https://doi.org/10.1177/0269881119862527 Journal of Psychopharmacology 1–9 © The Author(s) 2019 Article reuse guidelines: sagepub.com/journals-permissions DOI: 10.1177/0269881119862527 journals.sagepub.com/home/jop Introduction Dopaminergic neurotransmission has been implicated in the pro- cessing of conditioned and unconditioned aversive stimulation. For instance, a cue for fear decreased dopamine (DA) transmis- sion in the nucleus accumbens (NAc) core, but increased it in the NAc shell (Badrinarayan et al., 2012). Similarly, extracellular DA was decreased in the NAc core but not shell by the withhold- ing of anticipated reward (Biesdorf et al., 2015). Changes in NAc DA release occurred upon presentation of predictors of aversion (Wenzel et al., 2015), and predicted the extent of avoidance behavior (Pultorak et al., 2018). Pharmacological studies have also implicated DA in the various fear/anxiety-related behaviors, including conditioned and unconditioned fear-related responses (Brandão et al., 2015; Brandão and Coimbra, 2019; Garcia et al., 2005; Reis et al., 2004). DA has also been demonstrated to attenuate responses to aver- sive stimulation. Recently, we found in rats that intranasally applied DA (IN-DA) attenuated unconditioned fear responses, considering that it reduced escape behavior from bright light and ultrasound vocalizations in response to aversive restraint (Talbot et al., 2017). The present study follows up on this finding by examining the effects of acute IN-DA on (a) freezing induced by electric shock to the foot (as a measure of conditioned fear) one, two, and eight days after the conditioning session, and (b) freezing, escape, and post-stimulation freezing (unconditioned Intranasal dopamine attenuates fear responses induced by electric shock to the foot and by electrical stimulation of the dorsal periaqueductal gray matter Milene Cristina de Carvalho 1,2,3 , Rebeca Machado de Figueiredo 1,2 , Norberto Cysne Coimbra 1,2,3 , Christie Ramos Andrade Leite-Panissi 1,3,4 , Maria Angélica de Souza Silva 5 , Joseph P Huston 5 , Claudia Mattern 6,7 and Marcus Lira Brandão 1,3 Abstract Purpose: Intranasally applied dopamine (IN-DA), which likely reaches the brain via nasal–brain pathways and bypasses the blood–brain barrier, has been found to increase extracellular DA and bind to the DA2 transporter in the striatum. Recent studies suggest that DA plays a significant role in the processing of signaled and unconditioned aversive stimulation, including evidence that may attenuate responses to painful input. The purpose of this study was to examine the effects of IN-DA on fear-related behaviors induced by electric shock to the foot or by electrical stimulation of the dorsal periaqueductal gray matter (dPAG). Methods: DA hydrochloride suspended in a viscous castor oil gel (1 or 2 mg/kg) was applied (IN-DA) in a volume of 5 μL into the nostrils of adult Wistar male rats in order to evaluate its effects on (a) freezing induced by electric shock to the foot and (b) thresholds of freezing and escape and duration of post-stimulation freezing induced by electrical stimulation of the dPAG. Results: IN-DA attenuated freezing induced by electric shock to the foot in the three test trials, indicating that it reduced long-term fear responses. IN-DA also increased the threshold of dPAG stimulation-induced escape responses and reduced post-stimulation freezing. Conclusions: IN-DA, which has previously been shown to facilitate learning and to have antidepressive-like effects, attenuated unconditioned fear responses elicited by peripheral and intramesencephalic (dPAG) stimulation and reduced long-term conditioned fear responses. Keywords Unconditioned fear, conditioned fear, fear extinction, dopamine, dPAG, nasal drug application 1 Instituto de Neurociências e Comportamento (INeC), Ribeirão Preto, Brazil 2 Laboratory of Neuroanatomy and Neuropsychobiology, Department of Pharmacology, Ribeirão Preto Medical School of the University of São Paulo, Ribeirão Preto, Brazil 3 NAP-USP-Neurobiology of Emotions Research Centre (NuPNE), Ribeirão Preto School of Medicine of the University of São Paulo (FMRP-USP), Ribeirão Preto, Brazil 4 Department of Psychology, Ribeirão Preto School of Philosophy, Science and Literature of the University of São Paulo, Ribeirão Preto, Brazil 5 Center for Behavioral Neuroscience, Institute of Experimental Psychology, University of Düsseldorf, Düsseldorf, Germany 6 M et P Pharma AG, Emmetten, Switzerland 7 Oceanographic Center, Nova Southeastern University, Fort Lauderdale, FL, USA Corresponding author: Milene Cristina de Carvalho, Instituto de Neurociências e Comportamento-INeC, Av. do Café, Ribeirão Preto, 2450, Brazil. Email: mccarva@usp.br 862527JOP 0 0 10.1177/0269881119862527Journal of PsychopharmacologyCarvalho et al. research-article 2019 Original Paper