Sartim Ariandra G, Brito Bianca M, Gobira Pedro H, Joca Sâmia R L
Department of Physics and Chemistry, School of Pharmaceutical Sciences of Ribeirão Preto, University of São Paulo, Ribeirão Preto, São Paulo, Brazil.
Translational Neuropsychiatry Unit, Department of Clinical Medicine, Aarhus University, Aarhus, Denmark.
Behav Pharmacol. 2019 Feb;30(1):59-66. doi: 10.1097/FBP.0000000000000416.
The transient receptor potential vanilloid 1 (TRPV1) can modulate stress-related behaviours, thus representing an interesting target for new antidepressant drugs. TRPV1 can trigger glutamate release and nitric oxide synthesis in the brain, mechanisms also involved in the neurobiology of depression. However, it is not known if these mechanisms are involved in TRPV1-induced behavioural effects. Therefore, the aim of this study was to verify if the antidepressant-like effect induced by a TRPV1 antagonist in mice submitted to the forced swimming test (FST) would be facilitated by combined treatment with neuronal nitric oxide synthase (nNOS) inhibition and N-methyl-D-aspartate (NMDA) blockade. Male Swiss mice were given (intracerebroventricular) injections of capsazepine (CPZ) (TRPV1 antagonist - 0.05/0.1/0.3/0.6 nmol/µl), and AP7 (NMDA antagonist - 1/3/10 nmol/µl) or N-propyl-L-arginine (NPA, nNOS inhibitor - 0.001/0.01/0.1 nmol/µl), and 10 min later, submitted to an open field test, and immediately afterwards, to the FST. An additional group received coadministration of CPZ and AP7 or CPZ and NPA, in subeffective doses. The results demonstrated that CPZ (0.1 nmol/µl), AP7 (3 nmol/µl) and NPA (0.01/0.1 nmol/µl) induced antidepressant-like effects. Moreover, coadministration of subeffective doses of CPZ and AP7 or CPZ and NPA induced significant antidepressant-like effects. Altogether, the data indicate that blockade of TRPV1 receptors by CPZ induces antidepressant-like effects and that both nNOS inhibition and NMDA blockade facilitate CPZ effects in the FST.
瞬时受体电位香草酸亚型1（TRPV1）可调节与应激相关的行为，因此是新型抗抑郁药物的一个有趣靶点。TRPV1可触发大脑中的谷氨酸释放和一氧化氮合成，这些机制也与抑郁症的神经生物学有关。然而，尚不清楚这些机制是否参与TRPV1诱导的行为效应。因此，本研究的目的是验证在接受强迫游泳试验（FST）的小鼠中，TRPV1拮抗剂诱导的抗抑郁样效应是否会因联合使用神经元型一氧化氮合酶（nNOS）抑制剂和N-甲基-D-天冬氨酸（NMDA）受体拮抗剂而增强。给雄性瑞士小鼠（脑室内）注射辣椒素（CPZ）（TRPV1拮抗剂 - 0.05/0.1/0.3/0.6 nmol/µl）、AP7（NMDA拮抗剂 - 1/3/10 nmol/µl）或N-丙基-L-精氨酸（NPA，nNOS抑制剂 - 0.001/0.01/0.1 nmol/µl），10分钟后，进行旷场试验，随后立即进行FST。另一组接受亚有效剂量的CPZ与AP7或CPZ与NPA的联合给药。结果表明，CPZ（0.1 nmol/µl）、AP7（3 nmol/µl）和NPA（0.01/0.1 nmol/µl）均诱导出抗抑郁样效应。此外，亚有效剂量的CPZ与AP7或CPZ与NPA联合给药诱导出显著的抗抑郁样效应。总之，数据表明CPZ阻断TRPV1受体会诱导抗抑郁样效应，并且nNOS抑制和NMDA阻断均可增强CPZ在FST中的作用。
