Southam Eric, Cilia Jackie, Gartlon Jane E, Woolley Marie L, Lacroix Laurent P, Jennings Carol A, Cluderay Jane E, Reavill Charlie, Rourke Claire, Wilson David M, Dawson Lee A, Medhurst Andrew D, Jones Declan N C
GlaxoSmithKline, New Frontiers Science Park (North), Third Avenue, Harlow, Essex, CM195AW, UK.
Psychopharmacology (Berl). 2009 Jan;201(4):483-94. doi: 10.1007/s00213-008-1310-9. Epub 2008 Sep 3.
To test the novel nonimidazole histamine H3 receptor antagonist 5-[(3-cyclobutyl-2,3,4,5-tetrahydro-1H-3-benzazapin-7-yl)oxy]-N-methyl-2-pyrazinecarboxamide (GSK207040) in a series of behavioral and neurochemical paradigms designed to evaluate its antipsychotic potential.
Acute orally administered GSK207040 was investigated for its capacity to reverse a 24-h-induced deficit in novel object recognition memory, deficits in prepulse inhibition (PPI) induced by isolation rearing, and hyperlocomotor activity induced by amphetamine. The acute neurochemical effects of GSK207040 were explored by analyzing rat anterior cingulate cortex microdialysates for levels of dopamine, noradrenaline, and acetylcholine and by c-fos immunohistochemistry. The potential for interaction with the antipsychotic dopamine D2 receptor antagonist haloperidol was explored behaviorally (spontaneous locomotor activity and catalepsy), biochemically (plasma prolactin), and via ex vivo receptor occupancy determinations.
GSK207040 significantly enhanced object recognition memory (3 mg/kg) and attenuated isolation rearing-induced deficits in PPI (1.0 and 3.2 mg/kg) but did not reverse amphetamine-induced increases in locomotor activity. There was no evidence of an interaction of GSK207040 with haloperidol. GSK207040 (3.2 mg/kg) raised extracellular concentrations of dopamine, noradrenaline, and acetylcholine in the anterior cingulate cortex and c-fos expression in the core of the nucleus accumbens was increased at doses of 3.2 and 10.0 mg/kg.
The behavioral and neurochemical profile of GSK207040 supports the potential of histamine H3 receptor antagonism to treat the cognitive and sensory gating deficits of schizophrenia. However, the failure of GSK207040 to reverse amphetamine-induced locomotor hyperactivity suggests that the therapeutic utility of histamine H(3) receptor antagonism versus positive symptoms is less likely, at least following acute administration.
在一系列旨在评估新型非咪唑类组胺H3受体拮抗剂5-[(3-环丁基-2,3,4,5-四氢-1H-3-苯并氮杂卓-7-基)氧基]-N-甲基-2-吡嗪甲酰胺（GSK207040）抗精神病潜力的行为学和神经化学范式中对其进行测试。
研究急性口服GSK207040逆转24小时诱导的新物体识别记忆缺陷、隔离饲养诱导的前脉冲抑制（PPI）缺陷以及苯丙胺诱导的运动活动亢进的能力。通过分析大鼠前扣带回皮质微透析液中多巴胺、去甲肾上腺素和乙酰胆碱的水平以及c-fos免疫组织化学来探究GSK207040的急性神经化学作用。通过行为学（自发运动活动和僵住症）、生物化学（血浆催乳素）以及离体受体占有率测定来探究与抗精神病多巴胺D2受体拮抗剂氟哌啶醇相互作用的可能性。
GSK207040显著增强物体识别记忆（3毫克/千克）并减轻隔离饲养诱导的PPI缺陷（1.0和3.2毫克/千克），但未逆转苯丙胺诱导的运动活动增加。没有证据表明GSK207040与氟哌啶醇存在相互作用。GSK207040（3.2毫克/千克）提高了前扣带回皮质中多巴胺、去甲肾上腺素和乙酰胆碱的细胞外浓度，并且在3.2和10.0毫克/千克剂量下伏隔核核心中的c-fos表达增加。
GSK207040的行为学和神经化学特征支持组胺H3受体拮抗作用治疗精神分裂症认知和感觉门控缺陷的潜力。然而，GSK207040未能逆转苯丙胺诱导的运动活动亢进表明，至少在急性给药后，组胺H3受体拮抗作用对阳性症状的治疗效用较小。
