Garzón Miguel, Wang Gang, Chan June, Bourie Faye, Mackie Ken, Pickel Virginia M
Departamento de Anatomía, Histología y Neurociencia, Facultad de Medicina UAM, Madrid 28029, Spain.
Brain and Mind Research Institute, Weill Cornell Medicine, New York, NY 10065, USA.
IBRO Neurosci Rep. 2021 Oct 1;11:144-155. doi: 10.1016/j.ibneur.2021.09.005. eCollection 2021 Dec.
Long-term cannabis use during adolescence has deleterious effects in brain that are largely ascribed to the activation of cannabinoid-1 receptors (CB1Rs) by delta-9-tetrahydrocannabinol (∆9-THC), the primary psychoactive compound in marijuana. Systemic administration of ∆9-THC inhibits acetylcholine release in the prelimbic-prefrontal cortex (PL-PFC). In turn, PL-PFC acetylcholine plays a role in executive activities regulated by CB1R-targeting endocannabinoids, which are generated by cholinergic stimulation of muscarinic-1 receptors (M1Rs). However, the long-term effects of chronic administration of increasing doses of ∆9-THC in adolescent males on the distribution and function of M1 and/or CB1 receptors in the PL-PFC remains unresolved. We used C57BL\6J male mice pre-treated with vehicle or escalating daily doses of ∆9-THC to begin filling this gap. Electron microscopic immunolabeling showed M1R-immunogold particles on plasma membranes and in association with cytoplasmic membranes in varying sized dendrites and dendritic spines. These dendritic profiles received synaptic inputs from unlabeled, CB1R- and/or M1R-labeled axon terminals in the PL-PFC of both treatment groups. However, there was a size-dependent decrease in total (plasmalemmal and cytoplasmic) M1R gold particles in small dendrites within the PL-PFC of mice receiving ∆9-THC. Whole cell current-clamp recording in PL-PFC slice preparations further revealed that adolescent pretreatment with ∆9-THC attenuates the hyperpolarization and increases the firing rate produced by local muscarinic stimulation. Repeated administration of ∆9-THC during adolescence also reduced spontaneous alternations in a Y-maze paradigm designed for measures of PFC-dependent memory function in adult mice. Our results provide new information implicating M1Rs in cortical dysfunctions resulting from adolescent abuse of marijuana.
青少年长期使用大麻会对大脑产生有害影响，这在很大程度上归因于大麻中的主要精神活性成分Δ9-四氢大麻酚（Δ9-THC）对大麻素1型受体（CB1Rs）的激活。全身性给予Δ9-THC会抑制前边缘-前额叶皮质（PL-PFC）中的乙酰胆碱释放。反过来，PL-PFC中的乙酰胆碱在由靶向CB1R的内源性大麻素调节的执行活动中发挥作用，这些内源性大麻素是由毒蕈碱1型受体（M1Rs）的胆碱能刺激产生的。然而，青春期雄性小鼠长期给予递增剂量的Δ9-THC对PL-PFC中M1和/或CB1受体的分布和功能的长期影响仍未得到解决。我们使用预先用载体或递增的每日剂量的Δ9-THC处理的C57BL/6J雄性小鼠来开始填补这一空白。电子显微镜免疫标记显示，在不同大小的树突和树突棘的质膜上以及与细胞质膜相关联的位置有M1R免疫金颗粒。在两个治疗组的PL-PFC中，这些树突形态都接受了来自未标记的、CB1R和/或M1R标记的轴突终末的突触输入。然而，在接受Δ�9-THC的小鼠的PL-PFC内小树突中，总的（质膜和细胞质）M1R金颗粒数量出现了大小依赖性减少。在PL-PFC脑片制备中进行的全细胞电流钳记录进一步显示，青春期用Δ9-THC预处理会减弱超极化，并增加局部毒蕈碱刺激产生的放电频率。在青春期重复给予Δ9-THC也会减少在为测量成年小鼠PFC依赖性记忆功能而设计的Y迷宫范式中的自发交替行为。我们的结果提供了新信息，表明M1Rs与青少年滥用大麻导致的皮质功能障碍有关。
