UNCORRECTED PROOF 1 Dopamine abnormalities in the neocortex of patients with temporal lobe epilepsy 2 Luisa Q1 Rocha a, ⁎, Mario Alonso-Vanegas b , Juana Villeda-Hernández b , Mario Mújica b , 3 José Miguel Cisneros-Franco b , Mario López-Gómez b , Cecilia Zavala-Tecuapetla a , 4 Christian Lizette Frías-Soria a , José Segovia-Vila c , Anna Borsodi d 5 a Departamento de Farmacobiología, Centro de Investigación y de Estudios Avanzados, Mexico Q3 6 b Instituto Nacional de Neurología y Neurocirugía “Manuel Velasco Suárez”, Mexico 7 c Departamento de Fisiología, Biofísica y Neurociencias, Centro de Investigación y de Estudios Avanzados, Mexico 8 d Biological Research Center of the Hungarian Academy of Sciences, Szeged, Hungary 9 10 abstract article info 11 Article history: 12 Received 15 June 2011 13 Revised 3 September 2011 14 Accepted 13 September 2011 15 Available online xxxx 16 17 18 19 Keywords: 20 Temporal lobe epilepsy 21 Dopamine 22 D1 receptors 23 D2 receptors 24 Dopamine transporter 25 Neuropsychiatric disorders 26 Experiments were designed to evaluate different variables of the dopaminergic system in the temporal cortex 27 of surgically treated patients with temporal lobe epilepsy (TLE) associated with mesial sclerosis (MTLE, 28 n = 12) or with cerebral tumor or lesion (n = 8). In addition, we sought to identify dopaminergic abnormal- 29 ities in those patients with epilepsy that had comorbid anxiety and depression. Specifically, we investigated 30 changes in dopamine and its metabolites, D1 and D2 receptors, tyrosine hydroxylase (TH) and dopamine 31 transporter. Results obtained from patients with epilepsy were compared with those found in experiments 32 using autopsy material. The neocortex of patients with MTLE demonstrated high D1 expression (1680%, 33 p b 0.05) and binding (layers I–II, 31%, p b 0.05; layers V–VI, 28%, p b 0.05), and decreased D2 expression 34 (77%, p b 0.05). The neocortex of patients with TLE secondary to cerebral tumor or lesion showed high expres- 35 sion of D1 receptors (1100%, p b 0.05), and D2-like induced activation of G proteins (layers I–I, 503%; layers 36 III–IV, 557%; layers V–VI, 964%, p b 0.05). Both epileptic groups presented elevated binding to the dopamine 37 transporter and low tissue content of dopamine and its metabolites. Analysis revealed the following correla- 38 tions: a) D1 receptor binding correlated negatively with seizure onset age and seizure frequency, and posi- 39 tively with duration of epilepsy; b) D2 receptor binding correlated positively with age of seizure onset and 40 negatively with duration of epilepsy; c) dopamine transporter binding correlated positively with duration 41 of epilepsy and frequency of seizures; d) D2-like induced activation of G proteins correlated positively 42 with the age of patients. When compared with autopsies and patients with anxiety and depression, patients 43 without neuropsychiatric disorders showed high D2-like induced activation of G proteins, an effect that cor- 44 related positively with age of patient and seizure onset age, and negatively with duration of epilepsy. The 45 present study suggests that alterations of the dopaminergic system result from epileptic activity and could 46 be involved in the physiopathology of TLE and the comorbid anxiety and depression. 47 © 2011 Published by Elsevier Inc. 48 49 50 51 52 Introduction 53 Epilepsy Q4 is the second most important neurologic disorder with 54 diverse etiology. Temporal lobe epilepsy (TLE) is the most frequent 55 and becomes pharmacologically untreatable in a high percentage of 56 patients (Engel, 1996). In TLE associated with mesial sclerosis (MTLE), 57 the hippocampus represents the epileptic focus, while the temporal 58 neocortex is involved in propagation of epileptic seizures to other 59 brain areas (Chagnac-Amitai and Connors, 1989; Chervin et al., 1988; 60 Sloviter, Q5 1994). Neocortex has been proposed to be involved in 61 secondary epileptogenesis as a consequence of progressive extension 62 of the primary epileptogenic zone with increased duration of epilep- 63 sy (Morrell et al., 1987). 64 Epilepsy involves changes in several neurotransmitters (Fisher 65 and Leppik, 2008; Olsen and Avoli, 1997). Concerning the dopaminer- 66 gic system in temporal neocortex of patients with MTLE, studies using 67 Positron Emission Tomography (PET) indicate a reduction of D2/D3 68 receptor binding in the pole and lateral areas, ipsilateral to the epileptic 69 focus (Werhahn et al., 2006). Regarding tissue content of dopamine and 70 its metabolites, the results are controversial and it seems that changes 71 depend on the presence of epileptiform activity in the neocortex 72 (Louw et al., 1989; Mori et al., 1987; Pacia et al., 2001; Pintor et al., 73 1990). In relation with tyrosine hydroxylase (TH), the enzyme respon- 74 sible for DOPA synthesis (the precursor of dopamine), its activity is 75 not modified (Pintor et al., 1990). Despite the fact that D1 receptors 76 play a modulating role in the synaptic activity of the neocortex Neurobiology of Disease xxx (2011) xxx–xxx ⁎ Corresponding autor at: Depto. Farmacobiología, Cinvestav-Sede Sur, Calz. Tenorios 235, Col. Granjas Coapa, México, D.F. C.P. 14330, Mexico. E-mail address: lrocha@convestav.mx (L. Rocha). Available online on ScienceDirect (www.sciencedirect.com). YNBDI-02525; No. of pages: 9; 4C: 0969-9961/$ – see front matter © 2011 Published by Elsevier Inc. doi:10.1016/j.nbd.2011.09.006 Contents lists available at SciVerse ScienceDirect Neurobiology of Disease journal homepage: www.elsevier.com/locate/ynbdi Please cite this article as: Rocha, L., et al., Dopamine abnormalities in the neocortex of patients with temporal lobe epilepsy, Neurobiol. Dis. (2011), doi:10.1016/j.nbd.2011.09.006