ANTIDEPRESSANT-TYPE EFFECTS OF ENDOGENOUS ENKEPHALINS PROTECTED BY SYSTEMIC RB-101 ARE MEDIATED BY OPIOID-DELTA AND DOPAMINE-D1 RECEPTOR STIMULATION
ANTIDEPRESSANT-TYPE EFFECTS OF ENDOGENOUS ENKEPHALINS PROTECTED BY SYSTEMIC RB-101 ARE MEDIATED BY OPIOID-DELTA AND DOPAMINE-D1 RECEPTOR STIMULATION
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DOI：
10.1016/0014-2999(92)90356-9
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发表时间：
1992-06-05
影响因子：
5
通讯作者：
ROQUES, BP
中科院分区：
文献类型：
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作者：
BAAMONDE, A;DAUGE, V;ROQUES, BP
通过静脉注射rb101 (N-[(R，S)-2-苄基-3[（S)（2-氨基-4-甲基硫）丁基二硫]-1-氧丙基]- l-苯丙氨酸苄酯）研究内源性脑啡肽在小鼠行为控制中的作用。RB 101是最近报道的代谢脑啡肽中性内肽酶24.11和氨基肽酶n的两种酶的系统活性混合抑制剂前药。RB 101 （2.5-10 mg/kg）诱导小鼠在24小时前受到足震的环境中产生剂量依赖性的长期过度运动，并减轻运动的条条性抑制。此外，RB 101在强迫游泳试验中减少了不活动的持续时间。所有这些RB 101的作用都被选择性δ受体拮抗剂纳曲多所拮抗，支持δ受体优先参与这些脑啡肽控制的行为反应。先前给予选择性多巴胺D1拮抗剂SCH 23390也能抑制RB 101诱导的效应，而D2拮抗剂舒必利则不能。运动条件抑制的减弱与纹状体二羟基苯基乙酸(DOPAC)/多巴胺（DA）和同型香草酸(HVA)/DA比值的增加有关，这两种作用均可被纳曲多拮抗。后一种化合物也能有效抑制丙咪嗪在小鼠强迫游泳试验中的作用。综上所述，这些结果支持内源性脑啡肽通过刺激δ和D1受体对情绪相关行为进行强直性和阶段性控制，并提示未来可能使用这些混合抑制剂作为新的抗抑郁药。
The role of endogenous enkephalins in behavioural control in mice was investigated by i.v. injection of RB 101 (N-[(R,S)-2-benzyl-3[(S)(2-amino-4-methylthio)butyl dithio]-1-oxopropyl]-L-phenylalanine benzyl ester). RB 101 is a recently reported systemically active mixed inhibitor prodrug of the two enzymes which metabolize the enkephalins neutral endopeptidase 24.11 and aminopeptidase N. RB 101 (2.5-10 mg/kg) induced a dose-dependent long-lasting hyperlocomotion and attenuated the conditioned suppression of motility in mice placed in an environment where they had received footshocks 24 h before. In addition, RB 101 decreased the duration of immobility in the forced swim test. All these actions of RB 101 were antagonized by the selective delta antagonist, naltrindole, supporting the preferential involvement of delta opioid receptors in these enkephalin-controlled behavioural responses. The effects induced by RB 101 were also suppressed by prior administration of the selective dopamine D1 antagonist, SCH 23390, but not by the D2 antagonist, sulpiride. Attenuation of the conditioned suppression of motility was associated with increased striatal dihydroxyphenylacetic acid (DOPAC)/dopamine (DA) and homovanillic acid (HVA)/DA ratios, both effects being antagonized by naltrindole. This latter compound is also efficient to inhibit the effect of imipramine in the mouse forced swim test. Taken together, these results support the occurrence of tonic and phasic controls of mood-related behaviour by endogenous enkephalins through delta and D1 receptor stimulation and suggest a possible future use of these mixed inhibitors as new antidepressants.