Addiction Research Group, Schulich School of Medicine & Dentistry, University of Western Ontario, 468 Medical Science Building, Ontario, London, N6A5C1, Canada.
Department of Anatomy & Cell Biology, Schulich School of Medicine & Dentistry, University of Western Ontario London, Ontario, N6A5C1, Canada.
Psychopharmacology (Berl). 2022 Feb;239(2):509-524. doi: 10.1007/s00213-021-06029-w. Epub 2021 Dec 3.
Δ-tetrahydrocannabinol (THC) is the primary psychoactive compound in cannabis and is responsible for cannabis-related neuropsychiatric side effects, including abnormal affective processing, cognitive and sensory filtering deficits and memory impairments. A critical neural region linked to the psychotropic effects of THC is the nucleus accumbens shell (NASh), an integrative mesocorticolimbic structure that sends and receives inputs from multiple brain areas known to be dysregulated in various disorders, including schizophrenia and anxiety-related disorders. Considerable evidence demonstrates functional differences between posterior vs. anterior NASh sub-regions in the processing of affective and cognitive behaviours influenced by THC. Nevertheless, the neuroanatomical regions and local molecular pathways responsible for these psychotropic effects are not currently understood.
The objectives of this study were to characterize the effects of intra-accumbens THC in the anterior vs. posterior regions of the NASh during emotional memory formation, sensorimotor gating and anxiety-related behaviours.
We performed an integrative series of translational behavioural pharmacological studies examining anxiety, sensorimotor gating and fear-related associative memory formation combined with regionally specific molecular signalling analyses in male Sprague Dawley rats.
We report that THC in the posterior NASh causes distortions in emotional salience attribution, impaired sensory filtering and memory retention and heightened anxiety, through a glycogen-synthase-kinase-3 (GSK-3)-β-catenin dependent signalling pathway. In contrast, THC in the anterior NASh produces anxiolytic effects via modulation of protein kinase B (Akt) phosphorylation states.
These findings reveal critical new insights into the neuroanatomical and molecular mechanisms associated with the differential neuropsychiatric side effects of THC in dissociable nucleus accumbens sub-regions.
Δ-四氢大麻酚（THC）是大麻中的主要精神活性化合物，负责与大麻相关的神经精神副作用，包括异常情感处理、认知和感觉过滤缺陷以及记忆障碍。与 THC 的精神作用相关的一个关键神经区域是伏隔核壳（NASh），这是一个整合的中脑皮质边缘结构，它从多个大脑区域发送和接收输入，这些大脑区域在各种疾病中被认为是失调的，包括精神分裂症和焦虑相关障碍。大量证据表明，在受 THC 影响的情感和认知行为的处理中，NASh 的后区与前区之间存在功能差异。然而，目前尚不清楚负责这些精神作用的神经解剖区域和局部分子途径。
本研究的目的是描述在情绪记忆形成、感觉门控和焦虑相关行为中，NASh 的前区和后区中内ACC 的 THC 作用。
我们进行了一系列整合的转化行为药理学研究，检查了雄性 Sprague Dawley 大鼠中的焦虑、感觉门控和与恐惧相关的联想记忆形成，以及区域特异性分子信号分析。
我们报告说，NASh 后区的 THC 通过糖原合酶激酶 3（GSK-3）-β-连环蛋白依赖性信号通路引起情感显著归因的扭曲、感觉过滤受损和记忆保留以及焦虑增加。相比之下，NASh 前区的 THC 通过调节蛋白激酶 B（Akt）磷酸化状态产生抗焦虑作用。
这些发现揭示了与 THC 在可分离的伏隔核亚区中产生的不同神经精神副作用相关的神经解剖学和分子机制的关键新见解。
