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首页> 外文期刊>Behavioural pharmacology >Pharmacological profiles in rats of novel antipsychotics with combined dopamine D2/serotonin 5-HT1A activity: comparison with typical and atypical conventional antipsychotics.
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Pharmacological profiles in rats of novel antipsychotics with combined dopamine D2/serotonin 5-HT1A activity: comparison with typical and atypical conventional antipsychotics.

机译：具有多巴胺D2 / 5-羟色胺5-HT1A活性的新型抗精神病药在大鼠中的药理作用：与典型和非典型常规抗精神病药的比较。

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摘要

Combining antagonist/partial agonist activity at dopamine D2 and agonist activity at serotonin 5-HT1A receptors is one of the approaches that has recently been chosen to develop new generation antipsychotics, including bifeprunox, SSR181507 and SLV313. There have been, however, few comparative data on their pharmacological profiles. Here, we have directly compared a wide array of these novel dopamine D2/5-HT1A and conventional antipsychotics in rat models predictive of antipsychotic activity. Potency of antipsychotics to antagonize conditioned avoidance, methylphenidate-induced behaviour and D-amphetamine-induced hyperlocomotion correlated with their affinity at dopamine D2 receptors. Potency against ketamine-induced hyperlocomotion was independent of affinity at dopamine D2 or 5-HT1A receptors. Propensity to induce catalepsy, predictive of occurrence of extrapyramidal side effects, was inversely related to affinity at 5-HT1A receptors. As a result, preferential D2/5-HT1A antipsychotics displayed a large separation between doses producing 'antipsychotic-like' vs. cataleptogenic actions. These data support the contention that 5-HT1A receptor activation greatly reduces or prevents the cataleptogenic potential of novel antipsychotics. They also emphasize that interactions at 5-HT1A and D2 receptors, and the nature of effects (antagonism or partial agonism) at the latter has a profound influence on pharmacological activities, and is likely to affect therapeutic profiles.
机译：将对多巴胺D2的拮抗剂/部分激动剂活性与对5-羟色胺5-HT1A受体的激动剂活性相结合，是最近被选择开发新一代抗精神病药的方法之一，包括比非普仑，SSR181507和SLV313。但是，关于它们的药理作用的比较数据很少。在这里，我们直接在预测抗精神病活性的大鼠模型中比较了这些新型多巴胺D2 / 5-HT1A和常规抗精神病药物的种类。抗精神病药拮抗条件回避，哌醋甲酯诱导的行为和D-苯异丙胺诱导的运动过度的能力与其对多巴胺D2受体的亲和力相关。针对氯胺酮诱导的运动过度的能力独立于对多巴胺D2或5-HT1A受体的亲和力。可以预测到锥体束外副作用的发生，导致僵直的倾向与对5-HT1A受体的亲和力成反比。结果，优先的D2 / 5-HT1A抗精神病药在产生“类抗精神病药”作用和致病原作用的剂量之间显示出很大的距离。这些数据支持以下观点：5-HT1A受体激活会大大降低或阻止新型抗精神病药的致晕作用。他们还强调，在5-HT1A和D2受体上的相互作用以及对后者的作用性质（拮抗作用或部分激动作用）对药理活性具有深远的影响，并且可能会影响治疗效果。

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