Division of Pharmacology, Center of Excellence for Pharmaceutical Sciences, North-West University (Potchefstroom Campus), Potchefstroom, South Africa; South African MRC Unit on Risk and Resilience in Mental Disorders, Department of Psychiatry and Mental Health, University of Cape Town, Cape Town, South Africa.
Division of Pharmacology, Center of Excellence for Pharmaceutical Sciences, North-West University (Potchefstroom Campus), Potchefstroom, South Africa.
Res Vet Sci. 2021 Mar;135:175-183. doi: 10.1016/j.rvsc.2021.01.013. Epub 2021 Jan 23.
Non-selective α-adrenoreceptor (AR) stimulation delivers favourable sedative, analgesic, muscle relaxant and anxiolytic actions in companion animals, but is associated with cardiovascular and respiratory side effects. Anxiety conditions underscore monoamine disturbances amenable to α-AR modulation. We investigated sub-chronic (14 day s.c.) treatment with the selective α-AR antagonist, ORM-10921 (0.03, 0.1, 0.3 mg/kg/d) on hippocampal noradrenaline (NA), dopamine (DA), serotonin (5-HT) and their turnover levels in stress sensitive Flinders Sensitive Line (FSL) rats versus Flinders Resistant Line (FRL) controls, using high performance liquid chromatography. The effects of ORM-10921 were compared to the non-selective α-AR antagonist, idazoxan (IDAZ; 3 mg/kg/d), and to imipramine (IMI; 15 mg/kg/d), a reference antidepressant in this model. FSL rats displayed significantly reduced 5-HT (p = 0.03) and DA (p = 0.02) levels vs. FRL controls, while NA levels showed a similar trend. ORM-10921 significantly increased NA (all doses p ≤ 0.02), 5-HT (0.1 and 0.3 mg/kg p ≤ 0.03) and DA levels (all doses p ≤ 0.03), which correlated with decreased monoamine turnover. In contrast, IDAZ significantly elevated NA (p < 0.005) and DA (p < 0.004) but not 5-HT levels. IMI also significantly increased 5-HT (p < 0.009), with a tendency to increase NA (p = 0.09) but not DA. ORM-10921 exerts similar albeit broader effects on hippocampal monoamines than IDAZ, explaining earlier established efficacy associated with α-AR antagonism in animal models of depression and cognitive dysfunction. These and the current studies encourage application of ORM-10921 in depression in humans, as well as raise the intriguing possibility that selective α-AR antagonists may be beneficial in anxiety and stress-related disorders in companion animals. Both warrant further study.
非选择性α-肾上腺素受体（AR）刺激在伴侣动物中提供有利的镇静、镇痛、肌肉松弛和抗焦虑作用，但与心血管和呼吸系统副作用相关。焦虑症强调了可通过α-AR 调节来改善单胺类物质紊乱。我们研究了慢性（14 天皮下）用选择性α-AR 拮抗剂 ORM-10921（0.03、0.1、0.3mg/kg/d）治疗应激敏感的弗林德斯敏感系（FSL）大鼠与弗林德斯抗性系（FRL）对照品对海马去甲肾上腺素（NA）、多巴胺（DA）、5-羟色胺（5-HT）及其代谢产物水平的影响，采用高效液相色谱法。将 ORM-10921 的作用与非选择性α-AR 拮抗剂 IDAZ（3mg/kg/d）和该模型中的参考抗抑郁药丙咪嗪（IMI；15mg/kg/d）进行比较。FSL 大鼠与 FRL 对照品相比，5-HT（p=0.03）和 DA（p=0.02）水平显著降低，而 NA 水平呈类似趋势。ORM-10921 显著增加 NA（所有剂量 p≤0.02）、5-HT（0.1 和 0.3mg/kg p≤0.03）和 DA 水平（所有剂量 p≤0.03），这与单胺类物质代谢产物减少相关。相比之下，IDAZ 显著升高 NA（p<0.005）和 DA（p<0.004），但不升高 5-HT 水平。IMI 也显著升高 5-HT（p<0.009），NA 水平升高呈趋势（p=0.09），但 DA 水平不升高。ORM-10921 对海马单胺类物质的作用与 IDAZ 相似，尽管作用范围更广，这解释了先前在抑郁和认知功能障碍的动物模型中与 α-AR 拮抗作用相关的疗效。这些以及当前的研究鼓励在人类抑郁症中应用 ORM-10921，同时也提出了一个有趣的可能性，即选择性α-AR 拮抗剂可能对伴侣动物的焦虑和应激相关疾病有益。两者都需要进一步研究。
