Roncon Camila Marroni, Almada Rafael Carvalho, Maraschin Jhonatan Christian, Audi Elisabeth Aparecida, Zangrossi Hélio, Graeff Frederico Guilherme, Coimbra Norberto Cysne
Laboratory of Neuroanatomy & Neuropsychobiology, Department of Pharmacology, Ribeirão Preto Medical School of the University of São Paulo, Av. dos Bandeirantes, 3900, Ribeirão Preto, São Paulo 14049-900, Brazil; Behavioural Neurosciences Institute (INeC), Av. do Café, 2450, Monte Alegre, Ribeirão Preto, São Paulo 14050-220, Brazil.
Laboratory of Psychopharmacology, Department of Pharmacology and Therapeutics, State University of Maringá, Av. Colombo, 5790, Maringá, Paraná 87020-900, Brazil.
Neuropharmacology. 2015 Dec;99:620-6. doi: 10.1016/j.neuropharm.2015.08.037. Epub 2015 Aug 28.
Previously reported results have shown that the inhibitory effect of fluoxetine on escape behavior, interpreted as a panicolytic-like effect, is blocked by pretreatment with either the opioid receptor antagonist naloxone or the 5-HT1A receptor (5-HT1A-R) antagonist WAY100635 via injection into the dorsal periaqueductal gray matter (dPAG). Additionally, reported evidence indicates that the μ-opioid receptor (MOR) interacts with the 5-HT1A-R in the dPAG. In the present work, pretreatment of the dPAG with the selective MOR blocker CTOP antagonized the anti-escape effect of chronic fluoxetine (10 mg/kg, i.p., daily, for 21 days), as measured in the elevated T-maze (ETM) test, indicating mediation of this effect by the MOR. In addition, the combined administration of sub-effective doses of the selective MOR agonist DAMGO (intra-dPAG) and sub-effective doses of chronic as well as subchronic (7 days) fluoxetine increased avoidance and escape latencies, suggesting that the activation of MORs may facilitate and accelerate the effects of fluoxetine. The current observation that MORs located in the dPAG mediate the anti-escape effect of fluoxetine may open new perspectives for the development of more efficient and fast-acting panic-alleviating drugs.
先前报道的结果表明，氟西汀对逃避行为的抑制作用（被解释为类抗惊恐作用），可通过向背侧导水管周围灰质（dPAG）注射阿片受体拮抗剂纳洛酮或5-HT1A受体（5-HT1A-R）拮抗剂WAY100635进行预处理来阻断。此外，已报道的证据表明，μ-阿片受体（MOR）在dPAG中与5-HT1A-R相互作用。在本研究中，用选择性MOR阻滞剂CTOP对dPAG进行预处理，可拮抗慢性氟西汀（10 mg/kg，腹腔注射，每日一次，共21天）在高架T迷宫（ETM）试验中所测到的抗逃避作用，表明该作用由MOR介导。此外，联合给予亚有效剂量的选择性MOR激动剂DAMGO（脑室内注射至dPAG）以及亚有效剂量的慢性和亚慢性（7天）氟西汀，可增加回避和逃避潜伏期，提示MOR的激活可能促进并加速氟西汀的作用。目前关于位于dPAG的MOR介导氟西汀抗逃避作用的观察结果，可能为开发更高效、速效的抗惊恐药物开辟新的前景。
