Behavioural Brain Research 241 (2013) 112–119 Contents lists available at SciVerse ScienceDirect Behavioural Brain Research j ourna l ho me pa ge: www.elsevier.com/locate/bbr Research report Evidence that conditioned avoidance responses are reinforced by positive prediction errors signaled by tonic striatal dopamine Patricia A. Dombrowski a , Tiago V. Maia b,c , Suelen L. Boschen a , Mariza Bortolanza a , Etieli Wendler a , Rainer K.W. Schwarting d , Marcus Lira Brandão e , Philip Winn f , Charles D. Blaha g , Claudio Da Cunha a,∗ a Departamento de Farmacologia, UFPR, 81.531-980 Curitiba, PR, Brazil b Department of Psychiatry, Columbia University and New York State Psychiatric Institute, 1051 Riverside Dr., Unit 78, New York, NY 10032, USA c Instituto de Medicina Molecular, Faculdade de Medicina, Universidade de Lisboa, Lisbon, Portugal d Philipps-University of Marburg, Gutenbergstr. 18, 35032 Marburg, Germany e INeC, 14040-901 Ribeirão Preto, SP, Brazil f University of Strathclyde, 161 Cathedral Street, Glasgow, G4 0RE, Scotland, United Kingdom g Department of Psychology, University of Memphis, Memphis, TN 38152, USA h i g h l i g h t s ◮ Striatal tonic DA followed prediction errors changes during rat CAR learning. ◮ Tonic DA was unaffected by unpredictable, unavoidable, and inescapable footshocks. ◮ Thus, tonic DA does not seem to encode hedonic value or salience of aversive stimuli. ◮ Lesion of nigrostriatal DAergic neurons impaired CAR learning. ◮ Thus, CARs seem to be reinforced by prediction errors signaled by tonic dopamine. a r t i c l e i n f o Article history: Received 26 April 2012 Received in revised form 23 June 2012 Accepted 27 June 2012 Available online 3 July 2012 Keywords: Dopamine Prediction error Hedonia Salience Avoidance learning a b s t r a c t We conducted an experiment in which hedonia, salience and prediction error hypotheses predicted differ- ent patterns of dopamine (DA) release in the striatum during learning of conditioned avoidance responses (CARs). The data strongly favor the latter hypothesis. It predicts that during learning of the 2-way active avoidance CAR task, positive prediction errors generated when rats do not receive an anticipated foot- shock (which is better than expected) cause DA release that reinforces the instrumental avoidance action. In vivo microdialysis in the rat striatum showed that extracellular DA concentration increased during early CAR learning and decreased throughout training returning to baseline once the response was well learned. In addition, avoidance learning was proportional to the degree of DA release. Critically, exposure of rats to the same stimuli but in an unpredictable, unavoidable, and inescapable manner, did not pro- duce alterations from baseline DA levels as predicted by the prediction error but not hedonic or salience hypotheses. In addition, rats with a partial lesion of substantia nigra DA neurons, which did not show increased DA levels during learning, failed to learn this task. These data represent clear and unambigu- ous evidence that it was the factor positive prediction error, and not hedonia or salience, which caused increase in the tonic level of striatal DA and which reinforced learning of the instrumental avoidance response. © 2012 Published by Elsevier B.V. 1. Introduction It is well known that learning actions that lead to successful avoidance of negative aversive outcomes depend on release of dopamine (DA) in the striatum [1–3]. However, what causes striatal ∗ Corresponding author at: Laboratório de Fisiologia e Farmacologia do Sistema Nervoso Central, Departamento de Farmacologia, UFPR, C.P. 19.031, 81.531-980, Curitiba, PR, Brazil. Tel.: +55 41 3361 1717; fax: +55 41 3266 2042. E-mail address: dacunha@ufpr.br (C. Da Cunha). DA release during aversively motivated learning is controversial. Current hypotheses suggest that DA release is elicited by (i) forma- tion of positive prediction errors (which occur when the outcomes are better than expected) [4], (ii) stimuli with hedonic value [5], or (iii) stimuli that are salient regardless of hedonic valence [6–9]. Phasic and tonic DA release are also proposed to play different roles, the former encoding positive prediction errors [4] and the latter encoding negative prediction errors (outcomes worse than expected) as occurs in response to unexpected aversive stimuli or omission of expected rewards [10]. However, several microdial- ysis studies, which are believed to measure tonic release of DA 0166-4328/$ – see front matter © 2012 Published by Elsevier B.V. http://dx.doi.org/10.1016/j.bbr.2012.06.031