Griebel G, Curet O, Perrault G, Sanger D J
Synthélabo Recherche, Bagneux, France.
Neuropharmacology. 1998 Jul;37(7):927-35. doi: 10.1016/s0028-3908(98)00077-x.
This study investigated the effects of acute and chronic (one daily i.p. injection for 14 days) treatments with the non-selective irreversible monoamine-oxidase (MAO) inhibitor phenelzine (10 and 30 mg/kg) on defensive behaviors of Swiss mice in the mouse defense test battery (MDTB) which has been designed for screening anxiolytic and anti-panic drugs. In the MDTB, subjects were confronted with a natural threat (a rat) and situations associated with this threat. MAO-A and MAO-B activities and levels of brain monoamines (serotonin (5-HT), dopamine (DA) and norepinephrine (NE)) and their deaminated metabolites were subsequently measured. Behavioral results showed that acute administration of phenelzine did not specifically modify defensive behaviors. By contrast, after chronic treatment, phenelzine produced a significant reduction in avoidance distance when the rat was approaching, an effect which is consistent with an anti-panic-like action. In addition, phenelzine displayed weak anxiolytic-like effects as it increased risk assessment responses when mice were constrained in one part of the apparatus facing the rat which remained at a constant distance. No other specific drug effect was observed. These behavioral changes were associated with a dramatic increase in 5-HT levels, in particular after chronic treatment, while levels of DA and NE increased only slightly. Importantly, no significant differences in DA and NE levels between acute and chronic regimens were observed. Levels of deaminated metabolites of monoamines were markedly decreased. Measurements of MAO activity revealed substantial reductions in both type A and B forms with a full inhibition of both forms being observed only after chronic treatment with phenelzine. These results suggest that the effects of phenelzine may be due mainly to its effects on the 5-HT system and presumably related to the full inhibition of MAO-A and/or MAO-B.
本研究调查了非选择性不可逆单胺氧化酶（MAO）抑制剂苯乙肼（10毫克/千克和30毫克/千克）急性和慢性（每日腹腔注射一次，持续14天）治疗对瑞士小鼠在小鼠防御测试组合（MDTB）中防御行为的影响，该测试组合是为筛选抗焦虑和抗惊恐药物而设计的。在MDTB中，实验对象面临自然威胁（一只大鼠）以及与该威胁相关的情境。随后测量了MAO - A和MAO - B的活性、脑单胺（5 - 羟色胺（5 - HT）、多巴胺（DA）和去甲肾上腺素（NE））水平及其脱氨基代谢产物。行为学结果表明，急性给予苯乙肼并未特异性改变防御行为。相比之下，慢性治疗后，当大鼠靠近时，苯乙肼使回避距离显著缩短，这一效应与抗惊恐样作用一致。此外，当小鼠被限制在装置的一部分面对保持恒定距离的大鼠时，苯乙肼增加了风险评估反应，显示出微弱的抗焦虑样效应。未观察到其他特异性药物效应。这些行为变化与5 - HT水平的显著升高有关，尤其是在慢性治疗后，而DA和NE水平仅略有升高。重要的是，急性和慢性给药方案之间的DA和NE水平未观察到显著差异。单胺脱氨基代谢产物水平显著降低。MAO活性测量显示，A和B两种形式均大幅降低，仅在苯乙肼慢性治疗后才观察到两种形式的完全抑制。这些结果表明，苯乙肼的作用可能主要归因于其对5 - HT系统的影响，可能与MAO - A和/或MAO - B的完全抑制有关。
