Instituto de Farmacología Experimental Córdoba (IFEC-CONICET), Departamento de Farmacología, Facultad de Ciencias Químicas, Universidad Nacional de Córdoba, Córdoba, Argentina.
Centro de Investigaciones en Química Biológica de Córdoba (CIQUIBIC), CONICET, Facultad de Ciencias Químicas, Universidad Nacional de Córdoba, Córdoba, Argentina; Departamento de Química Biológica "Ranwel Caputto," Facultad de Ciencias Químicas, Universidad Nacional de Córdoba, Córdoba, Argentina.
Behav Brain Res. 2022 May 3;425:113809. doi: 10.1016/j.bbr.2022.113809. Epub 2022 Feb 23.
Schizophrenia is a chronic disease affecting 1% worldwide population, of which 30% are refractory to the available treatments: thus, searching for new pharmacological targets is imperative. The acute and repeated ketamine administration are validated preclinical models that recreate the behavioral and neurochemical features of this pathology, including the parvalbumin-expressing interneurons dysfunction. Angiotensin II, through AT receptors (AT-R), modulates the dopaminergic and GABAergic neurotransmission. We evaluated the AT-R role in the long-term neuronal activation and behavioral alterations induced by repeated ketamine administration. Adult male Wistar rats received AT-R antagonist candesartan/vehicle (days 1-10) and ketamine/saline (days 6-10). After 14 days of drug-free, neuronal activation and behavioral analysis were performed. Locomotor activity, social interaction and novel object recognition tests were assessed at basal conditions or after ketamine challenge. Immunostaining for c-Fos, GAD67 and parvalbumin were assessed after ketamine challenge in cingulate, insular, piriform, perirhinal, and entorhinal cortices, striatum, and hippocampus. Additionally, to evaluate the AT-R involvement in acute ketamine psychotomimetic effects, the same behavioral tests were performed after 6 days of daily-candesartan and a single-ketamine administration. We found that ketamine-induced long-lasting schizophrenia-like behavioral alterations, and regional-dependent neuronal activation changes, involving the GABAergic neurotransmission system and the parvalbumin-expressing interneurons, were AT-R-dependent. The AT-R were not involved in the acute ketamine psychotomimetic effects. These results add new evidence to the wide spectrum of action of ketamine and strengthen the AT-R involvement in endurable alterations induced by psychostimulants administration, previously proposed by our group, as well as their preponderant role in the development of psychiatric pathologies.
精神分裂症是一种影响全球 1%人口的慢性疾病，其中 30%的患者对现有治疗方法无反应：因此，寻找新的药理靶点是当务之急。急性和重复给予氯胺酮已被验证为可重现该病理学行为和神经化学特征的临床前模型，包括表达 parvalbumin 的中间神经元功能障碍。血管紧张素 II 通过 AT 受体（AT-R）调节多巴胺能和 GABA 能神经传递。我们评估了 AT-R 在重复给予氯胺酮引起的长期神经元激活和行为改变中的作用。成年雄性 Wistar 大鼠接受 AT-R 拮抗剂坎地沙坦/载体（第 1-10 天）和氯胺酮/盐水（第 6-10 天）。在无药物 14 天后，进行神经元激活和行为分析。在基础条件或氯胺酮挑战后评估运动活动、社交互动和新物体识别测试。在扣带回、岛叶、梨状皮层、边缘皮层和内嗅皮层、纹状体和海马体中评估氯胺酮挑战后的 c-Fos、GAD67 和 parvalbumin 免疫染色。此外，为了评估 AT-R 在急性氯胺酮致精神分裂症样效应中的作用，在每天给予坎地沙坦和单次给予氯胺酮 6 天后进行了相同的行为测试。我们发现，氯胺酮引起的持久的类似精神分裂症的行为改变，以及涉及 GABA 能神经传递系统和表达 parvalbumin 的中间神经元的区域依赖性神经元激活变化，依赖于 AT-R。AT-R 不参与急性氯胺酮致精神分裂症样效应。这些结果为氯胺酮的广泛作用增加了新的证据，并加强了我们小组先前提出的 AT-R 参与精神兴奋剂给药引起的持久改变及其在精神病理学发展中的主导作用。
