69602. 9 May 2011 | Volume 6 | Issue 5 | e19382 Convulsant Doses of a Dopamine D1 Receptor Agonist Result in Erk-Dependent Increases in 149488-17-5 cost Zif268 and Arc/ Arg3.1 Expression in Mouse Dentate Gyrus Giuseppe Gangarossa1., Manuela Di Benedetto1., Gerard J. O’Sullivan2, Mark Dunleavy3, Cristina Alcacer4,5,6, Alessandra Bonito-Oliva1, David C. Henshall3, John L. Waddington2, Emmanuel Valjent1″, Gilberto Fisone1″ 1 Department of Neuroscience, Karolinska Institutet, Stockholm, Sweden, 2 Molecular and Cellular Therapeutics, Royal College of Surgeons in Ireland, Dublin, Ireland, icale, UMR-S 3 Department of Physiology and Medical Physics, Royal College of Surgeons in Ireland, Dublin, Ireland, 4 Institut National de la Sante et de la Recherche Me ��839, Paris, France, 5 Universite Pierre et Marie Curie, Paris, France, 6 Institut du Fer a Moulin, Paris, France Abstract Activation of dopamine D1 receptors has been shown to induce epileptiform activity. We studied the molecular changes occurring in the hippocampus in response to the administration of the D1-type receptor agonist, SKF 81297. SKF 81297 at 2.5 and 5.0 mg/kg induced behavioural seizures. Electrophysiological recordings 15322237 in the dentate gyrus revealed the presence of epileptiform discharges peaking at 305 min post-injection and declining by 60 min. Seizures were prevented by the D1-type receptor antagonist, SCH 23390, or the cannabinoid CB1 receptor agonist, CP 55,940. The effect of SKF 
81297 was accompanied by increased phosphorylation of the extracellular signal-regulated protein kinases 1 and 2, in the granule cells of the dentate gyrus. This effect was also observed in response to administration of other D1-type receptor agonists, such as SKF83822 and SKF83959. In addition, SKF 81297 increased the phosphorylation of the ribosomal protein S6 and histone H3, two downstream targets of ERK. These effects were prevented by genetic inactivation of D1Rs, or by pharmacological inhibition of ERK. SKF 81297 was also able to enhance the levels of Zif268 and Arc/Arg3.1, two immediate early genes involved in transcriptional regulation and synaptic plasticity. These changes may be involved in forms of activity-dependent plasticity linked to the manifestation of seizures and to the ability of dopamine to affect learning and memory. Citation: Gangarossa G, Di Benedetto M, O’Sullivan GJ, Dunleavy M, Alcacer C, et al. Convulsant Doses of a Dopamine D1 Receptor Agonist Result in ErkDependent Increases in Zif268 and Arc/Arg3.1 Expression in Mouse Dentate Gyrus. PLoS ONE 6: e19415. doi:10.1371/journal.pone.0019415 icale, France Editor: Olivier Jacques Manzoni, Institut National de la Sante et de la Recherche Me Received December 11, 2010; Accepted March 29, 2011; Published May 3, 2011 Copyright: 2011 Gangarossa et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Funding: These studies were supported by Swedish Medical Research Council grants 20715 and 13482 and the Wenner-Gren Foundations, Science Foundation Ireland Principal Investigator grant 07/IN1/B960, Science Foundation Ireland Principal Investigator grant 08/IN1/B1875 and Health Research Board grant RP/2007/37, Irish Research Council for Science, Engineering & Technology INSPIRE fellowship, ATIP-Avenir grant and Sanofi-Aventis. The funders had no role in study desig