Depoortère R, Auclair A L, Bardin L, Bruins Slot L, Kleven M S, Colpaert F, Vacher B, Newman-Tancredi A
Division of Neurobiology 2, Centre de Recherche Pierre Fabre, Castres, France.
Br J Pharmacol. 2007 May;151(2):266-77. doi: 10.1038/sj.bjp.0707160. Epub 2007 Mar 20.
The D(2)/D(3) receptor antagonist, D(4) receptor partial agonist, and high efficacy 5-HT(1A) receptor agonist F15063 was shown to be highly efficacious and potent in rodent models of activity against positive symptoms of schizophrenia. However F15063 induced neither catalepsy nor the 'serotonin syndrome'. Here, we evaluated its profile in rat models predictive of efficacy against negative symptoms/cognitive deficits of schizophrenia.
F15063, given i.p., was assessed in models of behavioural deficits induced by interference with the NMDA/glutamatergic (phencyclidine: PCP) or cholinergic (scopolamine) systems.
Through 5-HT(1A) activation, F15063 partially alleviated (MED: 0.04 mg kg(-1)) PCP-induced social interaction deficit between two adult rats, without effect by itself, underlining its potential to combat negative symptoms. At doses above 0.16 mg kg(-1), F15063 reduced interaction by itself. F15063 (0.16 mg kg(-1)) selectively re-established PCP-impaired 'cognitive flexibility' in a reversal learning task, suggesting potential against adaptability deficits. F15063 (0.04-0.63 mg kg(-1)) also reversed scopolamine-induced amnesia in a juvenile-adult rat social recognition test, indicative of a pro-cholinergic influence. Activity in this latter test is consistent with its D(4) partial agonism, as it was blocked by the D(4) antagonist L745,870. Finally, F15063 up to 40 mg kg(-1) did not disrupt basal prepulse inhibition of startle reflex in rats, a marker of sensorimotor gating.
The balance of D(2)/D(3), D(4) and 5-HT(1A) receptor interactions of F15063 yields a promising profile of activity in models of cognitive deficits and negative symptoms of schizophrenia.
D(2)/D(3)受体拮抗剂、D(4)受体部分激动剂及高效5-HT(1A)受体激动剂F15063在啮齿动物模型中对精神分裂症阳性症状具有高效且强效的抗活性。然而，F15063既不诱发僵住症也不引发“血清素综合征”。在此，我们在预测对精神分裂症阴性症状/认知缺陷疗效的大鼠模型中评估了其特征。
腹腔注射给予F15063，在由干扰NMDA/谷氨酸能（苯环利定：PCP）或胆碱能（东莨菪碱）系统诱导的行为缺陷模型中进行评估。
通过5-HT(1A)激活，F15063部分缓解了（半数有效量：0.04 mg kg(-1)）PCP诱导的两只成年大鼠之间的社交互动缺陷，其自身无此作用，突显了其对抗阴性症状的潜力。在剂量高于0.16 mg kg(-1)时，F15063自身会减少互动。F15063（0.16 mg kg(-1)）在反转学习任务中选择性地恢复了PCP损害的“认知灵活性”，提示其对适应性缺陷具有潜在作用。F15063（0.04 - 0.63 mg kg(-1)）在幼龄 - 成年大鼠社交识别试验中也逆转了东莨菪碱诱导的失忆，表明其具有促胆碱能影响。后一试验中的活性与其D(4)部分激动作用一致，因为它被D(4)拮抗剂L745,870阻断。最后，高达40 mg kg(-1)的F15063并未破坏大鼠惊吓反射的基础前脉冲抑制，这是感觉运动门控的一个指标。
F15063的D(2)/D(3)受体、D(4)受体和5-HT(1A)受体相互作用的平衡在精神分裂症认知缺陷和阴性症状模型中产生了有前景且积极的特征。
