Frustration represents a particular aspect of the addictive process that is related to loss of control when the expected reward is not obtained. We aim to study the consequences of frustrated expected reward on gene expression in the mouse brain. For this purpose, we used an operant model of frustration using palatable food as reward combined with microarrays. Transcriptomic profiles of frontal cortex, ventral striatum and hippocampus were analysed in five groups of mice: (1) positive control receiving palatable food and the cue light as conditioned stimulus; (2) frustrated group only receiving the cue light; (3) extinction learning group that did not receive palatable food nor the light; (4) negative control that never received the reinforcer nor the light during the whole experiment; and (5) yoked that received palatable food passively. Gene expression changes produced by frustration were revealed in the frontal cortex and ventral striatum, but not in the hippocampus. Most of the changes, such as the modification of the dopamine-DARPP-32 signalling pathway, were common in both areas and estimated to have neuronal origin. Extinction learning induced transcriptional changes only in the ventral striatum, with most genes showing down-regulation and without alteration in the dopamine-DARPP-32 signalling pathway. Active palatable food-seeking behaviour induced changes in gene expression in ventral striatum mainly affecting cell communication. In conclusion, frustration behaviour-induced changes in frontal cortex and ventral striatum mainly related to dopamine-DARPP-32 signalling that could play an important role in the loss of behavioural control during the addictive processes.

This work was supported by the Spanish ‘Instituto de Salud Carlos III’ (RTA,RD06/001/001andPI11/01629), the Spanish ‘Ministerio de Ciencia e Innovación’ (SAF2007-64062 and SAF2012-33484), the Spanish ‘Ministerio de Sanidad y Política Social’ (Plan Nacional Sobre Drogas, no. 2009/022 and 2009/026), the Catalan Government (2009-SGR-00131 and 2014-SGR-0932), the ICREA Foundation (ICREA Academia-2008). The research leading to these results has also received funding from the European Community’s Seventh Framework Programme (FP7/2007–2013) under Grant Agreement No. 602805. A.B. was supported by a FI predoctoral fellowship of the Catalan Government, J.G-C. was supported by a ‘Juan de la Cierva’ post-doctoral fellowship from the Spanish ‘Ministerio de Ciencia e Innovación’, E.M-G. was supported by a ‘Sara Borrell’ post-doctoral fellowship from the Spanish ‘Instituto de Salud Carlos III’, N.F-C.was supported by a contract from the Biomedical Network Research Centre on Rare Diseases (CIBERER) and M.R. was supported by a ‘Miguel i Servet’ contract the Spanish ‘Instituto de Salud Carlos III’. Partial support from FEDER funds is also acknowledged