Nicotinic Receptors Underlying Nicotine Dependence: Evidence from Transgenic Mouse Models.

Nicotine underlies the reinforcing properties of tobacco cigarettes and e-cigarettes. After inhalation and absorption, nicotine binds to various nicotinic acetylcholine receptor (nAChR) subtypes localized on the pre- and postsynaptic membranes of cells, which subsequently leads to the modulation of cellular function and neurotransmitter signaling. In this chapter, we begin by briefly reviewing the current understanding of nicotine's actions on nAChRs and highlight considerations regarding nAChR subtype localization and pharmacodynamics. Thereafter, we discuss the seminal discoveries derived from genetically modified mouse models, which have greatly contributed to our understanding of nicotine's effects on the reward-related mesolimbic pathway and the aversion-related habenulo-interpeduncular pathway. Thereafter, emerging areas of research focusing on modulation of nAChR expression and/or function are considered. Taken together, these discoveries have provided a foundational understanding of various genetic, neurobiological, and behavioral factors underlying the motivation to use nicotine and related dependence processes, which are thereby advancing drug discovery efforts to promote long-term abstinence

Molecular Mechanisms Associated with Nicotine Pharmacology and Dependence.

Tobacco dependence is a leading cause of preventable disease and death worldwide. Nicotine, the main psychoactive component in tobacco cigarettes, has also been garnering increased popularity in its vaporized form, as derived from e-cigarette devices. Thus, an understanding of the molecular mechanisms underlying nicotine pharmacology and dependence is required to ascertain novel approaches to treat drug dependence. In this chapter, we review the field's current understanding of nicotine's actions in the brain, the neurocircuitry underlying drug dependence, factors that modulate the function of nicotinic acetylcholine receptors, and the role of specific genes in mitigating the vulnerability to develop nicotine dependence. In addition to nicotine's direct actions in the brain, other constituents in nicotine and tobacco products have also been found to alter drug use, and thus, evidence is provided to highlight this issue. Finally, currently available pharmacotherapeutic strategies are discussed, along with an outlook for future therapeutic directions to achieve to the goal of long-term nicotine cessation

Perfil da violência contra mulheres atendidas na Pousada de Maria Perfil de la violencia sufrida por mujeres atendidas en la Posada de María Profile of the violence committed against women assisted at Pousada de Maria lodging

Pesquisa exploratória, retrospectiva, realizada na Pousada de Maria, em Curitiba, em 2007. Teve como objetivo caracterizar o perfil da violência praticada contra mulheres residentes na Pousada de Maria, durante os anos de 1993 à 2007. Os dados foram obtidos através da análise de 886 fichas de registro das vítimas, transcritos para um instrumento construído para a pesquisa. As vítimas tinham idade entre 18 e 88 anos, baixa escolaridade, e sofreram violência física, psicológica, sexual e estrutural, principalmente pelos companheiros e pessoas conhecidas. Convivem com a violência para manter a união familiar, e rompem com ela na existência de programas sociais e abrigos. A violência é um fenômeno frequente entre mulheres solteiras, com ensino fundamental incompleto: 24,6% delas sofreram violência física, 24,15%, psicológica, 14,22%, violência estrutural. As solteiras, amasiadas e casadas devem ser inseridas como grupo de risco e objeto de atenção, pelos profissionais de saúde no planejamento de ações preventivas.<br>Investigación exploratoria retrospectiva, realizada en la Posada de María en Curitiba, Brasil, en el año 2007, con el fin de caracterizar el perfil de la violencia ejercida contra mujeres que residieron en dicha institución en el período comprendido entre 1993 a 2007. Los datos fueron obtenidos a través del análisis de 886 fichas de registro de las víctimas y transcriptos para un instrumento formulado para la investigación. Las víctimas tenían entre 18 y 88 años, bajo índice de escolaridad; fueron víctimas de violencia física, psicológica, sexual y estructural, inflingida principalmente por sus compañeros y personas conocidas. Convivieron con la violencia para mantener la unión familiar, se libraron de ella cuando tuvieron acceso a programas sociales y amparos. La violencia es un fenómeno frecuente entre mujeres solteras con enseñanza primaria incompleta, 24,6% de ellas sufrieron violencia física, 24,15% psicológica, 14,22% violencia estructural. Las mujeres solteras, en concubinato y casadas deben ser insertadas como grupo de riesgo y objeto de atención por parte de los profesionales de la salud, en la planificación de acciones preventivas.<br>This exploratory, retrospective study was performed at the Pousada de Maria lodging in Curitiba, Brazil in 2007, with the objective of characterizing the profile of the violence practiced against women staying at Pousada de Maria from 1993 to 2007. Data collection was performed by analyzing 886 records of the victims' registration and transcribed to an instrument formulated for the study. The victims were between 18 and 88 years old, with low education; they suffered physical, psychological, sexual and structural violence, mainly by their partners and acquaintances. They lived with violence to maintain their family union and decided to resolve the situation when they had access to social programs and shelters. Violence is a common phenomenon among single women with incomplete primary education; 24.6% suffered physical violence, 24.15% psychological, and 14.22% structural violence. Single women, whether in a common-law relationship or married, should be considered as an at-risk group and worthy subjects of attention by health professionals when planning preventive actions

Role of β4* nicotinic acetylcholine receptors in the habenulo-interpeduncular pathway in nicotine reinforcement in mice.

Nicotine exerts its psychopharmacological effects by activating the nicotinic acetylcholine receptor (nAChR), composed of alpha and/or beta subunits, giving rise to a diverse population of receptors with a distinct pharmacology. β4-containing (β4*) nAChRs are located almost exclusively in the habenulo-interpeduncular pathway. We examined the role of β4* nAChRs in the medial habenula (MHb) and the interpeduncular nucleus (IPN) in nicotine reinforcement using behavioral, electrophysiological, and molecular techniques in transgenic mice. Nicotine intravenous self-administration (IVSA) was lower in constitutive β4 knockout (KO) mice at all doses tested (7.5, 15, 30, and 60 μg/kg/infusion) compared with wild-type (WT) mice. In vivo microdialysis showed that β4KO mice have higher extracellular dopamine (DA) levels in the nucleus accumbens than in WT mice, and exhibit a differential sensitivity to nicotine-induced DA outflow. Furthermore, electrophysiological recordings in the ventral tegmental area (VTA) demonstrated that DA neurons of β4KO mice are more sensitive to lower doses of nicotine than that of WT mice. Re-expression of β4* nAChRs in IPN neurons fully restored nicotine IVSA, and attenuated the increased sensitivity of VTA DA neurons to nicotine. These findings suggest that β4* nAChRs in the IPN have a role in maintaining nicotine IVSAThis work was supported by the Spanish Instituto de Salud Carlos III (RD06/001/001 and PI10/01708; PI14/00210), FEDER funds, Ministerio de Ciencia e Innovación (#SAF2014-59648-P), the Catalan Government AGAUR (#2014-SGR-1547), Plan Nacional Sobre Drogas, Ministerio de Sanidad, Asuntos Sociales e Igualdad-MSASI (#PNSD- 2013-0068), FP7 ERANET program (NICO-GENE), the ICREA Foundation (ICREA Academia-2008), and a postdoctoral fellowship from CONACyT to AHS. The work in Paris was supported by the Institut Pasteur, Centre National de la Recherche Scientifique CNRS UMR 3571 (UM) and CNRS UMR 8246 (PF), the INSERM U1130 (PF), the Pierre et Marie Curie University (UM119), the Agence Nationale pour la Recherche (ANR Neuroscience), and FP7 ERANET program (NICO-GENE), Grant agreement n009 BLANC 20092009BLANC 20 NeuroCypres" project), Fondation EDF, the Fondation des Treilles, and the Foundation for Medical Research FMR (Equipe FRMDEQ20130326488 to PF). The groups of UM and PF are members of the Bio-Psy Labex. As such this work was supported by French state funds managed by the ANR within the Investissements d'Avenir programme under reference ANR-11-IDEX-0004-02. The teams of UM and PF are part of the École des Neurosciences de Paris Ile-de-France Network. We would like to thank Martine Soudant, Stephanie Pons, and Dulce Real for technical support, and Inés Ibañes-Tallon and Jessica/nAbles for providing the Tg(Chrnb4-cre)OL57Gsat/+ transgenic mic