Department of Pharmacology, Faculty of Medicine, School of Health Sciences, University of Ioannina, Ioannina, Greece.
Center of Clinical, Experimental Surgery and Translational Research, Biomedical Research Foundation of the Academy of Athens, Athens, Greece.
Br J Pharmacol. 2021 Apr;178(7):1722-1736. doi: 10.1111/bph.15394. Epub 2021 Feb 27.
Adolescent cannabis use is associated with adult psychopathology. When Δ -tetrahydrocannabinol (THC), mainly in high doses, is administered to adolescence rats there are also long lasting effects in adults. This study aims to determine the specific adult bio-behavioural profile after adolescent low-dose THC, which better mirrors adolescent recreational cannabis use.
Adolescent male Sprague-Dawley rats were treated with escalating low-dose of THC. In adulthood, they were evaluated for their spontaneous locomotion, sensorimotor gating, higher order and spatial cognitive functions. Dopaminergic activity and cannabinoid receptor expression were measured in distinct brain regions. Hippocampal neurogenic activity of neural stem cells was determined and protein levels of neuroplasticity-related biomarkers were quantified. Adolescent low-dose THC exposure increased spontaneous open-field activity, without affecting prepulse inhibition and attentional set-shifting performance. Region-specific dopaminergic alterations and CB receptor up-regulation in the prefrontal cortex were observed. Impaired spatial memory, as assessed with the object location task and Morris water maze test, was associated with significantly decreased proliferative activity (SOX2-positive cells), neurogenic potential (decreased doublecortin-positive cells) in the adult hippocampus and defective neuroplasticity, including reduced BDNF expression in the hippocampus and prefrontal cortex.
Our findings reveal the adverse impact of adolescent low-dose THC on the psychomotor profile, dopaminergic neurotransmission, compensatory cannabinoid receptor response, cognition-related neurobiological and behavioural functions.
Our adolescent low-dose THC animal model does not induce tangible psychotic-like effects, such as those reported in high-dose THC studies, but it impairs cognitive functions and points to hippocampal vulnerability and disrupted neurogenesis.
青少年吸食大麻与成年后出现精神病理学有关。当给予青春期大鼠高剂量的 Δ-四氢大麻酚（THC）时，也会在成年后产生持久的影响。本研究旨在确定青春期低剂量 THC 后特定的成年生物行为特征，这更能反映青少年消遣性大麻的使用情况。
青春期雄性 Sprague-Dawley 大鼠接受递增低剂量的 THC 治疗。成年后，评估它们的自发运动、感觉运动门控、高级和空间认知功能。测量不同脑区的多巴胺能活性和大麻素受体表达。确定海马神经干细胞的神经发生活性，并定量测定神经可塑性相关生物标志物的蛋白水平。
青少年低剂量 THC 暴露增加了自发旷场活动，而不影响前脉冲抑制和注意力定势转移表现。观察到前额叶特定区域多巴胺能改变和 CB 受体上调。在物体位置任务和 Morris 水迷宫测试中观察到空间记忆受损，与成年海马中增殖活性（SOX2 阳性细胞）和神经发生潜力（减少的双皮质素阳性细胞）显著降低以及神经可塑性缺陷相关，包括海马和前额叶皮质中 BDNF 表达减少。
我们的发现揭示了青少年低剂量 THC 对精神运动特征、多巴胺能神经传递、代偿性大麻素受体反应、认知相关神经生物学和行为功能的不利影响。
我们的青春期低剂量 THC 动物模型不会引起高剂量 THC 研究报告的明显类精神病样效应，但会损害认知功能，并表明海马易损性和神经发生中断。
