Olanzapine Treatment of Adolescent Rats Causes Enduring Specific Memory Impairments and Alters Cortical Development and Function

Antipsychotic drugs are increasingly used in children and adolescents to treat a variety of psychiatric disorders. However, little is known about the long-term effects of early life antipsychotic drug treatment. Most antipsychotic drugs are potent antagonists or partial agonists of dopamine D2 receptors; atypical antipsychotic drugs also antagonize type 2A serotonin receptors. Dopamine and serotonin regulate many neurodevelopmental processes. Thus, early life antipsychotic drug treatment can, potentially, perturb these processes, causing long-term behavioral- and neurobiological impairments. Here, we treated adolescent, male rats with olanzapine on post-natal days 28–49. As adults, they exhibited impaired working memory, but normal spatial memory, as compared to vehicle-treated control rats. They also showed a deficit in extinction of fear conditioning. Measures of motor activity and skill, habituation to an open field, and affect were normal. In the orbital- and medial prefrontal cortices, parietal cortex, nucleus accumbens core and dentate gyrus, adolescent olanzapine treatment altered the developmental dynamics and mature values of dendritic spine density in a region-specific manner. Measures of motor activity and skill, habituation to an open field, and affect were normal. In the orbital- and medial prefrontal cortices, D1 binding was reduced and binding of GABAA receptors with open Cl− channels was increased. In medial prefrontal cortex, D2 binding was also increased. The persistence of these changes underscores the importance of improved understanding of the enduring sequelae of pediatric APD treatment as a basis for weighing the benefits and risks of adolescent antipsychotic drug therapy, especially prophylactic treatment in high risk, asymptomatic patients. The long-term changes in neurotransmitter receptor binding and neural circuitry induced by adolescent APD treatment may also cause enduring changes in behavioral- and neurobiological responses to other therapeutic- or illicit psychotropic drugs.

抗精神病药物（Antipsychotic Drugs）目前正越来越多地被应用于儿童及青少年群体，用于治疗各类精神障碍。然而，学界对于生命早期接受抗精神病药物治疗的长期影响却知之甚少。多数抗精神病药物均为多巴胺D2受体（dopamine D2 receptors）的强效拮抗剂或部分激动剂；非典型抗精神病药物（Atypical Antipsychotic Drugs）还可拮抗2A型血清素（serotonin）受体。多巴胺与血清素可调控诸多神经发育进程。因此，生命早期的抗精神病药物治疗或会干扰此类进程，进而引发长期的行为与神经生物学功能损伤。

本研究于大鼠出生后第28至49日，对青春期雄性大鼠施以奥氮平（olanzapine）干预。与经赋形剂处理的对照组大鼠相比，干预后的成年大鼠表现出工作记忆受损，但空间记忆未受影响。该组大鼠同时还出现了恐惧条件反射消退缺陷。运动能力、运动技能、旷场实验习惯化反应以及情绪状态均未出现异常。

在眶前额叶皮层、顶叶皮层、伏隔核核心区以及齿状回中，青春期奥氮平干预以脑区特异性的方式改变了树突棘密度的发育动态与成熟值。运动能力、运动技能、旷场实验习惯化反应以及情绪状态均未出现异常。

在眶前额叶皮层与内侧前额叶皮层中，D1受体结合量降低，而开放氯离子通道的GABAA受体（GABAA receptors）结合量升高。在内侧前额叶皮层中，D2受体结合量亦有所升高。

上述改变的持续性凸显了加深对儿科抗精神病药物（APD）治疗所带来的长期后遗症的认知的重要性，以此作为权衡青春期抗精神病药物治疗（尤其是针对高危无症状患者的预防性治疗）的收益与风险的依据。青春期抗精神病药物治疗所引发的神经递质受体结合与神经环路的长期改变，或还会导致机体对其他治疗性或非法精神活性药物的行为与神经生物学反应产生持久变化。