Olanzapine treatment of adolescent rats alters adult reward behaviour and nucleus accumbens function.
Olanzapine treatment of adolescent rats alters adult reward behaviour and nucleus accumbens function.
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DOI：
10.1017/s1461145712001642
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发表时间：
2013-08
期刊：
影响因子：
--
通讯作者：
Frost DO
中科院分区：
文献类型：
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作者：
Vinish M;Elnabawi A;Milstein JA;Burke JS;Kallevang JK;Turek KC;Lansink CS;Merchenthaler I;Bailey AM;Kolb B;Cheer JF;Frost DO
抗精神病药物在儿童和青少年中越来越多地用于治疗各种精神障碍。然而，对早期抗精神病药物治疗的长期影响知之甚少。大多数APD是多巴胺(DA)D2受体的强效拮抗剂或部分激动剂；非典型APD也具有多种5-羟色胺能活性。DA和5-羟色胺调节许多神经发育过程。因此，早期生活动作障碍治疗可能会潜在地扰乱这些过程，导致长期的行为和神经生物学后遗症。我们在出生后28-49天用奥氮平(OLA)治疗青春期雄性大鼠，给药条件与在人类治疗中使用的剂量相似。成年后，与车辆处理的大鼠相比，它们对苯丙胺表现出更强的条件性位置偏好。在伏核核心，DA_1受体结合减少，D_2结合增加，电刺激腹侧被盖区引起的DA释放减少。因此，青春期OLA治疗持久地改变了对奖赏刺激的关键行为反应，并改变了伏隔核中的DAR能神经传递。这些变化的持续性表明，即使是在生命早期接受OLA治疗的有限时期，也可能导致其他与奖励有关的行为以及对治疗性和非法精神药物的行为和神经生物学反应的持久变化。这些结果强调了更好地了解儿童apd治疗的持久后遗症的重要性，作为衡量青少年apd治疗的益处和风险的基础，特别是在高危、无症状的患者中进行预防性治疗。
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 (APD) treatment. Most APDs are potent antagonists or partial agonists of dopamine (DA) D2 receptors ; atypical APDs also have multiple serotonergic activities. DA and serotonin regulate many neurodevelopmental processes. Thus, early life APD treatment can, potentially, perturb these processes, causing long-term behavioural and neurobiological sequelae. We treated adolescent, male rats with olanzapine (Ola) on post-natal days 28–49, under dosing conditions that approximate those employed therapeutically in humans. As adults, they exhibited enhanced conditioned place preference for amphetamine, as compared to vehicle-treated rats. In the nucleus accumbens core, DA D1 receptor binding was reduced, D2 binding was increased and DA release evoked by electrical stimulation of the ventral tegmental area was reduced. Thus, adolescent Ola treatment enduringly alters a key behavioural response to rewarding stimuli and modifies DAergic neurotransmission in the nucleus accumbens. The persistence of these changes suggests that even limited periods of early life Ola treatment may induce enduring changes in other reward-related behaviours and in behavioural and neurobiological responses to therapeutic and illicit psychotropic drugs. These results underscore the importance of improved understanding of the enduring sequelae of paediatric APD treatment as a basis for weighing the benefits and risks of adolescent APD therapy, especially prophylactic treatment in high-risk, asymptomatic patients.