Department of Psychiatry, Universidade Federal De São Paulo, São Paulo, SP, Brazil.
Department of Pharmacology, Universidade Federal De São Paulo, São Paulo, SP, Brazil.
Behav Brain Res. 2020 Aug 5;391:112674. doi: 10.1016/j.bbr.2020.112674. Epub 2020 May 14.
Obstetric complications, like maternal hypertension and neonatal hypoxia, disrupt brain development, leading to psychiatry disorders later in life, like schizophrenia. The exact mechanisms behind this risk are not yet well known. Spontaneously hypertensive rats (SHR) are a well-established model to study neurodevelopment of schizophrenia since they exhibit behavioral alterations mimicking schizophrenia that can be improved with antipsychotic drugs. SHR mothers are hypertensive, and the SHR offspring develop in preeclampsia-like conditions. Hypoxic conditions increase levels of adenosine, which play an important role in brain development. The enhanced levels of adenosine at birth could be related to the future development of schizophrenia. To investigate this hypothesis adenosine levels of brain neonatal Wistar rats and SHR were quantified. After that, caffeine, an antagonist of adenosinergic system, was administrated on PND (postnatal day) 7 (neurodevelopmental age similar to a human at delivery) and rats were observed at adolescent and adult ages. We also investigated the acute effects of caffeine at adolescent and adult ages. SHR control adolescent and adult groups presented behavioral deficits like hyperlocomotion, deficit in social interaction (SI), and contextual fear conditioning (CFC). In SHR, neonatal caffeine treatment on PND 7 normalized hyperlocomotion, improved SI, and CFC observed at adolescent period and adult ages, showing a beneficial effect on schizophrenia-like behaviors. Wistar rats neonatally treated with caffeine exhibited hyperlocomotion, deficit in SI and CFC when observed at adolescent and adult ages. Acutely caffeine treatment administrated at adolescent and adult ages increased locomotion and decreased SI time of Wistar rats and impair CFC in adult Wistars. No effects were observed in SHR. In conclusion, caffeine can be suggested as a useful drug to prevent behavioral deficits observed in this animal model of prenatal hypoxia-induced schizophrenia profile when specifically administered on PND 7.
产科并发症，如母体高血压和新生儿缺氧，会破坏大脑发育，导致日后出现精神疾病，如精神分裂症。这种风险的确切机制尚不清楚。自发性高血压大鼠（SHR）是研究精神分裂症神经发育的一种成熟模型，因为它们表现出类似于精神分裂症的行为改变，这些改变可以用抗精神病药物改善。SHR 母亲患有高血压，SHR 后代在子痫前期样条件下发育。缺氧条件会增加腺苷水平，而腺苷在大脑发育中起着重要作用。出生时腺苷水平升高可能与未来精神分裂症的发展有关。为了验证这一假说，我们对新生 Wistar 大鼠和 SHR 的大脑中的腺苷水平进行了量化。之后，在 PND7（出生后第 7 天，类似于人类分娩时的神经发育年龄）时给予咖啡因（一种腺苷能系统拮抗剂），并在青少年和成年时期观察大鼠。我们还研究了咖啡因在青少年和成年时期的急性作用。SHR 对照青少年和成年组表现出多动、社会互动（SI）缺陷和情境恐惧条件反射（CFC）缺陷等行为缺陷。在 SHR 中，PND7 时的新生咖啡因处理使青少年和成年时期的多动、SI 改善和 CFC 正常化，表现出对类精神分裂症行为的有益作用。新生期用咖啡因处理的 Wistar 大鼠在青少年和成年时期表现出多动、SI 缺陷和 CFC 缺陷。急性在青少年和成年时期给予咖啡因处理会增加 Wistar 大鼠的运动和减少 SI 时间，并损害成年 Wistar 大鼠的 CFC。在 SHR 中没有观察到这些影响。总之，当在 PND7 时特异性给予咖啡因时，它可以被认为是一种预防这种产前缺氧诱导的精神分裂症样动物模型中观察到的行为缺陷的有用药物。
