Antkiewicz-Michaluk Lucyna, Wąsik Agnieszka, Możdżeń Edyta, Romańska Irena, Michaluk Jerzy
Department of Neurochemistry, Institute of Pharmacology Polish Academy of Sciences, 31-343, Kraków, Poland,
Neurotox Res. 2014 Jul;26(1):85-98. doi: 10.1007/s12640-013-9454-8. Epub 2014 Jan 10.
Animal models are widely used to study antidepressant-like effect in rodents. However, it should be mentioned that pharmacological models do not always take into account the complexity of the disease process. In the present paper, we demonstrated that repeated but not acute treatment with a low dose of reserpine (0.2 mg/kg i.p.) led to a pharmacological model of depression which was based on its inhibitory effect on the vesicular monoamine transporter 2, and monoamines depleting action in the brain. In fact, we observed that chronic treatment with a low dose of reserpine induced a distinct depressive-like behavior in the forced swim test (FST), and additionally, it produced a significant decrease in the level of dopamine, noradrenaline, and serotonin in the brain structures. 1,2,3,4-Tetrahydroisoquinoline (TIQ) and its close methyl derivative, 1-methyl-1,2,3,4-tetrahydroisoquinoline (1MeTIQ) are exo/endogenous amines present naturally in the mammalian brain which demonstrated a significant antidepressant-like effect in the FST and the reserpine model of depression in the rat. Both compounds, TIQ and 1MeTIQ, administered chronically in a dose of 25 mg/kg (i.p.) together with reserpine completely antagonized reserpine-produced depression as assessed by the immobility time and swimming time. Biochemical data were in agreement with behavioral experiments and demonstrated that chronic treatment with a low dose of reserpine in contrast to acute administration produced a significant depression of monoamines in the brain structures and impaired their metabolism. These neurochemical effects obtained after repeated reserpine (0.2 mg/kg i.p.) in the brain structures were completely antagonized by joint TIQ or 1MeTIQ (25 mg/kg i.p.) administration with chronic reserpine. A possible molecular mechanism of action of TIQ and 1MeTIQ responsible for their antidepressant action is discussed. On the basis of the presented behavioral and biochemical studies, we suggest that both compounds may be effective for the therapy of depression in clinic as new antidepressants which, when administered peripherally easily penetrate the blood-brain barrier, and as endogenous compounds may not have adverse side effects.
动物模型被广泛用于研究啮齿动物的抗抑郁样作用。然而，应该指出的是，药理学模型并不总是考虑到疾病过程的复杂性。在本文中，我们证明低剂量利血平（0.2毫克/千克腹腔注射）重复给药而非急性给药会导致一种抑郁症药理学模型，该模型基于其对囊泡单胺转运体2的抑制作用以及在大脑中的单胺耗竭作用。事实上，我们观察到低剂量利血平慢性给药会在强迫游泳试验（FST）中诱导出明显的抑郁样行为，此外，它还会使大脑结构中的多巴胺、去甲肾上腺素和血清素水平显著降低。1,2,3,4 - 四氢异喹啉（TIQ）及其紧密的甲基衍生物1 - 甲基 - 1,2,3,4 - 四氢异喹啉（1MeTIQ）是哺乳动物大脑中天然存在的外源性/内源性胺类，它们在大鼠的FST和利血平诱导的抑郁症模型中表现出显著的抗抑郁样作用。TIQ和1MeTIQ这两种化合物以25毫克/千克（腹腔注射）的剂量与利血平一起长期给药，通过不动时间和游泳时间评估，完全拮抗了利血平引起的抑郁。生化数据与行为实验一致，并表明与急性给药相比，低剂量利血平慢性给药会使大脑结构中的单胺显著降低并损害其代谢。在大脑结构中重复给予利血平（0.2毫克/千克腹腔注射）后获得的这些神经化学效应，通过TIQ或1MeTIQ（25毫克/千克腹腔注射）与慢性利血平联合给药被完全拮抗。讨论了TIQ和1MeTIQ产生抗抑郁作用的可能分子作用机制。基于所呈现的行为和生化研究，我们认为这两种化合物作为新的抗抑郁药在临床上可能对抑郁症治疗有效，它们经外周给药时容易穿透血脑屏障，并且作为内源性化合物可能没有不良副作用。
