BackgroundTreatment of refractory bipolar disorder (BD) is extremely challenging. Deep brain stimulation (DBS) holds promise as an effective treatment intervention. However, we still understand very little about the mechanisms of DBS and its application on BD.AimThe present study aimed to investigate the behavioural and neurochemical effects of ventral tegmental area (VTA) DBS in an animal model of mania induced by methamphetamine (m‐amph).MethodsWistar rats were given 14 days of m‐amph injections, and on the last day, animals were submitted to 20 min of VTA DBS in two different patterns: intermittent low‐frequency stimulation (LFS) or continuous high‐frequency stimulation (HFS). Immediately after DBS, manic‐like behaviour and nucleus accumbens (NAc) phasic dopamine (DA) release were evaluated in different groups of animals through open‐field tests and fast‐scan cyclic voltammetry. Levels of NAc dopaminergic markers were evaluated by immunohistochemistry.ResultsM‐amph induced hyperlocomotion in the animals and both DBS parameters reversed this alteration. M‐amph increased DA reuptake time post‐sham compared to baseline levels, and both LFS and HFS were able to block this alteration. LFS was also able to reduce phasic DA release when compared to baseline. LFS was able to increase dopamine transporter (DAT) expression in the NAc.ConclusionThese results demonstrate that both VTA LFS and HFS DBS exert anti‐manic effects and modulation of DA dynamics in the NAc. More specifically the increase in DA reuptake driven by increased DAT expression may serve as a potential mechanism by which VTA DBS exerts its anti‐manic effects.

中文翻译：

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脑深部刺激腹侧被盖区对甲基苯丙胺躁狂动物模型的抗躁狂作用

背景难治性双相情感障碍（BD）的治疗极具挑战性。深部脑刺激（DBS）有望成为一种有效的治疗干预措施。然而，我们对DBS的机制及其在BD中的应用仍然知之甚少。目的本研究旨在探讨腹侧被盖区（VTA）DBS在甲基苯丙胺（m-amph）诱导的躁狂动物模型中的行为和神经化学效应。方法 Wistar 大鼠接受 14 天的 m-amph 注射，最后一天，动物接受 20 分钟的 VTA DBS，两种不同的模式：间歇性低频刺激 (LFS) 或连续高频刺激 (HFS) ）。 DBS 后，立即通过旷场测试和快速扫描循环伏安法评估不同组动物的躁狂样行为和伏隔核 (NAc) 阶段性多巴胺 (DA) 释放。通过免疫组织化学评估 NAc 多巴胺能标记物的水平。结果 M-amph 诱导动物过度运动，并且 DBS 参数逆转了这种变化。与基线水平相比，M-amph 增加了假手术后的 DA 再摄取时间，并且 LFS 和 HFS 都能够阻止这种改变。与基线相比，LFS 还能够减少阶段性 DA 释放。 LFS 能够增加 NAc 中的多巴胺转运蛋白 (DAT) 表达。结论这些结果表明，VTA LFS 和 HFS DBS 均发挥抗躁狂作用并调节 NAc 中的 DA 动力学。更具体地说，由 DAT 表达增加驱动的 DA 再摄取增加可能是 VTA DBS 发挥其抗躁狂作用的潜在机制。