Food palatability produces behavioral modifications that resemble those induced by drugs of abuse. Palatability-induced behavioral changes require both, the activation of the endogenous cannabinoid system, and changes in structural plasticity in neurons of the brain reward pathway. The ERK intracellular pathway is activated by CB1 receptors (CB1-R) and plays a crucial role in neuroplasticity. We investigated the activation of the ERK signaling cascade in the mesocorticolimbic system induced by operant training to obtain highly palatable isocaloric food and the involvement of the CB1-R in these responses. Using immunofluorescence techniques, we analyzed changes in ERK intracellular pathway activation in the mesocorticolimbic system of wild-type and CB1 knockout mice (CB1-/-) trained on an operant paradigm to obtain standard, highly caloric or highly palatable isocaloric food. Operant training for highly palatable isocaloric food, but not for standard or highly caloric food, produced a robust activation of the ERK signaling cascade in the same brain areas where this training modified structural plasticity. These changes induced by the operant training were absent in CB1-/-. We can conclude that the activation of the ERK pathway is associated to the neuroplasticity induced by operant training for highly palatable isocaloric food and might be involved in CB1-R mediated alterations in behavior and structural plasticity.

This work was supported by the Spanish “Ministerio de Ciencia e Innovación” (#SAF2007-64062 and #SAF2008-00962), “Instituto de Salud Carlos III” (#RD06/001/001), “Plan Nacional sobre Drogas, the Catalan Government” (SGR2009-00131 and SGR 2009-224), the “ICREA Foundation” (ICREA Academia-2008), the “DG Research of the European Commission” (GENADDICT, #LSHM-CT-2004-05166; and PHECOMP, #LSHM-CT-2007-037669) the “FIS” (PI07/0715), “ATIP-Avenir” and “Sanofi-Aventis” grants. This work was also supported by the “Plan Nacional Sobre Drogas” (#2009/026) to R.M