GABAA receptor binding is transiently increased in rat whisker barrels during the second postnatal week, at a time when neurons in the developing rat cortex are vulnerable to excitotoxic effects. To test whether these GABAA receptors might serve to protect neurons from excessive excitatory input, polymer implants containing the GABAA receptor antagonist bicuculline were placed over barrel cortex for a 4-day period in young (postnatal days 8 - 12) and adult rats. In the cortex of young, but not adult rats, the chronic blockade of GABAA receptors resulted in substantial tissue loss and neuron loss. The greater loss of neurons in young rats supports the hypothesis that a high density of GABAA receptors protects neurons from excessive excitatory input during a sensitive period in development.

Sensory neocortex contains a significant number of inhibitory neurons that use gamma-aminobutyric acid (GABA) as their neurotransmitter. Functional roles for these neurons have been identified in physiological studies. For example, in primary somatosensory cortex (SI), blockade of GABAa receptors with bicuculline leads to expansion of receptive fields (RFs). The magnitude of RF enlargement varies between SIpopulations of GABAergic neurons were identified by labeling specific calcium binding proteins.

Thèse numérisée par la Direction des bibliothèques de l'Université de Montréal.

by Priscilla, Ka-Yee Chan. / Thesis (M.Phil.)--Chinese University of Hong Kong, 1998. / Includes bibliographical references (leaves 77-100). / Abstract also in Chinese. / ACKNOWLEDGEMENTS --- p.4 / ABSTRACT --- p.5 / ABSTRACT (Chinese) --- p.7 / PUBLICATION --- p.8 / ABBREVIATION --- p.9 / Chapter CHAPTER 1 --- INTRODUCTION --- p.10 / Chapter 1.1 --- Overview of the study --- p.10 / Chapter 1.2. --- Substantia nigra pars reticulata (SNR) --- p.12 / Chapter 1.2.1 --- SNR and the basal ganglia / Chapter 1.2.2 --- GABA neurotransmission in SNR / Chapter 1.2.3 --- SNR and epilepsy / Chapter 1.3 --- GABAb receptors --- p.18 / Chapter 1.3.1 --- GABA receptors / Chapter 1.3.2 --- GABAb receptors and their classification / Chapter 1.3.3 --- Agonists and antagonists of GABAb receptor / Chapter 1.3.4 --- Distribution of GAB AB receptor / Chapter 1.3.5 --- GABAb receptors in epilepsy and the involvement of SNR / Chapter 1.4 --- Cannabinoid receptors --- p.24 / Chapter 1.4.1 --- Cannabinoid receptors and their classification / Chapter 1.4.2 --- Agonists and antagonists of cannabinoid receptor / Chapter 1.4.3 --- Distribution of cannabinoid receptors / Chapter 1.4.4 --- Cannabinoid receptors in epilepsy and the involvement of SNR / Chapter CHAPTER 2 --- METHODS --- p.31 / Chapter 2.1 --- Brain slice preparation and maintenance --- p.31 / Chapter 2.2 --- Experimental set-up --- p.32 / Chapter 2.2.1 --- Visualization of neurones / Chapter 2.2.2 --- Electrophysiological recordings / Chapter 2.2.3 --- Evoked stimulation / Chapter 2.2.4 --- Drug preparation and administration / Chapter 2.3 --- Identification of GAB A and dopamine neurones --- p.36 / Chapter 2.4 --- Data analysis --- p.37 / Chapter 2.4.1 --- Construction of dose-response curve / Chapter 2.4.2 --- Analysis of synaptic currents / Chapter 2.4.3 --- Statistics / Chapter CHAPTER 3 --- RESULTS --- p.39 / Chapter 3.1 --- Basic characteristics of IPSCs in SNR --- p.39 / Chapter 3.1.1 --- Spontaneous and miniature IPSCs / Chapter 3.1.2 --- Evoked IPSCs / Chapter 3.2 --- GABAb receptors in SNR --- p.42 / Chapter 3.2.1 --- Postsynaptic GABAb receptors in SNR neurones / Chapter 3.2.1.1 --- Baclofen-activated postsynaptic response / Chapter 3.2.1.2 --- Effects of GABAb receptor antagonist on IPSCs / Chapter 3.2.2 --- Presynaptic GABAb receptors / Chapter 3.2.3 --- Effects of GAB A uptake blocker / Chapter 3.3 --- Cannabinoid receptors in SNR --- p.51 / Chapter 3.3.1 --- Postsynaptic cannabinoid receptors in SNR neurones / Chapter 3.3.2 --- Presynaptic action of cannabinoids / Chapter CHAPTER 4 --- DISCUSSION and CONCLUSION --- p.55 / Chapter 4.1 --- General properties of IPSCs --- p.55 / Chapter 4.2 --- GABAb receptors in SNR neurones --- p.58 / Chapter 4.2.1 --- Postsynaptic GABAB receptors in SNR neurones / Chapter 4.2.2 --- GABAb component in spontaneous and evoked IPSCs / Chapter 4.2.3 --- Presynaptic GABAb receptors in SNR / Chapter 4.2.4 --- Role of GABA uptake / Chapter 4.3 --- Cannabinoid receptors in SNR neurones --- p.67 / Chapter 4.3.1 --- Postsynaptic cannabinoid receptors in SNR neurones / Chapter 4.3.2 --- Presynaptic cannabinoid receptors in SNR / Chapter 4.4 --- SNR GABAb and cannabinoid receptors - their role in epilepsy --- p.72 / Chapter 4.5 --- Concluding remarks and future direction --- p.75 / REFERENCES --- p.77

by Wu Cheok Wai. / Thesis (M.Phil.)--Chinese University of Hong Kong, 1998. / Includes bibliographical references (leaves 35-39 (2nd gp.)). / Abstract also in Chinese. / Abstract in English --- p.i / Abstract in Chinese --- p.iii / Acknowledgment --- p.v / Chapter Chapter 1: --- Introduction --- p.1 / Chapter 1.1 --- GABAa Mediated Neurotransmission --- p.1 / Chapter 1.2 --- Determinants of GABAa IPSC Kinetics --- p.3 / Chapter 1.3 --- Detection of the Spontaneous IPSCs --- p.5 / Chapter 1.4 --- The C++ Programming Language --- p.7 / Chapter Chapter 2: --- The Detection Algorithm --- p.11 / Chapter 2.1 --- Overview of the Algorithm --- p.11 / Chapter 2.2 --- Detection of Events --- p.12 / Chapter 2.3 --- Measurement of Parameters --- p.20 / Chapter Chapter 3: --- Performance Evaluation --- p.22 / Chapter 3.1 --- The Automatic Detection Software --- p.22 / Chapter 3.2 --- Performance of the Software --- p.23 / Chapter 3.3 --- Discussion --- p.25 / Chapter Chapter 4: --- Application --- p.28 / Chapter 4.1 --- Introduction --- p.28 / Chapter 4.2 --- Materials and Methods --- p.29 / Chapter 4.3 --- Results --- p.32 / Chapter 4.4 --- Discussion --- p.33 / Reference --- p.35 / Appendix --- p.40

Introdução: Os Benzodiazepínicos estão entre as drogas mais prescritas no mundo. Possuem características ansiolíticas, hipnóticas, miorelaxantes e anticonvulsivantes. Estudos prévios evidenciam inadequações nas prescrições de benzodiazepínicos, como uso equivocado para quadros inespecíficos, tratamento prolongado e abuso por idosos. Benzodiazepínicos podem trazer sérios efeitos adversos, sobretudo em idosos, como sonolência diurna, deterioro da memória e funções cognitivas, desequilíbrio e quedas. Objetivos: Analisar a prevalência do uso de benzodiazepínicos nos pacientes do Centro de Atenção Psicossocial (CAPS) de Campo Bom-RS em um período de 24 meses (Junho de 2013 a Maio de 2015), faixa etária, frequência de dispensações, dosagens, CIDs e especialidades dos médicos prescritores; bem como possíveis relações com a função cognitiva, afetiva, e quedas em idosos. Métodos: Estudo transversal, com informações coletadas e tabuladas a partir dos prontuários e prescrições médicas do CAPS Campo Bom, bem como do seu sistema informatizado de gerenciamento (Software Multi 24 Horas). Foram obtidos dados como idade, gênero, identificação dos CIDs; bem como informações sobre prescrições de Benzodiazepínicos, como frequência, quantidade, tipo de medicamento, posologia, profissional prescritor e demais medicamentos utilizados. Critério de inclusão: utilização de qualquer benzodiazepínico disponível na rede SUS: Clonazepam 0,5mg, Clonazepam 2,5 mg/ml, Clonazepam 2mg e Diazepam 5mg. Foram aplicados os testes MEEM e GDS nos pacientes idosos, em entrevistas individuais, nas quais também se avaliou a escolaridade, ocorrência e frequência de quedas, além das comorbidades auto relatadas. Para construção do banco de dados foi utilizado o Software Microsoft® Office Excel® 2007, e para análise estatística o Software PASW V18 (SPSS®). Resultados: O número total de pacientes ativos identificados no CAPS foi de 855 indivíduos, sendo 543 (63,5%) mulheres e 84 idosos (9,8%). A prevalência de utilização de BZD nesta população representou 47,2% (n=404 indivíduos). Foram identificadas 12.680 prescrições médicas dispensadas e, deste total, a prevalência de prescrições de benzodiazepínicos foi de 21,7% (n=2.748). Dentre os pacientes que receberam BZD, 297 (73,5%) eram mulheres e 59 idosos (14,6%), dos quais 56 foram entrevistados. Dentre os idosos entrevistados, 42 (75,0%) possuíram significativa sintomatologia depressiva (GDS≥5) e 32 (57,1%) apresentaram duas ou mais quedas no período de 1 ano. Dezoito pacientes idosos demonstraram fazer uso de dois ou mais BZDs. Houve correlação linear negativa entre os escores do MEEM e do GDS (r = - ,416; p=,002). Houve também uma correlação linear negativa entre o escore do MEEM e número de quedas em idosos (r = -,327 p=,016). Conclusões: Os benzodiazepínicos corresponderam a 21,7 % do total de prescrições do CAPS e do total dos indivíduos 47,2% receberam benzodiazepínicos. Proporcionalmente aos homens, as mulheres tenderam a receber mais prescrições de benzodiazepínicos (p<.001). A prevalência de significativa sintomatologia depressiva nos idosos usuários do CAPS foi alta (75,0%), assim como a incidência de quedas, sendo que mais da metade dos idosos caiu 2 ou mais vezes no período. Identificou-se uma correlação linear negativa entre a função cognitiva como avaliada pelo MEEM e a sintomatologia depressiva avaliada pelo GDS; bem como houve uma correlação linear negativa entre o MEEM e o número de quedas em idosos. / Introduction: Benzodiazepines are among the most prescribed drugs in the world, they have characteristics such as anxiolytic, hypnotic, muscle relaxants and anticonvulsants. Studies have pointed out distortions in benzodiazepines’ prescriptions, such as misuse for unspecific cases, prolonged treatment and use by elderly. Such medications may cause serious damage, particularly in the elderly, and its continued use causes side effects such as daytime somnolence, imbalance, memory and cognitive function loss, increased incidence of falls. Objectives: To assess the prevalence of benzodiazepine use among patients of the Center for Psychosocial Care in Campo Bom-RS within the period of June 2013 to May 2015. The variables analyzed were: age, frequency of dispensations, dosages, ICDs and specialties of prescribing doctors; as well as possible correlations between cognitive function, emotional function and falls in the elderly. Methods: Cross-sectional study, with data collected and tabulated from medical records and prescriptions, as well as from the management system from CAPS (Software Multi 24 hours). Data obtained was age, gender, ICDs identification; as well as frequency of prescriptions, quantity and type of medication, dosage, prescribing professional, others used drugs. Inclusion criteria: Use of any benzodiazepine available in the Health Unic System: Clonazepam 0,5 mg, Clonazepam 2,5 mg/ml, Clonazepam 2 mg and Diazepam 5mg. MMSE and GDS tests have been applied in the elderly, through individual interviews, in which we found about educational level, occurrence and frequency of falls and other self-reported comorbidities. The software Microsoft® Excel® 2007 was used to build database, and for statistical analysis the software PASW V18 (SPSS) was used. Results: The total number of active patients identified at CAPS was 855 individuals, of these 543 were women (63.5%) and 84 elderly (9.8%). The prevalence of benzodiazepines’ use in this population was 47.2 % (n = 404). We have found 12.680 prescriptions dispensed and the prevalence of benzodiazepines’ prescriptions was 21.7 % (n = 2.748). Among patients who received benzodiazepines, 297 (73.5%) were women and 59 elderly (14.6%), of these 56 were interviewed. From the interviewed patients, 42 (75.0%) had significant depressive symptomatology (GDS≥5) and 32 (57.1%) have suffered two or more falls. Eighteen elderly patients demonstrated to use two or more benzodiazepines. There was a negative linear correlation between MMSE and GDS scores (r = -.416, p =.002). There was also a negative linear correlation between MMSE scores and number of falls in elderly (r = -.327 p =. 016). Conclusions: Benzodiazepines accounted for 21.7% of the total CAPS’ prescriptions, and 47.2% individuals treated at CAPS received benzodiazepines. Women tended to receive more prescriptions of benzodiazepines (p <.001) than men. The prevalence of significant depressive symptomatology in the elderly was very high (75.0%). As well as the incidence of falls, since more than half of the elderly patients presented two or more falls in the period. We identified a negative linear correlation between cognitive function as assessed by MMSE and depressive symptoms assessed by the GDS; and there was a negative linear correlation between MMSE and the number of falls in the elderly.

Type-A Î3-amino-butyric acid receptors (GABA_ARs) are pentameric ligand-gated ion channels (pLGICs), which mediate the majority of fast inhibitory neurotransmission in the animal central nervous system. Their dysfunction is related to numerous conditions including epilepsy, insomnia, anxiety, panic disorders, depression and schizophrenia. GABA_ARs are therefore major targets of clinically important drugs, including benzodiazepines and the intravenous general anaesthetics etomidate and propofol, as well as endogenous modulators, for example neurosteroids. Despite recent progress in structural biology of pLGICs, GABA_AR structures remain notoriously elusive. Structural information available at the beginning of this project was limited to the benzamidine-bound homopentameric GABA_AR-Î23, in a desensitised conformation. A large number of fundamental questions, including the molecular architecture of physiological, heteromeric GABA_ARs, their signalling mechanisms, the binding and action modes of their numerous ligands, remained to be answered. During this DPhil project, I employed structural biology techniques (X-ray crystallography and single particle cryo-electron microscopy) to further the molecular understanding of human GABAARs. I used subunit-specific llama nanobodies to aid crystallization of homomeric GABA_A-β3 receptors, which led to a 3.16 Å structure in complex with the general anaesthetic etomidate. This structure elucidates the binding mode of the etomidate, the basis for its subunit selectivity and illustrates conformational changes it triggers. I then used cryo-electron microscopy to determine the first structure of a heteromeric GABA_AR, the human α1b3g2, bound to an activating llama nanobody at a medium (5.2 Å) resolution. The numerous other insights obtained range from unambiguously establishing the subunit arrangement and stoichiometry, to proposing a mechanism for receptor assembly and discovering an unexpected role played by N-linked glycans in this process. The work described here opens multiple avenues for future research. Immediate opportunities include high resolution structural characterization of heteromeric GABA_ARs, via cryo-electron microscopy, further development of nanobodies as novel, high affinity and subunit specific tools to modulate GABA-ergic signalling, and structural characterization of numerous small-molecule modulators, of clinical and physiological relevance, bound to human GABA_ARs.

Szeto Yi Ki. / Thesis submitted in: December 2000. / Thesis (M.Phil.)--Chinese University of Hong Kong, 2001. / Includes bibliographical references (leaves 83-113). / Abstracts in English and Chinese. / Acknowledgement --- p.iv / Abstract --- p.v / List of Abbreviations --- p.ix / Chapter CHATPER ONE --- INTRODUCTION / Chapter 1.1 --- Heroin --- p.1 / Chapter 1.1.1 --- Historical Background --- p.2 / Chapter 1.1.2 --- Manufacturing of Heroin --- p.5 / Chapter 1.1.3 --- Route of Administration and Absorption Rate --- p.6 / Chapter 1.1.4 --- Metabolism of Heroin --- p.8 / Chapter 1.1.5 --- Physical and Psychological Effects of Heroin --- p.9 / Chapter 1.2 --- Opioid Receptors --- p.10 / Chapter 1.2.1 --- Mu Opioid Receptors (MOR) --- p.11 / Chapter 1.2.2 --- Kappa Opioid Receptors (KOR) --- p.14 / Chapter 1.2.3 --- Delta Opioid Receptors (DOR) --- p.15 / Chapter 1.3 --- Dopamine Receptors --- p.17 / Chapter 1.4 --- Dopamine Transporter (DAT) --- p.19 / Chapter 1.5 --- Gamma-Aminobutyric Acid (GABA) Receptors --- p.21 / Chapter 1.6 --- Mesocorticolimbic Pathway --- p.22 / Chapter 1.6.1 --- Neural Substrates of Drug Reinforcement --- p.25 / Chapter 1.6.2 --- Molecular and Cellular Basis of Addiction --- p.26 / Chapter 1.6.3 --- Intracellular Substrates of Relapse --- p.29 / Chapter 1.7 --- Environmental Factors in Drug Addiction --- p.30 / Chapter 1.8 --- Genetic Factors in Drug Addiction --- p.32 / Chapter 1.9 --- Aim of Project --- p.35 / Chapter CHAPTER TWO --- MATERIALS AND METHODS / Chapter 2.1 --- Recruitment of Subjects 、 --- p.39 / Chapter 2.1.1 --- Heroin-dependent Subjects --- p.39 / Chapter 2.1.1.1 --- Phenotype Assessment --- p.39 / Chapter 2.1.1.2 --- Establishment of Socio-demographic Data --- p.40 / Chapter 2.1.2 --- Control Subjects --- p.42 / Chapter 2.2 --- DNA Extraction --- p.42 / Chapter 2.3 --- Genotyping --- p.43 / Chapter 2.3.1 --- A118G Polymorphism in Exon 1 of the Human MOR (hMOR) Gene --- p.43 / Chapter 2.3.2 --- C1031G Polymorphism in Intron 2 of the hMOR Gene --- p.45 / Chapter 2.3.3 --- T921C Polymorphism in Exon 3 of the Human DOR (hDOR) Gene --- p.46 / Chapter 2.3.4 --- 3'VNTR Polymorphism of the DAT Gene --- p.47 / Chapter 2.3.5 --- TaqI A Polymorphism of the DRD2 Gene --- p.48 / Chapter 2.3.6 --- NciI Polymorphism of the GABRG2 Gene --- p.48 / Chapter 2.4 --- DNA Sequencing --- p.49 / Chapter 2.5 --- Statistical Analysis --- p.50 / Chapter CHAPTER THREE --- RESULTS / Chapter 3.1 --- Socio-demographic Data --- p.52 / Chapter 3.1.1 --- Age of the Control and Heroin-dependent Subjects --- p.52 / Chapter 3.1.2 --- Education Standard of the Heroin-dependent Subjects --- p.52 / Chapter 3.1.3 --- Years of Heroin Use --- p.53 / Chapter 3.2 --- Addition Severity Index (ASI) --- p.53 / Chapter 3.2.1 --- ASI-Medical --- p.53 / Chapter 3.2.2 --- ASI-Employment --- p.54 / Chapter 3.2.3 --- ASI-Drug --- p.54 / Chapter 3.2.4 --- ASI-Legal --- p.54 / Chapter 3.2.5 --- ASI-Family/Social Relationships --- p.55 / Chapter 3.2.6 --- ASI-Psychiatry --- p.55 / Chapter 3.2.7 --- Correlation Among the Factors of ASI --- p.55 / Chapter 3.3 --- A118G Polymorphism in Exon 1 of the Human Mu Opioid Receptor (hMOR) Gene --- p.56 / Chapter 3.4 --- C1031G Polymorphism in Intron 2 of the hMOR Gene --- p.58 / Chapter 3.5 --- T921C Polymorphism in Exon 3 of the Human Delta Opioid Receptor (hDOR) Gene --- p.59 / Chapter 3.6 --- Interaction Between Genotypes --- p.60 / Chapter 3.6.1 --- Combined Genotypes of A118G and C1031G Polymorphisms of the hMOR Gene --- p.60 / Chapter 3.6.2 --- Combined Genotypes of A118G Polymorphism of the hMOR Gene and T921C Polymorphism of the hDOR Gene --- p.61 / Chapter 3.6.3 --- Combined Genotypes of C1031G Polymorphism of the hMOR Gene and T921C Polymorphism of the hDOR Gene --- p.61 / Chapter 3.7 --- Correlation Between Allelic Frequencies and Factors of the ASI --- p.62 / Chapter 3.8 --- 3'VNTR Polymorphism of DAT Gene --- p.62 / Chapter 3.9 --- TαqI A Polymorphism of DRD2 Gene --- p.63 / Chapter 3.10 --- NciI Polymorphism of GABRG2 Gene --- p.64 / Chapter CHAPTER FOUR --- DISCUSSION & CONCLUSION --- p.66 / REFERENCES --- p.83 / APPENDIX I The Addiction Severity Index / APPENDIX II Table of Severity Ratings / APPENDIX III Allelic Frequency of A118G Polymorphism in Different Populations / APPENDIX IV Details Information About the Single Nucleotide Polymorphisms In Present Study

A epilepsia do lobo temporal (ELT) é a um dos casos mais frequente epilepsia em humanos e de maior refratariedade nos pacientes. A maioria dos fármacos antiepilépticos são moduladores da atividade neuronal e atuam sobre canais iônicos do receptor GABAA. Estudos vêm demonstrando o papel das células gliais e da neuroinflamação na epileptogênese e a modulação desta resposta pode ser um alvo potencial para drogas adjuvantes aos fármacos anti-epilépticos. Astrócitos são células gliais participantes da sinapse tripartite, moduladores da atividade neuronal. Os astrócitos são capazes de promover a homeostase de íons e de neurotransmissores, são responsáveis pelo metabolismo energético e da produção de fatores neurotróficos, glutationa, glutamina, S100B e citocinas. Neste trabalho, induzimos status epilepticus (SE) em ratos jovens (PN28) através do modelo lítio-pilocarpina que mimetiza alterações neuronais, bioquímicas e morfológicas similares à ELT em humanos. Os animais foram divididos nos tempos 1, 14 e 56 dias após a indução de status epilepticus (SE). Estes períodos são caracterizados respectivamente como a fase aguda, latente e crônica da epilepsia. Inicialmente, analisamos as mudanças neuroquímicas e astrocitárias ao longo do tempo. Foi observada neuroinflamação inicial e transitória que promove morte neuronal e mudanças ao longo do tempo de astrogliose e disfunção astrocitária. Também foi observado que a proteína S100B, proteína ligante de cálcio, predominantemente astrocitária, pode ser considerado um marcador da disfunção neuronal e astrocitária promovida neste modelo de epilepsia. Em seguida, demonstramos que a modulação da secreção de S100B pelo anti-inflamatório dexametasona um dia após indução de SE reverte a neuroinflamação, astrogliose e disfunção astrocitária à curto e à longo prazo. Por conseguinte, observamos que a modulação do receptor GABAA através de agonistas e antagonistas GABAérgicos altera a secreção de S100B em fatias hipocampais agudas e em cultura de astrócitos. Portanto, pode-se sugerir que as alterações astrogliais e a neuroinflamação dependentes do tempo podem estar ligadas à excitabilidade neuronal e/ou à morte neuronal em ratos jovens em modelo de epilepsia; que a proteína S100B pode ser considerada um marcador deste modelo de epilepsia e que a modulação da sua secreção pode ser um possível alvo farmacológico no tratamento da epilepsia. / Temporal lobe epilepsy (TLE) is the most frequent type of epilepsy in humans and is more associated to refractory to anti-epileptic drugs (AED) in patients. The most AEDs are modulators of neuronal activity and act on ion channels, such as GABAA receptor. Studies have been demonstrating the role of glial cells and neuroinflammation in epileptogenesis. The modulation of this response may be a potential target for adjunctive drugs to anti-epileptic drugs. Astrocytes are glial cells that participated in the tripartite synapse and modulated neuronal activity. Astrocytes are able to promote homeostasis of ions and neurotransmitters, are responsible for energy metabolism and the production of neurotrophic factors, glutathione, glutamine, S100B and cytokines. In this work, we induced status epilepticus (SE) in young rats (PN28) through the lithiumpilocarpine model that mimics neuronal, biochemical and morphological alterations similar to ELT in humans. The animals were divided at times 1, 14 and 56 days after the induction of SE. These periods are characterized respectively as the acute, latent and chronic phase of epilepsy. Initially, we analyzed neurochemical and astrocytic changes over time. Initial and transient neuroinflammation was observed and promoted over time neuronal death, astrogliosis and astrocytic dysfunction. It has also been observed that the protein S100B, a calcium-binding protein, predominantly astrocytic, can be considered a marker of neuronal and astrocytic dysfunction promoted by this model of epilepsy. Next, we demonstrate that the modulation of S100B secretion by the antiinflammatory dexamethasone one day after SE induction reverses neuroinflammation, astrogliosis and astrocytic dysfunction in the acute and chronic time. Therefore, we analyzed that modulation of the GABAA receptor through GABAergics agonists and antagonists alters the secretion of S100B in acute hippocampal slices and in astrocyte culture. Therefore, it may be suggested that astroglial changes and time dependent neuroinflammation may be related to neuronal excitability and/or neuronal death in young rats in this epilepsy model; that S100B protein can be considered a marker of this epilepsy model and that the modulation of its secretion may be a possible pharmacological target in the treatment of epilepsy.

The mesolimbic dopamine (DA) system projects from the ventral tegmental area (VTA) to structures associated with the limbic system, primarily the nucleus accumbens (NAc). This system has been implicated in the rewarding effects of drugs of abuse. Many drugs of abuse act in the VTA, the NAc, or both. Dopamine neurons in the VTA that project to the NAc, and the GABA neurons that inhibit DA neurons locally in the VTA or project to the NAc, play an important role in mediating addiction to various drugs of abuse, in particular alcohol. There is a growing body of evidence of co-dependence of nicotine and ethanol drug abuse. Given this evidence, it is possible that both ethanol and nicotine target similar receptors in the NAc. The GABA-A and GABA-B receptors have also been implicated in the modulation of ethanol's reinforcing properties (Anstrom, Cromwell, Markowski, & Woodward, 2003; Besheer, Lepoutre, & Hodge, 2004; Colombo et al., 2000; Moore & Boehm, 2009; Stromberg, 2004; Walker & Koob, 2007). Thus, there is a growing literature suggesting that GABA receptors are implicated in ethanol reward. In these studies, we evaluated the possibility of co-dependence of nicotine and ethanol by activity on a similar receptor in the NAc. In addition, we evaluated the role of GABA modulation of DA release, in particular GABA-A receptors and GABA-B receptors, in modulating DA release in the NAc with acute ethanol exposure. The rationale for this study was predicated on the belief that advancement in the understanding of the brain mechanisms underlying the recreational use and abuse potential of alcohol will pave the way for more effective treatment strategies that could reverse alcohol dependence and co-dependence and save lives and resources throughout the world.