研究微透析和同时记录运动活动对精神分裂症大鼠苯环利定模型中内侧前额叶皮质中外源谷氨酸、GABA、多巴胺、去甲肾上腺素和 5-羟色胺水平的影响。

Effects of cariprazine on extracellular levels of glutamate, GABA, dopamine, noradrenaline and serotonin in the medial prefrontal cortex in the rat phencyclidine model of schizophrenia studied by microdialysis and simultaneous recordings of locomotor activity.

机构信息

Pronexus Analytical AB, Bromma, Sweden.

Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden.

出版信息

Psychopharmacology (Berl). 2018 May;235(5):1593-1607. doi: 10.1007/s00213-018-4874-z. Epub 2018 Apr 11.

RATIONALE

Aberrant glutamatergic, dopaminergic, and GABAergic neurotransmission has been implicated in schizophrenia. Cariprazine reverses the behavioral effects observed in the rat phencyclidine (PCP)-induced model of schizophrenia; however, little is known about its in vivo neurochemistry.

OBJECTIVES

The study aims to compare the effects of cariprazine and aripiprazole on PCP-induced changes in the extracellular levels of glutamate, dopamine, serotonin, noradrenaline, and GABA in the rat medial prefrontal cortex (mPFC), and on locomotor activation.

METHODS

Microdialysis was performed in awake rats with probes placed into the mPFC. Rats (n = 7/group) received vehicle (saline), cariprazine (0.05, 0.2, or 0.8 mg/kg), or aripiprazole (3 or 20 mg/kg) via gavage. After 60 min, 5 mg/kg PCP was administered intraperitoneally (i.p.). Samples were taken before drug administration, during pretreatment, and after PCP injection. Locomotor activity recording and microdialysis sampling occurred simultaneously.

RESULTS

PCP treatment increased extracellular levels of all the neurotransmitters tested except GABA, for which there were no significant changes. Cariprazine and aripiprazole dose-dependently inhibited the PCP-induced increases of tested neurotransmitters. Overall effects were significant for higher cariprazine doses and both aripiprazole doses for glutamate and noradrenaline, for higher cariprazine doses and 20 mg/kg aripiprazole for dopamine, and for 0.8 mg/kg cariprazine and 20 mg/kg aripiprazole for serotonin and locomotor activity.

CONCLUSION

Both cariprazine and aripiprazole dose-dependently attenuated PCP-induced hyperlocomotion and acute increases in glutamate, dopamine, noradrenaline, and serotonin levels in the mPFC; cariprazine was approximately 5-fold more potent than aripiprazole.

背景

谷氨酸能、多巴胺能和 GABA 能神经递质的异常与精神分裂症有关。卡利拉嗪可逆转精神分裂症大鼠苯环利定（PCP）诱导模型中观察到的行为效应；然而，其体内神经化学特性知之甚少。

目的

本研究旨在比较卡利拉嗪和阿立哌唑对 PCP 诱导的大鼠前额皮质（mPFC）中谷氨酸、多巴胺、5-羟色胺、去甲肾上腺素和 GABA 细胞外水平变化的影响，以及对运动激活的影响。

方法

在清醒大鼠中进行微透析，探针置于 mPFC 中。大鼠（n=7/组）经灌胃给予载体（生理盐水）、卡利拉嗪（0.05、0.2 或 0.8mg/kg）或阿立哌唑（3 或 20mg/kg）。60min 后，腹腔内注射 5mg/kg PCP。在药物给药前、预处理期间和 PCP 注射后采集样本。同时进行运动活性记录和微透析取样。

结果

PCP 处理增加了除 GABA 之外的所有测试神经递质的细胞外水平，GABA 没有明显变化。卡利拉嗪和阿立哌唑剂量依赖性地抑制了 PCP 诱导的测试神经递质的增加。较高的卡利拉嗪剂量和阿立哌唑的两种剂量对谷氨酸和去甲肾上腺素、较高的卡利拉嗪剂量和 20mg/kg 阿立哌唑对多巴胺、0.8mg/kg 卡利拉嗪和 20mg/kg 阿立哌唑对 5-羟色胺和运动活性均有显著的整体作用。