The Laboratory of the Biology of Addictive Diseases, The Rockefeller University, New York, New York.
Feil Family Brain and Mind Research Institute, Weill Cornell Medicine, New York, New York.
Synapse. 2021 Oct;75(10):e22218. doi: 10.1002/syn.22218.
Our prior studies demonstrated that the rat hippocampal opioid system can undergo sex-specific adaptations to external stimuli that can influence opioid-associated learning processes. This opioid system extensively overlaps with the cannabinoid system. Moreover, acute administration of Δ Tetrahydrocannabinoid (THC), the primary psychoactive constituent of cannabis, can alter cognitive behaviors that involve the hippocampus. Here, we use light and electron microscopic immunocytochemical methods to examine the effects of acute THC (5 mg/kg, i.p., 1 h) on mossy fiber Leu-Enkephalin (LEnk) levels and the distribution and phosphorylation levels of delta and mu opioid receptors (DORs and MORs, respectively) in CA3 pyramidal cells and parvalbumin dentate hilar interneurons of adult female and male Sprague-Dawley rats. In females with elevated estrogen states (proestrus/estrus stage), acute THC altered the opioid system so that it resembled that seen in vehicle-injected females with low estrogen states (diestrus) and males: (1) mossy fiber LEnk levels in CA2/3a decreased; (2) phosphorylated-DOR levels in CA2/3a pyramidal cells increased; and (3) phosphorylated-MOR levels increased in most CA3b laminae. In males, acute THC resulted in the internalization of MORs in parvalbumin-containing interneuron dendrites which would decrease disinhibition of granule cells. In both sexes, acute THC redistributed DORs to the near plasma membrane of CA3 pyramidal cell dendrites, however, the dendritic region varied with sex. Additionally, acute THC also resulted in a sex-specific redistribution of DORs within CA3 pyramidal cell dendrites which could differentially promote synaptic plasticity and/or opioid-associated learning processes in both females and males.
我们之前的研究表明，大鼠海马阿片系统可以对外部刺激进行性别特异性适应，从而影响与阿片相关的学习过程。这个阿片系统与大麻素系统广泛重叠。此外，急性给予大麻的主要精神活性成分 Δ-四氢大麻酚（THC）会改变涉及海马体的认知行为。在这里，我们使用光和电子显微镜免疫细胞化学方法检查急性 THC（5mg/kg，ip，1h）对成年雌性和雄性 Sprague-Dawley 大鼠 CA3 锥体神经元和颗粒细胞内嗅区中间神经元中苔藓纤维亮氨酸脑啡肽（LEnK）水平以及 δ 和 μ 阿片受体（DOR 和 MOR）分布和磷酸化水平的影响。在雌激素水平升高的雌性（发情前期/发情期）中，急性 THC 改变了阿片系统，使其类似于雌激素水平较低的载体注射雌性（发情后期）和雄性：（1）CA2/3a 中的苔藓纤维 LEnK 水平降低；（2）CA2/3a 锥体神经元中磷酸化 DOR 水平增加；（3）大多数 CA3b 层中的磷酸化 MOR 水平增加。在雄性中，急性 THC 导致 MOR 内在化颗粒细胞内嗅区中间神经元的树突中，这会减少颗粒细胞的去抑制。在两种性别中，急性 THC 将 DOR 重新分布到 CA3 锥体神经元树突的近质膜，但树突区域随性别而异。此外，急性 THC 还导致 CA3 锥体神经元树突内 DOR 的性别特异性再分布，这可能会以不同的方式促进雌性和雄性的突触可塑性和/或与阿片相关的学习过程。
