Rodríguez-Gaztelumendi Antonio, Rojo M Luisa, Pazos Angel, Díaz Alvaro
Departamento de Fisiología y Farmacología, Universidad de Cantabria. Instituto de Biomedicina y Biotecnología de Cantabria (CSIC-UC-IDICAN), Santander, Instituto de Salud Carlos III, Spain.
J Neurochem. 2009 Mar;108(6):1423-33. doi: 10.1111/j.1471-4159.2009.05898.x. Epub 2009 Jan 22.
Bilateral olfactory bulbectomy in the rat (OBX) induces behavioral, neurochemical, and structural abnormalities similar to those observed in human depression that are normalized after chronic, but not acute, treatment with antidepressants. In our study, OBX animals exhibited significant increases in both CB(1) receptor density ([(3)H]CP55490 binding) and functionality (stimulation of [(35)S]GTPgammaS binding by the cannabinoid (CB) agonist WIN 55212-2) at the prefrontal cortex (PFC). After chronic treatment with fluoxetine (10 mg/kg/day, 14 days, s.c.), OBX-induced hyperactivity in the open-field test was fully abolished. Interestingly, chronic fluoxetine fully reversed the enhanced CB(1)-receptor signaling in PFC observed following OBX. The CB agonist Delta(9)-tetrahydrocannabinol (5 mg/kg, i.p., 1 day) did not produce any behavioral effect in sham-operated animals but returned locomotor activity to control values in OBX rats. As both acute administration of Delta(9)-tetrahydrocannabinol and chronic fluoxetine elicited a similar behavioral effect in the OBX rat, it is not unlikely that the regionally selective enhancement of CB(1) receptor-signaling in the PFC could be related with the altered OBX behavior. Our findings reinforce the utility of this animal model to further investigating the implication of the endocannabinoid system in the modulation of emotional processes and its potential role in the adaptive responses to chronic antidepressants.
大鼠双侧嗅球切除术（OBX）会诱发行为、神经化学和结构异常，这些异常与人类抑郁症中观察到的异常相似，在长期而非急性使用抗抑郁药治疗后可恢复正常。在我们的研究中，OBX动物前额叶皮质（PFC）的CB(1)受体密度（[³H]CP55490结合）和功能（大麻素（CB）激动剂WIN 55212-2刺激[³⁵S]GTPγS结合）均显著增加。在用氟西汀（10 mg/kg/天，14天，皮下注射）进行长期治疗后，OBX诱导的旷场试验中的多动行为被完全消除。有趣的是，慢性氟西汀完全逆转了OBX后在PFC中观察到的增强的CB(1)受体信号传导。CB激动剂Δ⁹-四氢大麻酚（5 mg/kg，腹腔注射，1天）在假手术动物中未产生任何行为影响，但使OBX大鼠的运动活动恢复到对照值。由于急性给予Δ⁹-四氢大麻酚和慢性给予氟西汀在OBX大鼠中产生了相似的行为效应，PFC中CB(1)受体信号传导的区域选择性增强不太可能与OBX行为改变无关。我们的研究结果强化了这种动物模型在进一步研究内源性大麻素系统在情绪过程调节中的作用及其在慢性抗抑郁药适应性反应中的潜在作用方面的实用性。
