Dental School of Ribeirão Preto, Department of Basic and Oral Biology, University of São Paulo (USP), Ribeirão Preto, SP, Brazil.
Center for Interdisciplinary Research on Applied Neurosciences (NAPNA), USP, São Paulo, Brazil.
Neurotox Res. 2020 Dec;38(4):1049-1060. doi: 10.1007/s12640-020-00268-z. Epub 2020 Sep 15.
Schizophrenia patients show very complex symptoms in several psychopathological domains. Some of these symptoms remain poorly treated. Therefore, continued effort is needed to find novel pharmacological strategies for improving schizophrenia symptoms. Recently, minocycline, a second-generation tetracycline, has been suggested as an adjunctive treatment for schizophrenia. The antipsychotic-like effect of doxycycline, a minocycline analog, was investigated here. We found that both minocycline and doxycycline prevented amphetamine-induced prepulse inhibition (PPI) disruption. However, neither of them blocked MK801-induced effects, albeit doxycycline had a modest impact against ketamine-induced effects. Neither c-Fos nor nNOS expression, which was evaluated in limbic regions, were modified after acute or sub-chronic treatment with doxycycline. Therefore, apomorphine inducing either PPI disruption and climbing behavior was not prevented by doxycycline. This result discards a direct blockade of D2-like receptors, also suggested by the lack of doxycycline cataleptic-induced effect. Contrasting, doxycycline prevented SKF 38393-induced effects, suggesting a preferential doxycycline action at D1-like rather than D2-like receptors. However, doxycycline did not bind to the orthosteric sites of D1, D2, D3, D4, 5-HT2A, 5-HT1A, and A2A receptors suggesting no direct modulation of these receptors. Our data corroborate the antipsychotic-like effect of doxycycline. However, these effects are probably not mediated by doxycycline direct interaction with classical receptors enrolled in the antipsychotic effect.
精神分裂症患者在多个精神病理学领域表现出非常复杂的症状。其中一些症状仍未得到有效治疗。因此，需要继续努力寻找改善精神分裂症症状的新的药理学策略。最近，米诺环素，一种第二代四环素，已被提议作为精神分裂症的辅助治疗。本文研究了米诺环素类似物强力霉素的抗精神病样作用。我们发现米诺环素和强力霉素均可预防安非他命引起的前脉冲抑制（PPI）破坏。然而，它们都不能阻断 MK801 引起的作用，尽管强力霉素对氯胺酮引起的作用有一定影响。无论是在边缘区域评估的 c-Fos 还是 nNOS 表达，在急性或亚慢性强力霉素治疗后都没有改变。因此，强力霉素没有预防阿扑吗啡诱导的 PPI 破坏和攀爬行为。这一结果排除了强力霉素对 D2 样受体的直接阻断作用，这也被强力霉素缺乏对氯丙嗪引起的作用所证实。相反，强力霉素可预防 SKF 38393 引起的作用，提示强力霉素优先作用于 D1 样而非 D2 样受体。然而，强力霉素不与 D1、D2、D3、D4、5-HT2A、5-HT1A 和 A2A 受体的正位结合位点结合，表明对这些受体没有直接调节作用。我们的数据证实了强力霉素的抗精神病样作用。然而，这些作用可能不是通过强力霉素与参与抗精神病作用的经典受体的直接相互作用介导的。
