变构调节剂,我们检查了M4和M5受体在酒精消耗中的功能作用,上下文诱导的酒精寻求,运动活动,和食物/水的消耗。
长期饮酒和禁欲失调的基因的表达毒蕈碱受体在vSub,不在VTA。长期饮酒和禁欲后,Chrm4下调,而Chrm5在长期饮酒后上调。与这些数据一致,体内vSubM4受体的正变构调节剂(VU0467154)减少了背景诱导的寻求酒精,但不是酒精自我管理的动机,而M5受体负变构调节剂(ML375)降低了酒精自我给药的初始动机,但不是上下文诱导的酒精寻求。
集体,我们的数据强调了vSub中酒精诱导的胆碱能失调以及M4和M5受体变构调节剂在减少饮酒或寻求酒精方面的不同作用.
Muscarinic acetylcholine receptors mediate alcohol consumption and seeking in rats. While M4 and M5 receptors have recently been implicated to mediate these behaviours in the striatum, their role in other brain regions remain unknown. The ventral tegmental area (VTA) and ventral subiculum (vSub) both densely express M4 and M5 receptors and modulate alcohol-seeking, via their projections to the nucleus accumbens shell (AcbSh).
In Indiana alcohol-preferring (iP) male rats, we examined Chrm4 (M4 ) and Chrm5 (M5 ) expression in the VTA and vSub following long-term alcohol consumption and abstinence using RT-qPCR. Using a combination of retrograde tracing and RNAscope, we examined the localisation of Chrm4 and Chrm5 on vSub cells that project to the AcbSh. Using selective allosteric modulators, we examined the functional role of M4 and M5 receptors within the vSub in alcohol consumption, context-induced alcohol-seeking, locomotor activity, and food/water consumption.
Long-term alcohol and abstinence dysregulated the expression of genes for muscarinic receptors in the vSub, not in the VTA. Chrm4 was down-regulated following long-term alcohol and abstinence, while Chrm5 was up-regulated following long-term alcohol consumption. Consistent with these data, a positive allosteric modulator (VU0467154) of intra-vSub M4 receptors reduced context-induced alcohol-seeking, but not motivation for alcohol self-administration, while M5 receptor negative allosteric modulator (ML375) reduced initial motivation for alcohol self-administration, but not context-induced alcohol-seeking.
Collectively, our data highlight alcohol-induced cholinergic dysregulation in the vSub and distinct roles for M4 and M5 receptor allosteric modulators to reduce alcohol consumption or seeking.