Instituto de Neurociencias, Universidad Miguel Hernandez-CSIC, San Juan de Alicante, Alicante, Spain; Redes de Investigación Cooperativa Orientadas a Resultados en Salud (RICORS), Red de Investigación en Atención Primaria de Adicciones (RIAPAd), Instituto de Salud Carlos III, MICINN and FEDER, Madrid, Spain; Instituto de Investigación Sanitaria y Biomédica de Alicante (ISABIAL), Alicante, Spain.
Instituto de Neurociencias, Universidad Miguel Hernandez-CSIC, San Juan de Alicante, Alicante, Spain; Redes de Investigación Cooperativa Orientadas a Resultados en Salud (RICORS), Red de Investigación en Atención Primaria de Adicciones (RIAPAd), Instituto de Salud Carlos III, MICINN and FEDER, Madrid, Spain; Instituto de Investigación Sanitaria y Biomédica de Alicante (ISABIAL), Alicante, Spain.
Neuropharmacology. 2023 Aug 1;233:109549. doi: 10.1016/j.neuropharm.2023.109549. Epub 2023 Apr 19.
The main goal of this study was to evaluate if the administration of cannabidiol (CBD) regulates behavioral and gene expression alterations induced by spontaneous alcohol withdrawal (SAW) in mice. Increasing doses of ethanol were administered to C57BL/6J male mice for 15 days (2.5, 3 and 3.5 g/kg/12 h, p. o.), and SAW was studied at 6, 12, 24, and 72 h after the last ethanol administration. The efficacy of acute CBD (10, 20, and 40 mg/kg, i. p.) to regulate behavioral changes induced by SAW was explored at 6 h. Gene expression analyses of cannabinoid receptors 1 (Cnr1) and 2 (Cnr2), mu-opioid receptor (Opmr1), and proopiomelanocortin (Pomc) in the nucleus accumbens (NAcc), and Pomc and tyrosine hydroxylase (Th) in the ventral tegmental area (VTA), were carried out by real time-PCR. Pearson correlation was used to identify potential associations between the gene expression data and the anxiety-like behaviors. Biostatistical studies suggest associations between gene expression data and the anxiogenic behaviors in mice exposed to the SAW model and treated with VEH and 40 mg/kg of CBD. Mice exposed to the SAW model showed significant somatic withdrawal signs, anxiety-like behaviors, and remarkable changes in the gene expression of all brain targets at 6 h. CBD dose-dependently normalized the behavioral, somatic withdrawal signs and anxiety-like behaviors and modulated gene expression changes in the NAcc, but not in the VTA. The results of this study suggest that CBD may regulate specific alcohol withdrawal-associated alterations. However, further studies are required to explore the possible mechanisms involved.
本研究的主要目的是评估大麻二酚（CBD）的给药是否调节自发酒精戒断（SAW）诱导的小鼠行为和基因表达改变。将递增剂量的乙醇给予 C57BL/6J 雄性小鼠 15 天（2.5、3 和 3.5 g/kg/12 h，口服），并在最后一次乙醇给药后 6、12、24 和 72 h 研究 SAW。在 6 h 时，探索急性 CBD（10、20 和 40 mg/kg，ip）对调节 SAW 诱导的行为变化的疗效。通过实时 PCR 对伏隔核（NAcc）中的大麻素受体 1（Cnr1）和 2（Cnr2）、μ-阿片受体（Opmr1）和前阿黑皮素原（Pomc）以及腹侧被盖区（VTA）中的 Pomc 和酪氨酸羟化酶（Th）的基因表达进行分析。Pearson 相关性用于鉴定基因表达数据与焦虑样行为之间的潜在关联。生物统计学研究表明，在暴露于 SAW 模型并用 VEH 和 40 mg/kg CBD 治疗的小鼠中，基因表达数据与焦虑样行为之间存在关联。暴露于 SAW 模型的小鼠在 6 h 时表现出明显的躯体戒断体征、焦虑样行为以及所有脑靶基因表达的显著变化。CBD 呈剂量依赖性地使行为、躯体戒断体征和焦虑样行为正常化，并调节 NAcc 中的基因表达变化，但不在 VTA 中。本研究的结果表明，CBD 可能调节特定的酒精戒断相关改变。然而，需要进一步研究来探索涉及的可能机制。
