Corbett R, Hartman H, Kerman L L, Woods A T, Strupczewski J T, Helsley G C, Conway P C, Dunn R W
Department of Biological Research, Hoechst-Roussel Pharmaceuticals, Inc., Somerville, NJ 08876.
Pharmacol Biochem Behav. 1993 May;45(1):9-17. doi: 10.1016/0091-3057(93)90079-9.
There are numerous preclinical screening procedures that are predictive of clinical efficacy for the positive symptoms of schizophrenia but no assays for the negative symptoms such as social withdrawal. In the social interaction test in rats, the atypical antipsychotic drug clozapine (10.0 mg/kg) and two putative atypical agents risperidone (0.0625 mg/kg) and HP 873 (0.5 and 1.0 mg/kg) significantly increased social interaction behaviors between pairs of unfamiliar but not familiar rats. The benzodiazepine diazepam (1.25-5.0 mg/kg) increased social behaviors in both paradigms. Haloperidol, chlorpromazine, raclopride, and SCH23390 decreased social behaviors in these assays. In vitro receptor binding studies revealed that only clozapine, risperidone, and HP 873 displayed dopamine to serotonin affinity ratios for both D2/5-hydroxytryptamine2(5-HT2)/ and D1/5-HT1A of greater than or equal to 12.9 and 1.0, respectively. The present study suggests that antipsychotic agents that may be effective in social withdrawal can be identified in this modified social interaction paradigm. Further, our data suggests that a compound's effectiveness for the treatment of social withdrawal is at least in part due to its relative affinity for binding to dopamine D1 and serotonin 5-HT1A receptors.
有许多临床前筛查程序可预测精神分裂症阳性症状的临床疗效，但对于诸如社交退缩等阴性症状却没有检测方法。在大鼠社交互动试验中，非典型抗精神病药物氯氮平（10.0毫克/千克）以及两种假定的非典型药物利培酮（0.0625毫克/千克）和HP 873（0.5和1.0毫克/千克）显著增加了陌生但非熟悉大鼠对之间的社交互动行为。苯二氮䓬类药物地西泮（1.25 - 5.0毫克/千克）在两种模式下均增加了社交行为。氟哌啶醇、氯丙嗪、雷氯必利和SCH23390在这些试验中降低了社交行为。体外受体结合研究表明，只有氯氮平、利培酮和HP 873的多巴胺与5-羟色胺2（5-HT2）以及D1与5-HT1A的亲和力比值分别大于或等于12.9和1.0。本研究表明，在这种改良的社交互动范式中可以识别出可能对社交退缩有效的抗精神病药物。此外，我们的数据表明，一种化合物对社交退缩治疗的有效性至少部分归因于其与多巴胺D1和5-羟色胺5-HT1A受体结合的相对亲和力。
