Serotonin 2A (5-HT_2A) receptors are the primary site of action of hallucinogenic drugs and the target of atypical antipsychotics. 5-HT_2A receptors are also implicated in executive function, including behavioral flexibility. Previous studies showed that 5-HT_2A receptor blockade improved behavioral flexibility in rodent models related to autism spectrum disorder and schizophrenia. The current study instead was conducted to examine the impact of acute 5-HT_2A receptor activation on behavior flexibility in the control C57BL/6 J strain. Because of the therapeutic potential of serotonergic hallucinogens and the unknown impact of many of these compounds on cognition, the present study examined how the 5-HT_2A/2C agonist 1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane (DOI) and the more selective 5-HT_2A agonist 25CN-NBOH impacted behavioral flexibility in C57BL/6 J mice. Male mice were tested on a probabilistic spatial discrimination and reversal learning task after an intraperitoneal injection of vehicle, 2.5 mg/kg DOI, 1.0 mg/kg 25CN-NBOH, 1.0 mg/kg of the 5-HT_2C receptor antagonist SER-082 or combined treatment with SER-082 (1.0 mg/kg) and 2.5 mg/kg DOI before testing of probabilistic reversal learning. All groups demonstrated comparable performance on the initial spatial discrimination, i.e. similar trials to criterion. DOI alone did not impair reversal learning, whereas 25CN-NBOH increased the number of trials to criterion during reversal learning. Because 5-HT_2A and 5-HT_2C receptors have been shown to functionally antagonize each other in several behavioral paradigms, we also tested whether blockade of 5-HT_2C receptors would unmask 5-HT_2A receptor activation by DOI and impair reversal learning. Mice treated with SER-082 in combination with DOI required significantly more trials to reach criterion. In an additional experiment, a dose response experiment with 25CN-NBOH revealed that the 1.0 mg/kg dose tested in reversal learning did not affect locomotor activity. Together, these findings indicate that activation of 5-HT_2A receptors impairs probabilistic reversal learning and that 5-HT_2A and 5-HT_2C receptors exert opposing effects on behavioral flexibility in male mice.

血清素 2A (5-HT _2A ) 受体是致幻药物的主要作用部位，也是非典型抗精神病药物的靶点。5-HT _2A受体也涉及执行功能，包括行为灵活性。先前的研究表明，5-HT _2A受体阻断剂改善了与自闭症谱系障碍和精神分裂症相关的啮齿动物模型的行为灵活性。相反，目前的研究是为了检查急性 5-HT _2A受体激活对对照 C57BL/6 J 菌株的行为灵活性的影响。由于血清素能致幻剂的治疗潜力以及许多这些化合物对认知的未知影响，本研究检查了 5-HT _2A/2C激动剂 1-(2,5-二甲氧基-4-碘苯基)-2-氨基丙烷 (DOI) 和更具选择性的 5-HT _2A激动剂 25CN-NBOH 影响 C57BL/6 J 小鼠的行为灵活性。在腹腔注射赋形剂、2.5 mg/kg DOI、1.0 mg/kg 25CN-NBOH、1.0 mg/kg 5-HT _2C受体拮抗剂 SER-082 或在测试概率逆转学习之前，与 SER-082 (1.0 mg/kg) 和 2.5 mg/kg DOI 联合治疗。所有组在初始空间辨别上表现出可比的表现，即与标准相似的试验。仅 DOI 不会损害反向学习，而 25CN-NBOH 在反向学习期间将试验次数增加到标准。因为 5-HT _2A5-HT _2C受体和 5-HT _2C受体已被证明在几种行为范式中在功能上相互拮抗，我们还测试了 5-HT _2C受体的阻断是否会揭示DOI 对5-HT _2A受体的激活并损害逆转学习。用 SER-082 与 DOI 组合治疗的小鼠需要更多的试验才能达到标准。在另一个实验中，使用 25CN-NBOH 进行的剂量反应实验表明，在反向学习中测试的 1.0 mg/kg 剂量不会影响运动活动。总之，这些发现表明 5-HT _2A受体的激活会损害概率逆转学习，并且 5-HT _2A和 5-HT _2C 受体对雄性小鼠的行为灵活性产生相反的影响。