Background and Hypothesis Stress during adolescence is a major risk factor for schizophrenia. We have found previously in rats that adolescent stress caused, in adulthood, behavioral changes and enhanced ventral tegmental area (VTA) dopamine system activity, which were associated with dysregulation of the excitatory-inhibitory (E/I) balance in the ventral hippocampus (vHip). Levetiracetam, an anticonvulsant drug, regulates the release of neurotransmitters, including glutamate, via SV2A inhibition. It also modulates parvalbumin interneuron activity via Kv3.1 channels. Therefore, levetiracetam could ameliorate deficits in the E/I balance. We tested whether levetiracetam attenuate the adolescent stress-induced behavioral changes, vHip hyperactivity, and enhanced VTA dopamine system activity in adult rats. Study Design Male Sprague-Dawley rats were subjected to a combination of daily footshock (postnatal day [PD] 31–40), and three 1 h-restraint stress sessions (at PD31, 32, and 40). In adulthood (PD62), animals were tested for anxiety responses (elevated plus-maze and light-dark box), social interaction, and cognitive function (novel object recognition test). The activity of vHip pyramidal neurons and VTA dopamine neurons was also recorded. Study Results Adolescent stress produced anxiety-like responses and impaired sociability and cognitive function. Levetiracetam (10 mg/kg) reversed these changes. Levetiracetam also reversed the increased VTA dopamine neuron population activity and the enhanced firing rate of vHip pyramidal neurons induced by adolescent stress. Conclusions These findings suggest that levetiracetam attenuates the adverse outcomes associated with schizophrenia caused by stress during adolescence.

中文翻译：

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左乙拉西坦减轻成年大鼠青少年应激引起的与精神分裂症相关的行为和电生理变化

背景和假设青春期的压力是精神分裂症的主要危险因素。我们之前在大鼠身上发现，青春期压力会导致成年后的行为改变和腹侧被盖区（VTA）多巴胺系统活性增强，这与腹侧海马（vHip）兴奋性抑制（E/I）平衡失调有关。 ）。左乙拉西坦是一种抗惊厥药物，通过抑制 SV2A 来调节神经递质（包括谷氨酸）的释放。它还通过 Kv3.1 通道调节小清蛋白中间神经元活性。因此，左乙拉西坦可以改善 E/I 平衡的赤字。我们测试了左乙拉西坦是否能减轻成年大鼠青少年应激引起的行为变化、vHip 过度活跃和增强的 VTA 多巴胺系统活性。研究设计 雄性 Sprague-Dawley 大鼠接受每日足部电击（出生后第 31-40 天）和 3 次 1 小时约束应激训练（PD31、32 和 40）。在成年期（PD62），对动物进行焦虑反应（高架十字迷宫和明暗盒）、社交互动和认知功能（新物体识别测试）的测试。还记录了 vHip 锥体神经元和 VTA 多巴胺神经元的活动。研究结果 青少年压力会产生类似焦虑的反应，并损害社交能力和认知功能。左乙拉西坦（10 mg/kg）逆转了这些变化。左乙拉西坦还逆转了青春期压力引起的 VTA 多巴胺神经元群活动增加和 vHip 锥体神经元放电率增强。结论 这些研究结果表明，左乙拉西坦可减轻青春期压力引起的与精神分裂症相关的不良后果。