Nikiforuk Agnieszka, Hołuj Małgorzata, Potasiewicz Agnieszka, Popik Piotr
Department of Behavioral Neuroscience and Drug Development, Institute of Pharmacology, Polish Academy of Sciences, Krakow, Poland.
Department of Behavioral Neuroscience and Drug Development, Institute of Pharmacology, Polish Academy of Sciences, Krakow, Poland.
Behav Brain Res. 2015 Aug 1;289:149-56. doi: 10.1016/j.bbr.2015.04.030. Epub 2015 Apr 27.
The antagonists of serotonin 5-HT7 receptors have been demonstrated to ameliorate cognitive impairments in pharmacological animal models of schizophrenia that involve blockade of N-methyl-D-aspartate receptors (NMDARs). The administration of NMDAR antagonists evokes a broad range of cognitive deficits, including a loss of impulse control. The involvement of 5-HT7 receptors in the modulation of impulsivity has been recently suggested but has not been studied in great detail. The aim of the present study was to examine the effect of a selective 5-HT7 receptor antagonist SB-269970 on a measure of impulsive action, i.e., premature responding on the five-choice serial reaction time task (5-CSRTT) in rats. The antagonist of 5-HT2A receptor M100,907 was used as a positive control. The efficacies of both compounds were assessed in conditions of increased impulsivity that were produced by the administration of the NMDAR antagonist MK-801 or/and non-drug stimuli, i.e., using variable inter-trial intervals (vITIs). To examine the general ability of SB-269970 to counteract the MK-801-induced impairments, a discrete paired-trial delayed alternation task in a T-maze was employed. MK-801 significantly increased the number of premature responses in 5-CSRTT, and this effect was abolished by the administration of M100,907 (0.5 mg/kg) and SB-269970 (1 mg/kg). In addition, M100,907, but not SB-269970, reduced premature responding in the prolonged ITI trials. Both M100,907 and SB-269970 attenuated MK-801-induced working memory impairment in a T-maze. The present study demonstrated the efficacy of SB-269970 against MK-801-induced premature responding in the 5-CSRTT. This anti-impulsive action may offer additional benefits to the cognitive-enhancing effects of pharmacological blockade of 5-HT7 receptors.
血清素5-HT7受体拮抗剂已被证明可改善精神分裂症药理学动物模型中的认知障碍，这些模型涉及N-甲基-D-天冬氨酸受体（NMDARs）的阻断。给予NMDAR拮抗剂会引发广泛的认知缺陷，包括冲动控制能力丧失。最近有人提出5-HT7受体参与冲动调节，但尚未进行详细研究。本研究的目的是检查选择性5-HT7受体拮抗剂SB-269970对冲动行为测量指标的影响，即大鼠在五选择连续反应时任务（5-CSRTT）中的过早反应。5-HT2A受体拮抗剂M100,907用作阳性对照。在由给予NMDAR拮抗剂MK-801或/和非药物刺激（即使用可变的试验间隔（vITIs））产生的冲动增加的条件下评估两种化合物的疗效。为了检查SB-269970对抗MK-801诱导的损伤的一般能力，采用了T迷宫中的离散配对试验延迟交替任务。MK-801显著增加了5-CSRTT中的过早反应数量，而给予M100,907（0.5mg/kg）和SB-269970（1mg/kg）可消除这种效应。此外，M100,907而非SB-269970减少了延长ITI试验中的过早反应。M100,907和SB-269970均减轻了MK-801诱导的T迷宫工作记忆损伤。本研究证明了SB-269970对MK-801诱导的5-CSRTT过早反应的疗效。这种抗冲动作用可能为5-HT7受体药理学阻断的认知增强作用提供额外益处。
