Pharmacological evidence for the mediation of the panicolytic effect of fluoxetine by dorsal periaqueductal gray matter m-opioid receptors Camila Marroni Roncon a, d , Rafael Carvalho Almada a, d , Jhonatan Christian Maraschin b , Elisabeth Aparecida Audi b ,H  elio Zangrossi Jr. c, e , Frederico Guilherme Graeff d, e , Norberto Cysne Coimbra a, d, e, * a Laboratory of Neuroanatomy & Neuropsychobiology, Department of Pharmacology, Ribeir~ ao Preto Medical School of the University of S~ ao Paulo, Av. dos Bandeirantes, 3900, Ribeir~ ao Preto, S~ ao Paulo 14049-900, Brazil b Laboratory of Psychopharmacology, Department of Pharmacology and Therapeutics, State University of Maring a, Av. Colombo, 5790, Maring a, Paran a 87020-900, Brazil c Department of Pharmacology, Ribeir~ ao Preto Medical School of the University of S~ ao Paulo, Av. dos Bandeirantes, 3900, Ribeir~ ao Preto, S~ ao Paulo 14049- 900, Brazil d Behavioural Neurosciences Institute (INeC), Av. do Caf e, 2450, Monte Alegre, Ribeir~ ao Preto, S~ ao Paulo 14050-220, Brazil e Neurobiology of Emotions Research Centre (NAP-USP-NuPNE), Ribeir~ ao Preto School of Medicine of the University of S~ ao Paulo (FMRP-USP), Av. dos Bandeirantes, 3900, Ribeir~ ao Preto, S~ ao Paulo 14049-900, Brazil article info Article history: Received 26 May 2015 Received in revised form 20 August 2015 Accepted 21 August 2015 Available online 28 August 2015 Keywords: Dorsal periaqueductal gray matter m-opioid receptor 5-HT 1A receptor Fluoxetine Elevated T-maze Panic abstract 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-HT 1A receptor (5-HT 1A -R) antagonist WAY100635 via injection into the dorsal periaqueductal gray matter (dPAG). Additionally, reported evidence indicates that the m-opioid receptor (MOR) interacts with the 5-HT 1A -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. © 2015 Elsevier Ltd. All rights reserved. 1. Introduction A wealth of reported evidence supports a key role of the dorsal periaqueductal gray matter (dPAG) in the regulation of both behavioral and neurovegetative manifestations of defensive re- actions (Graeff, 1990, 1994; Bandler and Shipley, 1994; Lovick, 2000; Eichenberger et al., 2002; Ribeiro et al., 2005; Coimbra et al., 2006; Twardowschy and Coimbra, 2015). Electrical or chemical stimulation of the dPAG in rodents causes behavioral changes characterized by vigorous, non-oriented escape reactions accompanied by autonomic responses, such as tachycardia, exophthalmia and increased blood pressure, which resemble those expressed in highly aversive situations such as during a predatory attack (Schutz et al., 1985; Jenck et al., 1995; Schenberg et al., 2001; Ullah et al., 2015; Almada and Coimbra, 2015; Almada et al., 2015). In humans, electrical stimulation of this structure evokes marked fear or terror, feelings of imminent death, and an urge to flee (Amano et al., 1978; Nashold et al., 1969). It has been suggested that the dPAG is fundamental for the organization of defensive behav- iors related to coping with proximal threat/danger (Fanselow and Lester, 1988; Fanselow, 1991) and that malfunctioning of this Abbreviations: 5-HT 1A -R, 5-HT 1A receptor; dPAG, dorsal periaqueductal gray matter; MOR, m-opioid receptor; ETM, elevated T maze; 5-HT, serotonin. * Corresponding author. Laboratory of Neuroanatomy & Neuropsychobiology, Department of Pharmacology, Ribeir~ ao Preto Medical School of the University of S~ ao Paulo, Av. dos Bandeirantes, 3900, Ribeir~ ao Preto, S~ ao Paulo 14049-900, Brazil. E-mail address: nccoimbr@fmrp.usp.br (N.C. Coimbra). Contents lists available at ScienceDirect Neuropharmacology journal homepage: www.elsevier.com/locate/neuropharm http://dx.doi.org/10.1016/j.neuropharm.2015.08.037 0028-3908/© 2015 Elsevier Ltd. All rights reserved. Neuropharmacology 99 (2015) 620e626