Department of Psychiatry, Mount Sinai School of Medicine, New York, NY 10029, USA.
Psychopharmacology (Berl). 2013 Jan;225(1):217-26. doi: 10.1007/s00213-012-2809-7. Epub 2012 Jul 28.
In schizophrenia patients, optimal treatment with antipsychotics requires weeks to months of sustained drug therapy. However, single administration of antipsychotic drugs can reverse schizophrenia-like behavioral alterations in rodent models of psychosis. This raises questions about the physiological relevance of such antipsychotic-like activity.
This study evaluates the effects of chronic treatment with clozapine on the cellular and behavioral responses induced by the hallucinogenic serotonin 5-HT(2A) receptor agonist lysergic acid diethylamide (LSD) as a mouse model of psychosis.
Mice were treated chronically (21 days) with 25 mg/kg/day clozapine. Experiments were conducted 1, 7, 14, and 21 days after the last clozapine administration. [(3)H]Ketanserin binding and 5-HT ( 2A ) mRNA expression were determined in mouse somatosensory cortex. Head-twitch behavior, expression of c-fos, which is induced by all 5-HT(2A) agonists, and expression of egr-1 and egr-2, which are LSD-like specific, were assayed.
Head-twitch response was decreased and [(3)H]ketanserin binding was downregulated in 1, 7, and 14 days after chronic clozapine. 5-HT ( 2A ) mRNA was reduced 1 day after chronic clozapine. Induction of c-fos, but not egr-1 and egr-2, was rescued 7 days after chronic clozapine. These effects were not observed after short treatment (2 days) with clozapine or chronic haloperidol (1 mg/kg/day).
Our findings provide a murine model of chronic atypical antipsychotic drug action and suggest downregulation of the 5-HT(2A) receptor as a potential mechanism involved in these persistent therapeutic-like effects.
在精神分裂症患者中，抗精神病药物的最佳治疗需要数周至数月的持续药物治疗。然而，抗精神病药物的单次给药可以逆转精神分裂症样行为改变在精神病的啮齿动物模型。这就提出了一个问题，即这种抗精神病样活性的生理相关性。
本研究评估氯氮平慢性治疗对致幻性 5-羟色胺 5-HT（2A）受体激动剂麦角酸二乙酰胺（LSD）诱导的细胞和行为反应的影响，作为一种精神分裂症的小鼠模型。
小鼠用 25mg/kg/天氯氮平慢性治疗（21 天）。实验在最后一次氯氮平给药后 1、7、14 和 21 天进行。在小鼠体感皮层中测定 [(3)H]酮色林结合和 5-HT（2A）mRNA 表达。进行头部抽搐行为，所有 5-HT（2A）激动剂诱导的 c-fos 的表达，以及 LSD 样特异的 egr-1 和 egr-2 的表达进行测定。
慢性氯氮平后 1、7 和 14 天，头部抽搐反应减少，[(3)H]酮色林结合下调。慢性氯氮平后 1 天 5-HT（2A）mRNA 减少。慢性氯氮平后 7 天，c-fos 的诱导得到挽救，但 egr-1 和 egr-2 没有。这些作用在氯氮平短期（2 天）治疗或慢性氟哌啶醇（1mg/kg/天）治疗后未观察到。
我们的研究结果提供了一个慢性非典型抗精神病药物作用的小鼠模型，并表明 5-HT（2A）受体的下调可能是这些持久治疗样作用的潜在机制。
