Divergent outcomes of delta 9 - tetrahydrocannabinol (THC) in adolescence on mesocortical dopamine and cognitive development in male and female mice.

IF 3.3 3区医学 Q2 NEUROSCIENCES

Psychopharmacology Pub Date : 2025-10-01 Epub Date: 2025-07-14 DOI:10.1007/s00213-025-06791-1

Tanya Capolicchio, Giovanni Hernandez, Sammy Shun Wai Shi, Emilie Dube, Katherina Estrada, Michel Giroux, Brian J Nieman, Zdenka Pausova, Cecilia Flores

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Abstract

The increasing exposure to delta 9-tetrahydrocannabinol (THC) in youth sparks concerns about disruption of ongoing neurodevelopment. During adolescence, dopamine axons continue to grow from the striatum to the prefrontal cortex, promoting the refinement of inhibitory control. This process is coordinated by the Netrin-1 receptor, DCC, which is regulated by microRNA miR-218. In addition, microglial actions significantly influence adolescent cortical refinement. Here, we show that THC in adolescent mice has sex-specific effects on dopamine innervation in the adult prefrontal cortex. While females show no changes, in males, THC leads to a reduction in the volume occupied by dopamine axons in the medial prefrontal cortex and a decrease in the density of their presynaptic sites. However, it increases dopamine innervation in the orbitofrontal cortex. Assessment of the effects of THC in adolescence on impulse control in adulthood, using the Go-No/Go task, revealed male-specific alterations - THC increased premature responding but reduced the number of commission errors. Molecular analysis showed that, one week after adolescent THC, males display increased Dcc and decreased miR-218 levels. In contrast, females exhibit decreased Dcc levels without changes in miR-218. Furthermore, in the medial prefrontal cortex, females show smaller microglia soma size, potentially mitigating the impact of decreased Dcc on dopamine development. These findings suggest that in adolescent males, THC dysregulates the miR-218/DCC pathway, prompting mistargeting of dopamine axons and diverting their growth from medial to orbitofrontal regions. This work highlights the sex-specific impact of adolescent THC on dopamine and impulse control development and uncovers potential divergent molecular and epigenetic processes.

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青春期δ 9 -四氢大麻酚（THC）对雌雄小鼠中皮质多巴胺和认知发育的影响存在差异。

青少年越来越多地接触到δ 9-四氢大麻酚（THC），这引发了人们对正在进行的神经发育中断的担忧。在青春期，多巴胺轴突继续从纹状体生长到前额叶皮层，促进抑制控制的细化。这一过程由Netrin-1受体DCC协调，并受microRNA miR-218调控。此外，小胶质细胞的活动显著影响青少年皮层的细化。在这里，我们发现青春期小鼠的四氢大麻酚对成年前额叶皮层的多巴胺神经支配具有性别特异性影响。虽然雌性没有表现出变化，但在雄性中，THC导致内侧前额皮质多巴胺轴突占用的体积减少，突触前部位的密度下降。然而，它增加了眶额皮质的多巴胺神经支配。通过Go- no /Go任务，评估青春期四氢大麻酚对成年期冲动控制的影响，揭示了男性特有的变化——四氢大麻酚增加了过早反应，但减少了指令错误的数量。分子分析显示，青少年THC后一周，男性显示Dcc升高，miR-218水平降低。相比之下，女性的Dcc水平下降，miR-218没有变化。此外，在内侧前额叶皮层，女性显示出较小的小胶质细胞体大小，可能减轻Dcc减少对多巴胺发育的影响。这些发现表明，在青春期男性中，THC失调miR-218/DCC通路，促使多巴胺轴突的错误靶向，并将其生长从内侧转移到眶额区。这项工作强调了青少年THC对多巴胺和冲动控制发育的性别特异性影响，并揭示了潜在的不同分子和表观遗传过程。

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来源期刊

Psychopharmacology 医学-精神病学

CiteScore

7.10

自引率

5.90%

发文量

257

审稿时长

2-4 weeks

期刊介绍： Official Journal of the European Behavioural Pharmacology Society (EBPS) Psychopharmacology is an international journal that covers the broad topic of elucidating mechanisms by which drugs affect behavior. The scope of the journal encompasses the following fields: Human Psychopharmacology: Experimental This section includes manuscripts describing the effects of drugs on mood, behavior, cognition and physiology in humans. The journal encourages submissions that involve brain imaging, genetics, neuroendocrinology, and developmental topics. Usually manuscripts in this section describe studies conducted under controlled conditions, but occasionally descriptive or observational studies are also considered. Human Psychopharmacology: Clinical and Translational This section comprises studies addressing the broad intersection of drugs and psychiatric illness. This includes not only clinical trials and studies of drug usage and metabolism, drug surveillance, and pharmacoepidemiology, but also work utilizing the entire range of clinically relevant methodologies, including neuroimaging, pharmacogenetics, cognitive science, biomarkers, and others. Work directed toward the translation of preclinical to clinical knowledge is especially encouraged. The key feature of submissions to this section is that they involve a focus on clinical aspects. Preclinical psychopharmacology: Behavioral and Neural This section considers reports on the effects of compounds with defined chemical structures on any aspect of behavior, in particular when correlated with neurochemical effects, in species other than humans. Manuscripts containing neuroscientific techniques in combination with behavior are welcome. We encourage reports of studies that provide insight into the mechanisms of drug action, at the behavioral and molecular levels. Preclinical Psychopharmacology: Translational This section considers manuscripts that enhance the confidence in a central mechanism that could be of therapeutic value for psychiatric or neurological patients, using disease-relevant preclinical models and tests, or that report on preclinical manipulations and challenges that have the potential to be translated to the clinic. Studies aiming at the refinement of preclinical models based upon clinical findings (back-translation) will also be considered. The journal particularly encourages submissions that integrate measures of target tissue exposure, activity on the molecular target and/or modulation of the targeted biochemical pathways. Preclinical Psychopharmacology: Molecular, Genetic and Epigenetic This section focuses on the molecular and cellular actions of neuropharmacological agents / drugs, and the identification / validation of drug targets affecting the CNS in health and disease. We particularly encourage studies that provide insight into the mechanisms of drug action at the molecular level. Manuscripts containing evidence for genetic or epigenetic effects on neurochemistry or behavior are welcome.