Centre de Recherches sur la Cognition Animale (CRCA), Centre de Biologie Intégrative (CBI), Université Paul Sabatier Toulouse III, Bât4R3, 118 Route de Narbonne, 31062, Toulouse, Cedex 09, France.
Pharmacoepidemiology Research Unit, INSERM-Université Toulouse 3, UMR 1027, 31000, Toulouse, France.
Psychopharmacology (Berl). 2019 Jul;236(7):2069-2082. doi: 10.1007/s00213-019-05198-z. Epub 2019 Mar 16.
Pregabalin is a psychoactive drug indicated in the treatment of epilepsy, neuropathic pain, and generalized anxiety disorders. Pregabalin acts on different neurotransmission systems by inactivating the alpha2-delta subunit of voltage-gated calcium channels. In light of this pharmacological property, the hypothesis has been raised that pregabalin may regulate the mesolimbic dopamine pathway and thereby display a potential for misuse or abuse as recently observed in humans. Although some preclinical data support this possibility, the rewarding properties of gabapentinoid are still a matter for debate.
The aim of this work was to evaluate the rewarding properties of pregabalin and to determine its putative mechanism of action in healthy mice.
Pregabalin alone (60 mg/kg; s.c.) produced a rewarding effect in the conditioned place preference (CPP) test albeit to a lower extent than cocaine (30 mg/kg; s.c.). Interestingly, when assessing locomotor activity in the CPP, the PGB60 group, similarly to the cocaine group, showed an increased locomotor activity. In vivo single unit extracellular recording showed that pregabalin had mixed effects on dopamine (DA) neuronal activity in the ventral tegmental area since it decreased the activity of 50% of neurons and increased 28.5% of them. In contrast, cocaine decreased 75% of VTA DA neuronal activity whereas none of the neurons were activated. Intracerebal microdialysis was then conducted in awake freely mice to determine to what extent such electrophysiological parameters influence the extracellular DA concentrations ([DA]ext) in the nucleus accumbens. Although pregabalin failed to modify this parameter, cocaine produced a robust increase (800%) in [DA]ext.
Collectively, these electrophysiological and neurochemical experiments suggest that the rewarding properties of pregabalin result from a different mode of action than that observed with cocaine. Further experiments are warranted to determine whether such undesirable effects can be potentiated under pathological conditions such as neuropathic pain, mood disorders, or addiction and to identify the key neurotransmitter system involved.
普瑞巴林是一种精神活性药物，用于治疗癫痫、神经性疼痛和广泛性焦虑症。普瑞巴林通过使电压门控钙通道的α2-δ亚基失活而作用于不同的神经递质系统。鉴于这种药理学特性，有人提出普瑞巴林可能调节中脑边缘多巴胺通路，并因此显示出潜在的误用或滥用的可能性，正如最近在人类中观察到的那样。尽管一些临床前数据支持这种可能性，但加巴喷丁类药物的奖赏特性仍存在争议。
本工作旨在评估普瑞巴林的奖赏特性，并确定其在健康小鼠中的潜在作用机制。
普瑞巴林（60mg/kg；sc）单独使用可在条件性位置偏爱（CPP）试验中产生奖赏作用，但其作用程度低于可卡因（30mg/kg；sc）。有趣的是，在 CPP 中评估运动活性时，PGB60 组与可卡因组相似，表现出运动活性增加。体内单细胞外记录显示，普瑞巴林对腹侧被盖区（VTA）多巴胺（DA）神经元活性有混合作用，因为它降低了 50%神经元的活性，并增加了 28.5%神经元的活性。相比之下，可卡因降低了 75%的 VTA DA 神经元活性，而没有神经元被激活。然后在清醒自由活动的小鼠中进行脑室内微透析，以确定这种电生理参数在何种程度上影响伏隔核（NAc）中的细胞外 DA 浓度（[DA]ext）。尽管普瑞巴林未能改变这一参数，但可卡因却使[DA]ext 产生了强烈的增加（800%）。
总之，这些电生理和神经化学实验表明，普瑞巴林的奖赏特性来自于与可卡因观察到的不同作用模式。需要进一步的实验来确定在神经病理性疼痛、情绪障碍或成瘾等病理条件下，这些不良作用是否会增强，并确定涉及的关键神经递质系统。
