Olanzapine antipsychotic treatment of adolescent rats causes long term changes in glutamate and GABA levels in the nucleus accumbens.
Olanzapine antipsychotic treatment of adolescent rats causes long term changes in glutamate and GABA levels in the nucleus accumbens.
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DOI：
10.1016/j.schres.2014.10.034
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发表时间：
2015-02
影响因子：
4.5
通讯作者：
Frost, Douglas O.
中科院分区：
文献类型：
--
作者：
Xu, Su;Gullapalli, Rao P.;Frost, Douglas O.
非典型抗精神病药物（AAPD）广泛用于儿童和青少年治疗各种精神疾病。然而，在大脑完全发育之前，对AAPD治疗的长期影响知之甚少。事实上，我们和其他人以前曾报道，在出生后第28-49天，在接近人类治疗所用剂量条件下，用奥氮平（奥拉;一种广泛使用的AAPD）治疗青春期大鼠，导致长期行为和神经生物学紊乱。我们已经开始研究这些影响的机制。多巴胺（DA）和5-羟色胺（5-HT）调节许多神经发育过程。目前批准的AAPD主要通过其DA能活性发挥其治疗作用，尽管在精神分裂症（SZ）和一些其他AAPD处方疾病中，DA能功能障碍伴随着谷氨酸能（GLU能）和γ-氨基丁酸能（GABA能）传递异常。在这里，我们使用质子磁共振波谱（1H MRS），以证明长期减少的GLU和GABA的水平在成年大鼠与奥拉在青春期处理的丘脑核（NAc）。NAc是大脑“奖励”系统的关键节点，其功能在精神分裂症中也被破坏。进一步研究潜在的，OLA诱导的NAc和其他大脑区域中GLU和GABA水平的变化，以及这些变化的动力学和机制，是为现有AAPD设计新的辅助治疗和设计新药物的重要一步。
Atypical antipsychotic drugs (AAPDs) are widely used in children and adolescents to treat a variety of psychiatric disorders. However, little is known about the long-term effects of AAPD treatment before the brain is fully developed. Indeed, we and others have previously reported that treatment of adolescent rats with olanzapine (OLA; a widely prescribed AAPD) on post-natal days 28–49, under dosing conditions that approximate those employed therapeutically in humans, causes long-term behavioral and neurobiological perturbations. We have begun to study the mechanisms of these effects. Dopamine (DA) and serotonin (5HT) regulate many neurodevelopmental processes. Currently approved AAPDs exert their therapeutic effects principally through their DAergic activities, although in schizophrenia (SZ) and some other diseases for which AAPDs are prescribed, DAergic dysfunction is accompanied by abnormalities of glutamatergic (GLUergic) and γ-aminobutyric acidergic (GABAergic) transmission. Here, we use proton magnetic resonance spectroscopy (1H MRS) to demonstrate long-term reductions in the levels of both GLU and GABA in the nucleus accumbens (NAc) of adult rats treated with OLA during adolescence. The NAc is a key node in the brain’s “reward” system, whose function is also disrupted in schizophrenia. Further research into potential, OLA-induced changes in the levels of GLU and GABA in the NAc and other brain areas, and the dynamics and mechanisms of those changes, are an essential step for devising new adjunct therapies for existing AAPDs and for designing new drugs that increase therapeutic effects and reduce long-term abnormalities when administered to pediatric patients.
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