De Deurwaerdère Philippe, Casarrubea Maurizio, Cassar Daniel, Radic Manuela, Puginier Emilie, Chagraoui Abdeslam, Crescimanno Giuseppe, Crunelli Vincenzo, Di Giovanni Giuseppe
Centre National de la Recherche Scientifique, UMR 5287, Bordeaux Cedex, France.
Laboratory of Behavioral Physiology, Department of Biomedicine, Neuroscience and Advanced Diagnostics (Bi.N.D.), Human Physiology Section "Giuseppe Pagano", University of Palermo, Palermo, Italy.
Front Cell Neurosci. 2022 May 23;16:886033. doi: 10.3389/fncel.2022.886033. eCollection 2022.
Childhood absence epilepsy (CAE) is characterized by absence seizures, which are episodes of lack of consciousness accompanied by electrographic spike-wave discharges. About 60% of children and adolescents with absence seizures are affected by major neuropsychological comorbidities, including anxiety. Endocannabinoids and monoamines are likely involved in the pathophysiology of these CAE psychiatric comorbidities. Here, we show that the synthetic cannabinoid receptor type 1/2 (CB1/2R) agonist WIN 55,212-2 (2 mg/kg) has a strain-dependent effect on anxiety-like and motor behavior when assess in the hole board test and cerebral monoaminergic levels in Genetic Absence Epilepsy Rats from Strasbourg (GAERS) and their non-epileptic control (NEC) rat strain. Using quantitative and Temporal pattern (T-pattern) analyses, we found that WIN 55,212-2 did not affect the emotional status of GAERS, but it was anxiolytic in NEC. Conversely, WIN 55,212-2 had a sedative effect in GAERS but was ineffective in NEC. Moreover, vehicle-treated GAERS more motivated to explore by implementing more complex and articulated strategies. These behavioral changes correlate with the reduction of 5-HT in the hippocampus and substantia nigra (SN) and noradrenaline (NA) in the entopeduncular nucleus (EPN) in vehicle-treated GAERS compared to NEC rats, which could contribute to their low anxiety status and hypermotility, respectively. On the other hand, the increased level of NA in the EPN and 5-HT in the SN is consistent with an activation of the basal ganglia output-mediated motor suppression observed in WIN 55,212-2-treated GAERS rats. These data support the view of a strain-dependent alteration of the endocannabinoid system in absence epilepsy by adding evidence of a lower emotional responsiveness and a basal ganglia hypersensitivity to cannabinoids in GAERS compared to NEC rats.
儿童失神癫痫（CAE）的特征是失神发作，即意识丧失发作并伴有脑电图棘慢波放电。约60%有失神发作的儿童和青少年受到包括焦虑在内的主要神经心理共病的影响。内源性大麻素和单胺可能参与了这些CAE精神共病的病理生理过程。在此，我们表明，合成的1型/2型大麻素受体（CB1/2R）激动剂WIN 55,212-2（2mg/kg）在斯特拉斯堡遗传性失神癫痫大鼠（GAERS）及其非癫痫对照（NEC）大鼠品系的洞板试验和脑单胺能水平评估中，对焦虑样行为和运动行为具有品系依赖性影响。通过定量和时间模式（T模式）分析，我们发现WIN 55,212-2不影响GAERS的情绪状态，但对NEC具有抗焦虑作用。相反，WIN 55,212-2对GAERS有镇静作用，但对NEC无效。此外，与NEC大鼠相比，接受赋形剂处理的GAERS通过实施更复杂和明确的策略更有探索的积极性。这些行为变化与接受赋形剂处理的GAERS相比NEC大鼠海马和黑质（SN）中5-羟色胺（5-HT）的减少以及脚内核（EPN）中去甲肾上腺素（NA）的减少相关，这可能分别导致它们的低焦虑状态和多动。另一方面，EPN中NA水平的升高和SN中5-HT水平的升高与在WIN 55,212-2处理的GAERS大鼠中观察到的基底神经节输出介导的运动抑制的激活一致。这些数据通过提供证据表明与NEC大鼠相比，GAERS中内源性大麻素系统存在品系依赖性改变，表现为对大麻素的情绪反应性较低和基底神经节超敏反应，支持了失神癫痫中内源性大麻素系统品系依赖性改变的观点。
