Sotty Florence, Damgaard Trine, Montezinho Liliana P, Mørk Arne, Olsen Christina K, Bundgaard Christoffer, Husum Henriette
Department of Neurophysiology, H. Lundbeck A/S, Valby, Denmark.
J Pharmacol Exp Ther. 2009 Mar;328(3):951-62. doi: 10.1124/jpet.108.146944. Epub 2008 Dec 19.
Dopaminergic (DAergic) neurons in the ventral tegmental area express both KCNQ2 and KCNQ4 channels, which opening is expected to decrease neuronal excitability via neuronal hyper-polarization. Because psychotic symptoms are believed to be associated with an increased excitability of dopamine (DA) cells in the mesencephalon, KCNQ channels might represent a new potential target for the treatment of psychosis. The aim of our study was to investigate the antipsychotic-like potential of KCNQ channel opening via modulation of neuronal activity within the mesolimbic DAergic system. We report that retigabine [N-(2-amino-4-(fluorobenzylamino)-phenyl)carbamic acid ester], a KCNQ opener, dose-dependently reduced basal DA firing rate and more potently suppressed burst firing activity in the ventral tegmental area, whereas XE-991 [10,10-bis(pyridinylmethyl)-9(10H)-anthracenone], a selective KCNQ blocker, induced opposite effects. In addition, retigabine prevented d-amphetamine-induced DA efflux in the nucleus accumbens and d-amphetamine-induced locomotor hyperactivity. In contrast, XE-991 potentiated both the locomotor hyperactivity and DA efflux evoked by d-amphetamine. These data strongly suggest that the activation of KCNQ channels attenuates DAergic neurotransmission in the mesolimbic system, particularly in conditions of excessive DAergic activity. In a model predictive of antipsychotic activity, the conditioned avoidance response paradigm, retigabine was found to inhibit avoidance responses, an effect blocked by coadministration of XE-991. Furthermore, retigabine was found to significantly inhibit the hyperlocomotor response to a phencyclidine (PCP) challenge in PCP-sensitized animals, considered as a disease model for schizophrenia. Taken together, our studies provide evidence that KCNQ channel openers represent a potential new class of antipsychotics.
腹侧被盖区的多巴胺能（DAergic）神经元同时表达KCNQ2和KCNQ4通道，其开放预计会通过神经元超极化降低神经元兴奋性。由于精神症状被认为与中脑多巴胺（DA）细胞兴奋性增加有关，KCNQ通道可能代表治疗精神病的一个新的潜在靶点。我们研究的目的是通过调节中脑边缘多巴胺能系统内的神经元活动来研究KCNQ通道开放的抗精神病样潜力。我们报告，瑞替加滨[N-(2-氨基-4-(氟苄基氨基)-苯基]氨基甲酸酯]，一种KCNQ开放剂，剂量依赖性地降低基础DA放电率，并更有效地抑制腹侧被盖区的爆发性放电活动，而XE-991[10,10-双(吡啶基甲基)-9(10H)-蒽酮]，一种选择性KCNQ阻滞剂，产生相反的作用。此外，瑞替加滨可预防d-苯丙胺诱导的伏隔核DA外流和d-苯丙胺诱导的运动亢进。相反，XE-991增强了d-苯丙胺诱发的运动亢进和DA外流。这些数据强烈表明，KCNQ通道激活减弱了中脑边缘系统中的多巴胺能神经传递，特别是在多巴胺能活动过度时。在一个预测抗精神病活性模型即条件性回避反应范式中发现，瑞替加滨可抑制回避反应，但这种作用可被同时给予XE-991阻断。此外，在被视为精神分裂症疾病模型的苯环利定（PCP）致敏动物中，发现瑞替加滨可显著抑制对PCP激发的运动亢进反应。综上所述，我们的研究提供证据表明KCNQ通道开放剂代表一类潜在的新型抗精神病药
