Antipsychotic drugs (APDs) are essential for the treatment of schizophrenia and other neuropsychiatric illnesses such as bipolar disease. However, they are also extensively prescribed off-label for many other conditions, a practice that is controversial given their potential for long-term side effects. There is clinical and preclinical evidence that chronic treatment with some APDs may lead to impairments in cognition and decreases in brain volume, although the molecular mechanisms of these effects are unknown. The purpose of the rodent studies described here was to evaluate a commonly prescribed APD, risperidone, for chronic effects on recognition memory, brain-derived neurotrophic factor (BDNF), its precursor proBDNF, as well as relevant downstream signaling molecules that are known to influence neuronal plasticity and cognition. Multiple cohorts of adult rats were treated with risperidone (2.5 mg/kg/day) or vehicle (dilute acetic acid solution) in their drinking water for 30 or 90 days. Subjects were then evaluated for drug effects on recognition memory in a spontaneous novel object recognition task and protein levels of BDNF-related signaling molecules in the hippocampus and prefrontal cortex. The results indicated that depending on the treatment period, a therapeutically relevant daily dose of risperidone impaired recognition memory and increased the proBDNF/BDNF ratio in the hippocampus and prefrontal cortex. Risperidone treatment also led to a decrease in Akt and CREB phosphorylation in the prefrontal cortex. These results indicate that chronic treatment with a commonly prescribed APD, risperidone, has the potential to adversely affect recognition memory and neurotrophin-related signaling molecules that support synaptic plasticity and cognitive function.

抗精神病药（APD）对于治疗精神分裂症和其他神经精神疾病（例如双相情感障碍）至关重要。但是，对于许多其他情况，它们也被广泛开出处方，鉴于其可能产生长期副作用，这种做法引起争议。有临床和临床前证据表明，尽管这些作用的分子机制尚不清楚，但某些APD的长期治疗可能会导致认知障碍和脑容量下降。此处描述的啮齿动物研究的目的是评估常用的APD利培酮对识别记忆，脑源性神经营养因子（BDNF），其前体proBDNF以及已知会影响相关下游信号分子的慢性影响神经元可塑性和认知。用成年大鼠的饮用水中使用利培酮（2.5 mg / kg /天）或溶媒（稀乙酸溶液）治疗多个成年大鼠，持续30或90天。然后评估受试者在自发的新对象识别任务中对识别记忆的药物作用以及海马和前额叶皮层中BDNF相关信号分子的蛋白质水平。结果表明，根据治疗时间的不同，利培酮的治疗相关日剂量会损害识别记忆并增加海马和前额叶皮层中proBDNF / BDNF的比例。利培酮治疗还导致额叶前皮质Akt和CREB磷酸化水平降低。这些结果表明，通常使用APD，利培酮，