Depression has a multifactorial etiology that arises from environmental, psychological, genetic, and biological factors. Environmental stress and genetic factors acting through immunological and endocrine responses generate structural and functional changes in the brain, inducing neurogenesis and neurotransmission dysfunction. Terpineol, monoterpenoid alcohol, has shown immunomodulatory and neuroprotective effects, but there is no report about its antidepressant potential. Herein, we used a single lipopolysaccharide (LPS) injection to induce a depressive-like effect in the tail suspension test (TST) and the splash test (ST) for a preventive and therapeutic experimental schedule. Furthermore, we investigated the antidepressant-like mechanism of action of terpineol while using molecular and pharmacological approaches. Terpineol showed a coherent predicted binding mode mainly against CB1 and CB2 receptors and also against the D2 receptor during docking modeling analyses. The acute administration of terpineol produced the antidepressant-like effect, since it significantly reduced the immobility time in TST (100-200 mg/kg, p.o.) as compared to the control group. Moreover, terpineol showed an antidepressant-like effect in the preventive treatment that was blocked by a nonselective dopaminergic receptor antagonist (haloperidol), a selective dopamine D2 receptor antagonist (sulpiride), a selective CB1 cannabinoid receptor antagonist/inverse agonist (AM281), and a potent and selective CB2 cannabinoid receptor inverse agonist (AM630), but it was not blocked by a nonselective adenosine receptor antagonist (caffeine) or a β-adrenoceptor antagonist (propranolol). In summary, molecular docking suggests that CB1 and CB2 receptors are the most promising targets of terpineol action. Our data showed terpineol antidepressant-like modulation by CB1 and CB2 cannabinoid receptors and D2-dopaminergic receptors to further corroborate our molecular evidence.

中文翻译：

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萜品醇在抑郁症炎症模型中的抗抑郁样作用：大麻素系统和 D2 多巴胺受体的参与。


抑郁症的病因有多种，包括环境、心理、遗传和生物因素。环境压力和遗传因素通过免疫和内分泌反应作用，导致大脑结构和功能发生变化，诱导神经发生和神经传递功能障碍。萜品醇（单萜醇）已显示出免疫调节和神经保护作用，但尚无关于其抗抑郁潜力的报道。在此，我们使用单次脂多糖（LPS）注射在悬尾试验（TST）和飞溅试验（ST）中诱导类似抑郁的效果，用于预防和治疗实验计划。此外，我们利用分子和药理学方法研究了萜品醇的抗抑郁样作用机制。在对接模型分析期间，萜品醇显示出主要针对 CB1 和 CB2 受体以及 D2 受体的连贯预测结合模式。急性给予萜品醇产生了抗抑郁样作用，因为与对照组相比，它显着缩短了 TST（100-200 mg/kg，口服）中的不动时间。此外，萜品醇在预防性治疗中表现出抗抑郁样作用，该作用被非选择性多巴胺能受体拮抗剂（氟哌啶醇）、选择性多巴胺 D2 受体拮抗剂（舒必利）、选择性 CB1 大麻素受体拮抗剂/反激动剂（AM281）和一种有效的选择性 CB2 大麻素受体反向激动剂 (AM630)，但它不能被非选择性腺苷受体拮抗剂（咖啡因）或 β-肾上腺素受体拮抗剂（普萘洛尔）阻断。总之，分子对接表明 CB1 和 CB2 受体是萜品醇作用最有希望的靶标。 我们的数据显示 CB1 和 CB2 大麻素受体和 D2 多巴胺能受体具有萜品醇抗抑郁样调节作用，进一步证实了我们的分子证据。