Behavioural Brain Research 199 (2009) 271–277 Contents lists available at ScienceDirect Behavioural Brain Research journal homepage: www.elsevier.com/locate/bbr Research report Role of dopamine receptors in the ventral tegmental area in conditioned fear Amanda Ribeiro de Oliveira a,b , Adriano Edgar Reimer a,b , Marcus Lira Brandão a,b,∗ a Laboratório de Psicobiologia, FFCLRP - USP, Ribeirão Preto, SP, Brazil b Instituto de Neurociências & Comportamento - INeC, Campus USP, Ribeirão Preto, SP, Brazil article info Article history: Received 3 November 2008 Received in revised form 29 November 2008 Accepted 2 December 2008 Available online 7 December 2008 Keywords: Ventral tegmental area Fear potentiated startle SKF 38393 SCH 23390 Quinpirole Sulpiride abstract The increased startle reflex in the presence of a stimulus that has been previously paired with foot- shock has been termed fear-potentiated startle (FPS) and is considered a reliable index of anxiety. Some studies have suggested an association between stressful situations and alterations in dopaminergic (DA) transmission. Many studies converge on the hypothesis that the mesocorticolimbic pathway, originating from DA neurons in the ventral tegmental area (VTA), is particularly sensitive to fear-arousing stimuli. The present study explored the involvement of VTA DA receptors in the acquisition and expression of conditioned fear to a light conditioned stimulus (CS). We evaluated the effects of intra-VTA administra- tion of SKF 38393 (D 1 agonist), SCH 23390 (D 1 antagonist), quinpirole (D 2 agonist), and sulpiride (D 2 antagonist) on FPS. All drugs were administered bilaterally into the VTA (1.0 g/0.2 l/site). Locomotor activity/exploration and motor coordination were evaluated in the open-field and rotarod tests. None of the drugs produced significant effects on FPS when injected before conditioning, indicating that VTA DA receptors are not involved in the acquisition of conditioned fear to a light-CS. In contrast, when injected before the test session, quinpirole significantly reduced FPS, whereas the other drugs had no effect. Quin- pirole’s ability to decrease FPS may be the result of an action on VTA D 2 presynaptic autoreceptors that decrease dopamine levels in terminal fields of the mesocorticolimbic pathway. Altogether, the present results suggest the importance of VTA DA neurons in the fear-activating effects of Pavlovian conditioning. In addition to demonstrating the importance of dopaminergic mechanisms in the motivational conse- quences of footshock, the present findings also indicate that these neural circuits are mainly involved in the expression, rather than acquisition, of conditioned fear. © 2008 Elsevier B.V. All rights reserved. 1. Introduction A sudden and unexpected burst of noise triggers a whole-body response consisting of skeletal muscle contraction known as the acoustic startle reflex [13,26]. The biological functions of acoustic startle are determined by the reduction of the latency of a flight reaction and/or protection from a predator’s attack from behind by contraction of the dorsal neck muscles [13,26,39,52]. When the startle-inducing noise occurs in the presence of a conditioned stim- ulus (CS) that has been paired with an aversive unconditioned stimulus (US), for example a footshock, the startle response is enhanced. This increase in the startle reflex is taken as an index of fear and is termed fear-potentiated startle (FPS) [8]. FPS is sensitive to the anxiolytic action of benzodiazepines and has been considered a model of generalized anxiety disorder [2,35,40,43,49,52]. Although considerable work has been done relating specific circuits of the brain to fear conditioning, less is known about its regulation by neuromodulators, the understanding of which ∗ Corresponding author. Fax: +55 16 3602 4830. E-mail address: mbrandao@usp.br (M.L. Brandão). would be therapeutically relevant for fear-related diseases [5–7,30]. Dopamine (DA) is one of the neuromodulators most active on the mechanisms underlying states of fear and anxiety. The association between changes in DA transmission and threatening challenges has been demonstrated by numerous reports. Dopaminergic mech- anisms have been related to the production and elaboration of acute and chronic stress [12]. In fact, alterations in DA trans- mission always occur following exposure to a wide variety of acute stressors [1,17]. Additionally, recent evidence suggests that dopaminergic mechanisms are significant for different aspects of affective memory, namely its formation, expression, and retrieval [38]. The aforementioned findings could be taken as evidence for a secondary involvement of DA in fear-like states elicited by acute aversive stimuli. However, behavioral studies aimed at assessing the involvement of DA in anxiety have reported anxiolytic-like, anxiogenic-like, and lack of effects with the use of dopamin- ergic agonists and antagonists in animal models of anxiety [9,15,18,23,35,41,42]. These effects have been shown to depend on the nature of the aversive stimulus (i.e., the signal of the dopaminer- gic mechanism modulating defensive behavior will depend on the type of emotional stimuli triggering the coping reaction). 0166-4328/$ – see front matter © 2008 Elsevier B.V. All rights reserved. doi:10.1016/j.bbr.2008.12.004