Zheng Wenhua, Zeng Zhiwen, Bhardwaj Sanjeev K, Jamali Sara, Srivastava Lalit K
Department of Neuropharmacology, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou, China.
Neuroreport. 2013 Jul 10;24(10):560-5. doi: 10.1097/WNR.0b013e3283623725.
Administration of the psychostimulant drug amphetamine (AMPH) to animals causes hyperactivity and deficit in prepulse inhibition (PPI) of startle, behaviors that are often observed in neuropsychiatric disorders such as schizophrenia and bipolar disorder. Enhanced central dopamine (DA) transmission is believed to mediate AMPH-induced behavioral alterations. Lithium, a drug used primarily in the treatment of bipolar disorder, is reported to interact with the DA system and antagonize some DA-related behaviors. Here, we provide evidence that AMPH and lithium reciprocally regulate the activity of the transcription factor forkhead box, class O1 (FoxO1), a downstream target of Akt. Administration of d-AMPH (3 mg/kg, intraperitoneally) to Sprague-Dawley rats resulted in a concomitant decrease in levels of phosphorylated (p) Akt as well as p-FoxO1 in the striatum, whereas lithium chloride (LiCl,100 mg/kg, intraperitoneally) exerted the opposite effect, that is, it increased levels of p-Akt and p-FoxO1. Pretreatment of animals with lithium prevented an AMPH-induced decrease in striatal p-Akt and p-FoxO1 levels. Pretreatment of animals with lithium also attenuated AMPH-induced locomotor activity and decreased prepulse inhibition. These in-vivo data suggest that the Akt-FoxO1 pathway may be a common target for the action of dopaminergic and antidopaminergic drugs, and its modulation may be relevant to the treatment of neuropsychiatric disorders.
给动物施用精神兴奋药物苯丙胺（AMPH）会导致多动以及惊吓前脉冲抑制（PPI）缺陷，这些行为在精神分裂症和双相情感障碍等神经精神疾病中经常出现。人们认为中枢多巴胺（DA）传递增强介导了AMPH诱导的行为改变。锂是一种主要用于治疗双相情感障碍的药物，据报道它与DA系统相互作用并拮抗一些与DA相关的行为。在此，我们提供证据表明AMPH和锂相互调节转录因子叉头框O1类（FoxO1）的活性，FoxO1是Akt的下游靶点。给Sprague-Dawley大鼠腹腔注射d-AMPH（3mg/kg）会导致纹状体中磷酸化（p）Akt以及p-FoxO1水平同时降低，而腹腔注射氯化锂（LiCl，100mg/kg）则产生相反的效果，即它会增加p-Akt和p-FoxO1的水平。用锂对动物进行预处理可防止AMPH诱导的纹状体p-Akt和p-FoxO1水平降低。用锂对动物进行预处理还可减弱AMPH诱导的运动活性并降低前脉冲抑制。这些体内数据表明，Akt-FoxO1通路可能是多巴胺能和抗多巴胺能药物作用的共同靶点，对其调节可能与神经精神疾病的治疗有关。
