Letty S, Child R, Dumuis A, Pantaloni A, Bockaert J, Rondouin G
Laboratoire de Médecine Expérimentale, Inserm U 249, CNRS 9008, Institut de Biologie, Montpellier, France.
Neuropharmacology. 1997 Apr-May;36(4-5):681-7. doi: 10.1016/s0028-3908(96)00169-4.
Serotonin (5-HT) is involved in a large variety of physiological functions and it appears now that it could play a role in cognitive processes through the activation of 5-HT4 receptors. The present study was conducted to determine the effect of BIMU1, a mixed 5-HT4 agonist/5-HT3 antagonist on social olfactory recognition in rats, a behaviour test which has previously been shown to access short-term memory and to be sensitive to cholinergic drugs. This test is based on the investigation of an unfamiliar juvenile by an adult rat during two distinct 5-min presentations. At a 30-min delay after each presentation adults recognized the juvenile, whereas after a 2-hr delay all the adults had forgotten it. When administered intraperitoneally immediately after the first presentation, BIMU1 (10 mg/kg) enhanced short-term memory (i.e. recognition of the juvenile after a 2-hr delay). Ondansetron (10 and 100 micrograms/kg injected intraperitoneally), a 5-HT3 antagonist, had no significant effect on this form of memory. The effect of BIMU1 was antagonized by intraperitoneal injection of GR 125487, a very selective and potent 5-HT4 antagonist. The antagonistic effect was obtained at 1 and 10 mg/kg of GR 125487, but not at 0.1 mg/kg. It is certainly a specific effect on brain 5-HT4 receptors, since we determined a brain concentration of GR 125487 equal to 3.8 x 10(-7) M after the intraperitoneal injection of 10 mg/kg of this drug. This GR 125487 concentration is certainly sufficient to occupy all the 5-HT4 brain receptors (Kd = 10(-10) M) but not to occupy 5-HT3 receptors (Kd > 10(-6) M). The 5-HT4 specificity of the blockade by GR 125487 is further demonstrated by the fact that a 10-fold lower dose of GR 125487 (1 mg/kg) is also effective to inhibit the BIMU1 effect.
血清素（5-羟色胺，5-HT）参与多种生理功能，目前看来它可能通过激活5-HT4受体在认知过程中发挥作用。本研究旨在确定BIMU1（一种5-HT4激动剂/5-HT3拮抗剂）对大鼠社会嗅觉识别的影响，社会嗅觉识别是一种行为测试，此前已证明该测试可用于评估短期记忆且对胆碱能药物敏感。该测试基于成年大鼠在两个不同的5分钟展示过程中对陌生幼鼠的探究。每次展示后30分钟，成年大鼠能识别幼鼠，而在2小时延迟后，所有成年大鼠都已忘记。首次展示后立即腹腔注射BIMU1（10毫克/千克）可增强短期记忆（即2小时延迟后对幼鼠的识别）。昂丹司琼（腹腔注射10和100微克/千克），一种5-HT3拮抗剂，对这种记忆形式无显著影响。腹腔注射GR 125487（一种非常选择性且强效的5-HT4拮抗剂）可拮抗BIMU1的作用。腹腔注射10毫克/千克该药物后，1毫克/千克和10毫克/千克的GR 125487可产生拮抗作用，但0.1毫克/千克则无此作用。这肯定是对脑5-HT4受体的特异性作用，因为我们测定腹腔注射10毫克/千克该药物后，脑内GR 125487浓度等于3.8×10⁻⁷ M。该GR 125487浓度肯定足以占据所有脑5-HT4受体（解离常数Kd = 10⁻¹⁰ M），但不足以占据5-HT3受体（Kd > 10⁻⁶ M）。GR 125487阻断作用的5-HT4特异性进一步通过以下事实得到证明：低10倍剂量的GR 125487（1毫克/千克）也可有效抑制BIMU1的作用。
