Leung L Stan, Jin Miao, Chu Liangwei, Ma Jingyi
Department of Physiology and Pharmacology, The University of Western Ontario, London, Ontario, N6A 5C1, Canada.
Department of Physiology and Pharmacology, The University of Western Ontario, London, Ontario, N6A 5C1, Canada.
Neuropharmacology. 2016 Nov;110(Pt A):154-164. doi: 10.1016/j.neuropharm.2016.07.017. Epub 2016 Jul 18.
Hippocampal seizures decreased the function of GABAB receptors, which may further increase seizure susceptibility and contribute to development of schizophrenia-like behaviors. Recent literature indicates that GABAB receptor agonist may normalize schizophrenia-like behaviors and prevent drug-induced behavioral sensitization. We hypothesized that positive modulation of GABAB receptor function during seizure induction will reduce seizure-induced schizophrenia-like behaviors. Using a partial hippocampal kindling model, afterdischarges were induced after injection of saline or dimethyl sulfoxide (vehicle-kindled rats), or a GABAB receptor positive allosteric modulator CGP7930, at 1 mg/kg i.p. (CGP1-kindled) or 5 mg/kg i.p. (CGP5-kindled). The increase in the primary afterdischarge duration during kindling was not different among the groups. However, the CGP5-kindled group showed a lower afterdischarge starting frequency as compared to vehicle-kindled or CGP1-kindled groups. Partial hippocampal kindling (21 afterdischarges) resulted in decreased prepulse inhibition and decreased gating of hippocampal auditory evoked potentials in vehicle-kindled and CGP1-kindled rats, as compared to saline-injected non-kindled rats, recorded 3-4 days after the last afterdischarge. However, CGP5-kindled rats showed normal prepulse inhibition and hippocampal auditory gating (compared to non-kindled rats), which was significantly higher than the respective measure in vehicle-kindled rats. CGP5-kindled group also showed methamphetamine-induced locomotion that was significant lower than the vehicle-kindled or CGP1-kindled group, but slightly higher than the saline-injected non-kindled rats. In conclusion, this study provides original data that a GABAB receptor positive allosteric modulator could therapeutically prevent or normalize some seizure-induced behavioral disruptions in a model of temporal lobe epilepsy.
海马体癫痫发作会降低GABAB受体的功能，这可能会进一步增加癫痫易感性，并导致精神分裂症样行为的发展。最近的文献表明，GABAB受体激动剂可能会使精神分裂症样行为恢复正常，并预防药物诱导的行为敏化。我们假设在癫痫发作诱导期间对GABAB受体功能进行正向调节将减少癫痫发作诱导的精神分裂症样行为。使用部分海马体点燃模型，在注射生理盐水或二甲基亚砜（溶剂点燃大鼠），或腹腔注射1mg/kg（CGP1点燃）或5mg/kg（CGP5点燃）的GABAB受体正变构调节剂CGP7930后诱导发作后放电。在点燃过程中，各组的初级发作后放电持续时间的增加没有差异。然而，与溶剂点燃或CGP1点燃组相比，CGP5点燃组的发作后放电起始频率较低。与注射生理盐水的未点燃大鼠相比，部分海马体点燃（21次发作后放电）导致溶剂点燃和CGP1点燃大鼠的前脉冲抑制降低以及海马体听觉诱发电位的门控降低，这是在最后一次发作后放电后3-4天记录的。然而，CGP5点燃大鼠表现出正常的前脉冲抑制和海马体听觉门控（与未点燃大鼠相比），这显著高于溶剂点燃大鼠的相应测量值。CGP5点燃组还表现出甲基苯丙胺诱导的运动，其显著低于溶剂点燃或CGP1点燃组，但略高于注射生理盐水的未点燃大鼠。总之，本研究提供了原始数据，表明GABAB受体正变构调节剂可以在颞叶癫痫模型中治疗性地预防或使一些癫痫发作诱导的行为破坏恢复正常。
