Changes on D2-like receptor induced Gi protein activation and hippocampal dopamine release in kindled rats David Alcantara-Gonzalez a , Benjamin Floran b , Erik Escartin b , Luisa Rocha a, ⁎ a Department of Pharmacobiology, Center for Research and Advanced Studies, Mexico City, Mexico b Department of Physiology, Biophysics and Neuroscience, Center for Research and Advanced Studies, Mexico City, Mexico abstract article info Article history: Received 3 July 2012 Received in revised form 10 October 2012 Accepted 12 October 2012 Available online 18 October 2012 Keywords: D2-like receptors Dopamine Gi protein Hippocampus Kindling The present study aimed to characterize dopamine release in the hippocampus and D2-like receptor-induced Gi protein activation in several brain areas of fully kindled rats. During the interictal period, kindled rats showed lower extracellular levels of dopamine when compared with those obtained in the control group under basal conditions, a situation that was not modified when an afterdischarge was evoked. Hippocampal perfusion of sulpiride, a D2 receptor antagonist, enhanced dopamine release, which was more evident when an afterdischarge was induced in kindled rats. In addition, sulpiride perfusion was associated with longer sei- zure duration. Functional autoradiography experiments revealed increased [ 35 S]GTPγS incorporation as a consequence of D2-like receptor activation in different brain areas of fully kindled animals, including the ven- tral hippocampus. The present study reveals that hippocampal kindling is associated with alterations in do- pamine release and D2-like receptor-induced neurotransmission. © 2012 Elsevier Inc. All rights reserved. 1. Introduction Epilepsy is a chronic disease of the central nervous system that in- volves alterations in several neurotransmitters (Fisher and Leppik, 2008). The dopaminergic system plays an important role in epilepsy. However, during the last years, few studies have focused on elucidat- ing this issue. Patients with epilepsy present significant changes in D2/D3 receptor binding (Werhahn et al., 2006) and dopamine tissue content, which are dependent on the presence of epileptiform activity (Mori et al., 1987; Pacia et al., 2001). Evaluation of dopaminergic re- ceptors in temporal neocortex obtained from patients with temporal lobe epilepsy (TLE) has led to suggest that the effects mediated by D2 receptors are inversely related to epilepsy duration, a situation that may be associated to lower incidence of anxiety and/or depres- sion (Rocha et al., 2012). D2 receptors are coupled to inhibitory G-proteins (Gi), which dis- sociate from the receptor upon agonist binding and inhibit down- stream signaling mechanisms. Somatodendritic D2 autoreceptors modulate the firing rate (Paladini et al., 2003), whereas auto- receptors located on nerve terminals regulate dopamine synthesis and release (Cubeddu and Hoffmann, 1982; Wolf and Roth, 1990). The majority of D2 heteroreceptors located on postsynaptic neurons induce inhibitory effects on neuronal activity (Hsu et al., 1996) through different mechanisms, including hyperpolarization mediat- ed by Ca 2+ -activated K + conductance (Benardo and Prince, 1982); modulation of NMDA/AMPA receptor activation by phosphorylation mechanisms (Otmakhova and Lisman, 1998); or by protein–protein interaction, such as transactivation of platelet derived growing fac- tor receptor (PDGFr) (Beazely et al., 2006; Kotecha et al., 2002). According to this information, it is clear that impaired D2 receptor function would likely lead to changes in neuronal excitability and dopamine release. Using kindling, an experimental model of epilepsy and epilep- togenesis, it has been demonstrated that activation of D2 receptors in specific regions of the basal ganglia decreases the severity and duration of seizure activity (Wahnschaffe and Löscher, 1991). Kindling has been associated with alterations in the extracellular levels of dopamine (Gören et al., 2003) and D2 receptors in specific brain structures (Csernansky et al., 1988a). On the other hand, the kindling process itself leads to changes in sensitivity to dopaminergic effects. Superkindled rats (kindled animals receiving electrical stimulations during 3 addi- tional weeks after achieving the kindled stage) are supersensitive to the effects of apomorphine, an effect associated with increased D2 re- ceptor densities (Csernansky et al., 1988b). Kindling of the ventral teg- mental area produces neuroplastic changes in the brain, which result in supersensitivity of the dopaminergic system (Watanabe et al., 2004). Amygdaloid-kindling augments methamphetamine-induced stereo- typed behaviors in cats, lasting at least 10 days after the final seizure (Sato, 1983). At present, it is unknown if changes in dopamine release and sen- sitivity to D2 receptors in kindled rats are produced in the hippocam- pus, which constitutes the epileptic focus in this experimental model. Progress in Neuro-Psychopharmacology & Biological Psychiatry 40 (2013) 246–251 Abbreviations: [ 35 S]GTPγS, guanosine 5′-O-[gamma-thio [ 35 S] triphosphate]; ADT, afterdischarge threshold; ANOVA, analysis of variance; Gi, G protein of i subtype; TLE, temporal lobe epilepsy. ⁎ Corresponding author. Tel.: +52 55 5483 2859; fax: +52 55 5483 2863. E-mail address: lrocha@cinvestav.mx (L. Rocha). 0278-5846/$ – see front matter © 2012 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.pnpbp.2012.10.007 Contents lists available at SciVerse ScienceDirect Progress in Neuro-Psychopharmacology & Biological Psychiatry journal homepage: www.elsevier.com/locate/pnp