Dalton G L, Lee M D, Kennett G A, Dourish C T, Clifton P G
Department of Psychology, Sussex University, Brighton BN1 9QG, UK.
Neuropharmacology. 2004 Apr;46(5):663-71. doi: 10.1016/j.neuropharm.2003.11.012.
The serotonin receptor agonist mCPP induces hyperlocomotion in 5-HT2C receptor knockout (KO) mice or in the presence of a 5-HT2C receptor antagonist. In the present group of experiments, we evaluate the role of 5-HT1A, 5-HT1B and 5-HT2A receptors in mCPP-induced hyperactivity in 5-HT2C KO mice. We also assess the ability of agonists at these receptors to induce hyperactivity in wildtype (WT) mice pre-treated with a selective 5-HT2C receptor antagonist. As previously reported, mCPP (3 mg/kg) induced hyperactivity in 5-HT2C KO mice. A combination of the 5-HT1B receptor agonist CP-94,253 (20 mg/kg) and the 5-HT1A receptor agonist 8-OH-DPAT (0.5 mg/kg) induced marked hyperactivity in WT but not in 5-HT2C KO mice, nor in mice treated with the selective 5-HT2C receptor antagonist, SB 242084 (1.5 mg/kg). Neither CP-94,253 nor 8-OH-DPAT had any intrinsic effect on locomotion in WTs. mCPP-induced hyperactivity was attenuated in 5-HT2C KO mice by the 5-HT1B receptor antagonist SB 224289 (2.5 mg/kg), and the 5-HT2A receptor antagonists ketanserin (0.3 mg/kg) and M100907 (0.01 mg/kg) but not by the 5-HT1A receptor antagonist WAY 100635 (1 mg/kg). The 5-HT(2A/2B/2C) receptor agonist, Ro 60-0175 (3 mg/kg), induced a modest increase in locomotor activity in WT mice pre-treated with SB 242084. However, the combination of Ro 60-0175 with CP-94,253 induced a substantial increase in activity in 5-HT2C KO mice, an effect comparable to mCPP-induced hyperactivity. Thus, joint activation of 5-HT1A and 5-HT1B receptors stimulates locomotion in WT mice but this response is dependent on a functional 5-HT2C receptor population and hence is absent in 5-HT2C KO mice. By contrast, mCPP-induced hyperactivity depends on the inactivation of a separate 5-HT2C receptor population and is mediated by 5-HT2A and 5-HT1B receptor activation.
血清素受体激动剂mCPP在5-HT2C受体基因敲除（KO）小鼠中或存在5-HT2C受体拮抗剂时会诱发活动亢进。在本组实验中，我们评估了5-HT1A、5-HT1B和5-HT2A受体在mCPP诱导的5-HT2C KO小鼠活动亢进中的作用。我们还评估了这些受体的激动剂在经选择性5-HT2C受体拮抗剂预处理的野生型（WT）小鼠中诱发活动亢进的能力。如先前报道，mCPP（3毫克/千克）在5-HT2C KO小鼠中诱发活动亢进。5-HT1B受体激动剂CP-94,253（20毫克/千克）和5-HT1A受体激动剂8-OH-DPAT（0.5毫克/千克）联合使用在WT小鼠中诱发了明显的活动亢进，但在5-HT2C KO小鼠中以及在用选择性5-HT2C受体拮抗剂SB 242084（1.5毫克/千克）处理的小鼠中未诱发。CP-94,253和8-OH-DPAT对WT小鼠的运动均无内在影响。5-HT1B受体拮抗剂SB 224289（2.5毫克/千克）、5-HT2A受体拮抗剂酮色林（0.3毫克/千克）和M100907（0.01毫克/千克）可减弱mCPP在5-HT2C KO小鼠中诱发的活动亢进，但5-HT1A受体拮抗剂WAY 100635（1毫克/千克）则无此作用。5-HT(2A/2B/2C)受体激动剂Ro 60-0175（3毫克/千克）在用SB 242,084预处理的WT小鼠中使运动活性适度增加。然而，Ro 60-0175与CP-94,253联合使用在5-HT2C KO小鼠中使活动大幅增加，其效果与mCPP诱发的活动亢进相当。因此，5-HT1A和5-HT1B受体的联合激活刺激WT小鼠的运动，但这种反应依赖于功能性5-HT2C受体群体，因此在5-HT2C KO小鼠中不存在。相比之下，mCPP诱发的活动亢进依赖于另一群5-HT2C受体的失活，并由5-HT2A和5-HT1B受体的激活介导。
