The present magisterial work explores issues of substance abuse while focusing on psychosocial factors influencing the onset of drug dependency. Definitions of what is a drug, what is drug dependency, history of drugs, and a list of most frequently abused types of drugs are discussed in the theoretical part of the present work. In addition, this part includes a discussion of possible prevention ways. The practical part describes qualitative research observations of 13 selected adult participants that are drug dependent. Theoretical approaches are applied to the given authentic narratives and the stories are finely analyzed. The aim of the work is to examine some assertions concerned with the causes and development of {\clqq}drug dependency`` phenomenon. Our findings indicate that in case {\clqq}drug dependency`` is an illness, it is an atypical illness: the individuals` paths from a healthy state to the state of illness are unique for each individual, though similar in its symptoms, nevertheless differing in their causes. Drug dependency does not seem to be a civilization disease and is not influenced by cultural or social factors. Thus it has not been determined whether drug abuse is truly an illness. However, the final stage of the {\clqq}drug path`` {--} i.e., drug dependency- is seen as illness, its onset is individual and partially genetically determined, with no parenting influence.

Estudos realizados anteriormente com pacientes adictos demonstram que embora não exista uma estrutura psíquica estável e profunda, específica aos comportamentos de dependência, alguns aspectos são recorrentes nesses pacientes. Dentre eles, podem-se destacar a incapacidade desses indivíduos pensarem, refletirem, adiarem e a substituição dessas habilidades pela ação; a profunda sensação de vazio existencial, com a qual não podem se deparar, devido à fraqueza egóica que não lhes permite tolerar as frustrações; uma permanente demanda por preenchimento; constante busca de um objeto mágico, exterior, capaz de aliviar a angústia existencial; precária capacidade de integrarem as imagens parentais que poderiam servir de modelos identificatórios, prejudicando identificações ulteriores e, conseqüentemente, o estabelecimento de relações duradouras; além de uma grande dificuldade no processo de identificação sexual. Estas dificuldades estendem-se, inevitavelmente, ao âmbito do tratamento, em que é verificada alta taxa de evasão. O presente estudo visa, por meio de cinco estudos de casos de pacientes drogadictos, investigar as características próprias da dinâmica afetiva desses indivíduos, expressas no Método de Rorschach e no processo de atendimento psicológico. Foram atendidos quatro jovens do sexo masculino e uma jovem do sexo feminino, adictos a drogas ilícitas, com idades variando entre 17 e 23 anos, em sessões individuais de psicoterapia de orientação psicanalítica, na Clínica Psicológica do Instituto de Psicologia da USP. O Método de Rorschach foi classificado e avaliado de acordo com a nomenclatura e os estudos franceses, articulados a uma leitura psicanalítica do material, com referencial kleiniano e winnicottiano. As sessões foram todas registradas e supervisionadas, seguindo esta mesma linha teórica. Nos casos estudados, há indícios que denotam dificuldades no âmbito afetivo, que nem sempre encontram expressão de maneira semelhante para cada indivíduo. A dinâmica revelada por meio do Método de Rorschach e dos atendimentos clínicos evidencia problemas na construção da identidade, que resulta em permanente sentimento de vazio, de incerteza e de inconsistência interior. O intenso trabalho pulsional, de origem agressiva, na maior parte dos casos, não consegue ser simbolizado e encontra descarga imediata. O estabelecimento de relacionamentos com as figuras parentais e, em decorrência, com as outras pessoas, apresenta-se prejudicado. As origens dessa problemática parecem estar ligadas ao desenvolvimento precoce desses indivíduos, em que não foi possível a vivência da relação mãe-filho de maneira satisfatória. As falhas não são totais, o que pode ser verificado pelo potencial intelectual desses pacientes, bem como pela preservação dos vínculos com a realidade. No entanto, a maternagem não foi suficientemente boa de maneira a permitir o sentimento de continuidade de ser, base para a força do ego. Assim, a intervenção com esse tipo de paciente pode encontrar melhores perspectivas na medida em que, em termos winnicottianos, o trabalho possa fornecer um novo ambiente, favorável e confiável, onde possam experimentar uma continuidade de ser, favorecendo a integração do self, permitindo a retomada do desenvolvimento emocional. / Previously studies with addicted patients have indicated that, although there is no stable and profound psychic structure, specific to dependency behaviors, some aspects are recurrent, with respect to these patients. Among them, we could emphasize these individuals incapability to think, reflect, postpone, as well as the substitution of these abilities by action; the profound sensation of existential emptiness, with which they cannot be confronted, due to the ego weakness, which does not allow them to tolerate frustrations; a permanent demand for fulfillment; constant search for a magic object, external, capable to relieve existential anguishes; precarious capacity to integrate parental images that could serve as identification models, jeopardizing ulterior identifications and, consequently, the establishment of everlasting relationships; beyond a great difficulty in the process of sexual identification. These difficulties, inevitably, extend themselves to the treatment field, in which a significant rate of evasion is observed. This study intends to investigate the corresponding characteristics of the affective dynamic of five drug addicted patients, as expressed in the Rorschach Test, as well as in the psychological practice. Four drug addicted men and one young woman were treated, with ages varying from 17 to 23, in individual psychoanalytical orientation psychotherapy sessions, at the Psychological Clinic of the Psychology Institute - São Paulo University. The Rorschach Test was classified and evaluated, in accordance with the French nomenclature and studies, articulated to a psychoanalytical material evaluation, with Klein and Winnicott references. All sessions were registered and supervised, in accordance with this same theoretical line. In the evaluated cases, there are indications that denote difficulties in the affective environment, which not always find similar expression as regards to each individual. The dynamic, revealed through the Rorschach Test and through the clinical sessions, indicates problems in the identity construction, which result in permanent feeling of emptiness, of uncertainty and interior inconsistency. The intensive drive work, of aggressive origin, in the great majority of cases, does not manage to be symbolized and finds immediate discharge. The establishments of relationships with parental figures and, as a result, with other people, are jeopardized. The origins of this problematic appear to be linked to the precocious development of these individuals, in which the mother-child relationship had not been made possible, in a satisfactory way. The failures are not absolute, as shown by the intellectual potential of these patients, as well as by the maintenance of their links with the reality. However, maternal links were not sufficiently good, in a way to allow the feeling of continuity of being, a base to the ego strength. Therefore, intervention with this kind of patient may find better perspectives when, in winnicottian terms, the work is able to provide a new environment, favorable and trustworthy, where they could experiment a continuity of being, which enables the self integration and permits the emotional development to go on.

Os problemas decorrentes do uso, abuso e dependência de drogas tornaram-se uma preocupação mundial, mobilizando recursos e ações interventivas na atenção aos usuários e dependentes. Entre os grupos, encontramos as mulheres, com características próprias, exigindo pesquisas e programas de tratamento específicos. Esta pesquisa procura privilegiar as especificidades do feminino e a dependência de drogas, através dos referenciais teóricos da psicanálise sobre a sexualidade feminina e a feminilidade. Utilizam-se, também, as concepções sobre o sujeito do grupo, que implicam uma subjetividade constituída nos e pelos conjuntos intersubjetivos, conforme desenvolve René Kaës. Considera-se que, de acordo com os postulados desse autor, a negatividade está na base de todo laço social, configurando as alianças inconscientes e as formações intermediárias no vínculo entre os sujeitos. Nesse sentido, propõe-se uma linha de investigação psicanalítica sobre a dependência química como um sintoma partilhado, objetivando: a) investigar os processos psíquicos relacionados à produção de sintomas em mulheres dependentes químicas, através dos discursos produzidos em uma situação de grupo; b) investigar as formações intermediárias e as modalidades de negatividade na manutenção do sintoma e do laço social. Como procedimento, foi utilizado um grupo psicoterapêutico em um Centro de Atenção Psicossocial Álcool e outras drogas (CAPS ad) e na análise foram consideradas: a interdiscursividade e a linearidade dos enunciados; a transferência e a contratransferência; e a realidade psíquica do/no grupo. Através da análise do discurso em situação de grupo, foram elaboradas três categorias representantes da produção intersubjetiva: as formações intermediárias (porta-voz, porta-sintoma, porta-ideal), as modalidades de negatividade (a negatividade de obrigação e a negatividade radical) e o complexo fraterno. Conclui-se que a dependência química em mulheres é uma formação intermediária, representando aspectos denegados dos conjuntos intersubjetivos a que pertencem (família e instituição de tratamento). Através do pacto denegativo, a vulnerabilidade e o desamparo são expulsos da dinâmica intersubjetiva e intrapsíquica marcas da feminilidade na constituição subjetiva. A aliança inconsciente fundamenta-se, portanto, na denegação dos elementos relacionados à dimensão do sensível, do corpo, da sexualidade, do desejo e da incompletude humana. A dependência química feminina configura-se como portavoz do que é intolerável na feminilidade. / The problems arisen from drug use, abuse and dependence became a global issue, mobilizing resources and interventional actions concerning recreational users and addicts. Among different groups of users there are women, with their own characteristics that demand specific research and treatment programs. This research aims at focusing the specificity of the feminine and drug dependence through theoretical psychoanalytical references about feminine sexuality and femininity. We will also use the concept of subject of a group that implies constituted subjectivity within and by inter-subjective groups, according to René Kaës. He states that negativity is in the base of every social tie, configuring unconscious alliances and intermediary formations regarding connections among subjects. In this sense, we propose a psychoanalytical investigative method about chemical dependency as a shared symptom aiming at: a) investigating the chemical processes related to symptoms production in chemical dependent women through speeches produced in a group situation; b) investigating the intermediary formations and the modalities of negativity in symptoms and social ties maintenance. We worked with a psychotherapy group in an Alcohol and other drugs Psychosocial Attention Center (CAPS ad). In our analysis we considered: the interdiscursivity and the linearity of the utterances; the transference and the countertransference; the psychic reality of/in the group. Through discourse analysis, we elaborated three representative categories of the inter-subjective production: the intermediary formations (spokesperson, symptomatic-person, ideal-person), the modalities of negativity (the negativity of obligation and the radical negativity) and the sibling complex. We can conclude that chemical dependency in women is an intermediary formation, representing denied aspects of the inter-subjective groups which they belong to (family and treatment institution). Through the pact of denial, the vulnerability and the defenseless are driven out of the inter-subjective and intra-psychic dynamic which are aspects of the femininity in the subjective constitution. The unconscious alliance is founded, thus, on the denial of the elements related to the dimension of the sensibility, of the body, of the sexuality, of the desire and of the human incompleteness. The feminine chemical dependency takes form as the spokesperson of what is unbearable in femininity.

Esta pesquisa estuda a relação entre o ambiente em que ratos se desenvolvem e a auto-administração de etanol (ET) na idade adulta. Usualmente, a pesquisa comportamental com animais em laboratório utiliza sujeitos mantidos em isolamento em caixas individuasi (I). Uma das espécies mais usadas é o rato, um animal social que em habitat natural vive em colônias. Que efeitos tem o isolamento nesses ratos? Propõe-se que a baixa disponibilidade de reforçadores alternativos seja um dos fatores determinantes do abuso de drogas. Algumas pesquisas mostraram que o isolamento, que caracteriza ambientes de baixa disponibilidade de reforçadores, leva a um aumento no consumo de morfina, anfetamina e barbital em relação a ratos criados em ambientes com maior disponibilidade de reforçadores (AE), e mais ET comparados a animais criados em grupo. No entanto, outras pesquisas observaram que animais criados em AE consomem mais ET do que animais criados em isolamento. Utilizando medidas de comportamento operante de ingestão de ET, o presente experimento visou observar se a disponibilidade de reforçadores no ambiente de criação e/ou concorrentes ao álcool no ambiente experimental altera o consumo, o valor reforçador e a elasticidade da demanda dessa droga. Ratos Wistar machos foram criados em I ou em AE. O consumo e o valor reforçador do ET foram medidos nos esquemas operantes de FR2 e Razão Progressiva (RP), respectivamente. O ET foi introduzido por fade in/fade out de sacarose, culminando numa solução de ET 10% adoçada com sacarina 0,25%. O teste de RP foi conduzido para solução de ET, depois para sacarina. Os animais foram submetidos também ao teste de ansiedade no labirinto em cruz elevado e sua atividade motora foi estimada em caixa de atividade. Os ratos I consumiram e responderam significativamente mais pelo ET comparados aos ratos AE. Os ratos I evidenciaram aumento do valor reforçador do ET, mas não da sacarina, medido em RP, quando comparados aos do grupo AE. Os grupos AE e I não apresentaram diferenças significativas em ansiedade. Os animais do grupo I mostraram-se significativamente mais ativos do que os do grupo AE. A elasticidade da demanda foi medida em um modelo concorrente no qual uma alternativa dispensava solução de ET e a outra uma solução isocalórica ao ET, e as exigências em VR foram aumentadas progressivamente, primeiro para a alternativa isocalórica, e depois para o ET. A introdução de reforçadores concorrentes alterou o consumo de ET dos animais criados em I sem alterar o comportamento dos animais criados em AE. A criação nos diferentes ambientes não alterou a elasticidade da demanda por ET, porém alterou a elasticidade da demanda pelo reforçador concorrente. Os animais do grupo I, apesar de consumirem significativamente mais da solução alternativa ao ET, apresentaram uma demanda mais elástica em relação a esse reforçador quando comparados aos do grupo AE. A dependência de drogas, e do álcool em especial, pode e deve ser entendida dentro das mesmas leis que regulam o comportamento em geral, e os modelos de escolha são essenciais para essa compreensão. / This research investigated the influence of different types of rearing environment on ethanol (ET) self-administration in adult rats. Usually behavioral research is conducted using isolated animals (I), one widely used animal is the rat, a social animal that under normal circumstances lives at large colonies. What kind of effects could this unnatural isolation have? It has been proposed that one major factor in drug abuse and dependence is the lack for alternative reinforcers to the drug. Animals raised in limited environments with few reinforcers (I) consume more morphine, amphetamine and barbital than animals raised in enriched environments (EE), which present different opportunities of behavior. These isolated rats have also been shown to consume more ET; however, there are some contradictory results within studies: some have even shown enhanced consumption in EE rats. The present study proposed to investigate whether differential presence of reinforcers during rearing or concurrently to the presentation of ET would influence its consumption, reiforcer value and demand elasticity. Male Wistar rats were raised either in EE or I. Using a self administration paradigm, consumption and reiforcer value were estimated in a FR2 and Progressive Ratio (PR), respectively. ET was introduced by fade in as sucrose was faded out from the solution, resulting in a 10% ET solution sweetened with saccharin 0,25% as the reinforcer solution. The PR procedure was first conducted using the ET solution and then with just the saccharin solution (vehicle). Anxiety was estimated using the elevated cross maze model, and motor activity was accessed in the activity box. I rats consumed and responded more for ET than EE rats in FR2 schedule. They also presented higher reiforcer value for ET in the PR paradigm, but not for saccharin, when compared to EE rats. There was no significant difference between groups in anxiety levels, but I rats were significantly more active. Using a concurrent model, with ET solution and an isochaloric solution as reiforcers, the demand elasticity was accessed by increasingly VRs, first for the isochaloric alternative, then for the ET solution. The introduction of an isochaloric concurrent reiforcer altered ET consumption of I rats, without affecting EE rats consumption. Groups did not differ in demand elasticity for ET, but it was shown that this demand is relatively inelastic while demand for the isochaloric solution is very elastic, especially for I rats, though. I rats consumed more isochaloric solutions than EE rats. Drug abuse and dependency must be understood using the same laws that regulate so called normal behavior, these phenomena do not belong to a special category, and choice models are essential for that understanding.

Alcohol and tobacco are drugs of abuse which are legal to sell and consume in most western societies. Addiction to these two substances has major social and health implications worldwide. The brain structure known to mediate addictive behaviour is the dopaminergic mesocorticolimbic system. Dopaminegic neurons arise from the ventral tegmental area, project to the nucleus accumbens and interact with the amygdala and the prefrontal cortex. Chronic alcoholism elicits marked damage in the prefrontal cortex with significant loss of neurons and glia. The key components of addiction, tolerance and dependence, are thought to be the result of semipermanent adaptive changes in gene expression. Gene expression profiling of the mesocorticolimbic system from human alcoholics and alcohol-dependent animals has revealed highly region-specific alterations. How these molecular changes result in the development of alcohol dependence in humans is not fully understood. Complicating factors in human alcoholism include a high comorbidity with smoking, socioeconomic factors and the prevalence of underlying psychological pathologies. Gene expression profiling of the prefrontal cortex of six alcoholics and six controls resulted in the identification of functional gene groups sensitive to alcoholism. Mitochondrial function was found down regulated while mRNA levels of genes involved in stress response and cell protection were elevated. These results correlate with the pathology of the prefrontal cortex in chronic alcoholism. Some of the control cases used for gene expression profiling were later identified as chronic smokers, while all of the alcoholics were heavy smokers. To date the heavy co-morbidity of alcoholism with smoking has not been taken into account. Thus the expression of selected genes were investigated by realtime PCR in an extended case set of non-smoking alcoholics, smoking alcoholics, smoking non-alcoholics and non-smoking, non-alcoholics. This study revealed that alcoholism itself had a significant impact on the expression of midkine, the high affinity glial glutamate transporter, member 1 and the tissue inhibitor of the metalloproteinase 3. Heavy smoking itself led to a small but significant elevation of MDK mRNA levels as well as an increase in variation of excitatory amino acid transporter 1 and metalloproteinase inhibitor, member 3 expression. Apolipoprotein D however was induced by chronic smoking but not by alcohol dependence. These results highlight the need of careful case selection in future studies on gene expression in the human alcoholic brain. Peptide antibodies were produced to midkine and a polyclonal antibody against the excitatory amino acid transporter 1 was obtained from a collaborating laboratory. Western blots utilizing these antibodies revealed a marked increase in midkine and excitatory amino acid transporter 1 protein in alcoholics compared to non-smoking and non-drinking controls. In coronal sections of human prefrontal cortex of alcoholics and non-smoking non-drinking controls, immunofluorescence of midkine was obtained from nuclei throughout the layers of the cortex and from the cell bodies of a distinct set of astrocytes in cortical layer II. Double staining with glial fibrillary acidic protein revealed that a portion of midkine-positive nuclei were localised in glial cells. There was no difference in immunostaining of alcohol and control sections with midkine. In summary these results indicate that midkine protein is induced in the prefrontal cortex of the chronic alcoholic. However, this increase in protein may not be strong enough to be visualised by immunohistochemistry. Midkine induction may be reflective of reparative processes in the prefrontal cortex of the chronic alcoholic. Excitatory amino acid transporter 1 staining in non-alcoholic, non-smoking control cases were obtained as a confluent band in cortical layer II and sparsely in deeper cortical layers. Excitatory amino acid transporter 1 immunoreactivity overlapped partially with glial fibrillary acidic protein labelling. In chronic alcoholics, excitatory amino acid transporter 1 staining in the area between the cortical layer II and VI was significantly increased. At withdrawal, glutamate levels may reach toxic levels in the cortex. The increase in cells expressing excitatory amino acid transporter 1 throughout the cortical layers may indicate a protective measure of this brain region in the chronic alcoholic. Additionally, layer specific expression of midkine and excitatory amino acid transporter 1 in the prefrontal cortex of the healthy individual may implicate a specialised role of these astrocytes.

Alcohol and tobacco are drugs of abuse which are legal to sell and consume in most western societies. Addiction to these two substances has major social and health implications worldwide. The brain structure known to mediate addictive behaviour is the dopaminergic mesocorticolimbic system. Dopaminegic neurons arise from the ventral tegmental area, project to the nucleus accumbens and interact with the amygdala and the prefrontal cortex. Chronic alcoholism elicits marked damage in the prefrontal cortex with significant loss of neurons and glia. The key components of addiction, tolerance and dependence, are thought to be the result of semipermanent adaptive changes in gene expression. Gene expression profiling of the mesocorticolimbic system from human alcoholics and alcohol-dependent animals has revealed highly region-specific alterations. How these molecular changes result in the development of alcohol dependence in humans is not fully understood. Complicating factors in human alcoholism include a high comorbidity with smoking, socioeconomic factors and the prevalence of underlying psychological pathologies. Gene expression profiling of the prefrontal cortex of six alcoholics and six controls resulted in the identification of functional gene groups sensitive to alcoholism. Mitochondrial function was found down regulated while mRNA levels of genes involved in stress response and cell protection were elevated. These results correlate with the pathology of the prefrontal cortex in chronic alcoholism. Some of the control cases used for gene expression profiling were later identified as chronic smokers, while all of the alcoholics were heavy smokers. To date the heavy co-morbidity of alcoholism with smoking has not been taken into account. Thus the expression of selected genes were investigated by realtime PCR in an extended case set of non-smoking alcoholics, smoking alcoholics, smoking non-alcoholics and non-smoking, non-alcoholics. This study revealed that alcoholism itself had a significant impact on the expression of midkine, the high affinity glial glutamate transporter, member 1 and the tissue inhibitor of the metalloproteinase 3. Heavy smoking itself led to a small but significant elevation of MDK mRNA levels as well as an increase in variation of excitatory amino acid transporter 1 and metalloproteinase inhibitor, member 3 expression. Apolipoprotein D however was induced by chronic smoking but not by alcohol dependence. These results highlight the need of careful case selection in future studies on gene expression in the human alcoholic brain. Peptide antibodies were produced to midkine and a polyclonal antibody against the excitatory amino acid transporter 1 was obtained from a collaborating laboratory. Western blots utilizing these antibodies revealed a marked increase in midkine and excitatory amino acid transporter 1 protein in alcoholics compared to non-smoking and non-drinking controls. In coronal sections of human prefrontal cortex of alcoholics and non-smoking non-drinking controls, immunofluorescence of midkine was obtained from nuclei throughout the layers of the cortex and from the cell bodies of a distinct set of astrocytes in cortical layer II. Double staining with glial fibrillary acidic protein revealed that a portion of midkine-positive nuclei were localised in glial cells. There was no difference in immunostaining of alcohol and control sections with midkine. In summary these results indicate that midkine protein is induced in the prefrontal cortex of the chronic alcoholic. However, this increase in protein may not be strong enough to be visualised by immunohistochemistry. Midkine induction may be reflective of reparative processes in the prefrontal cortex of the chronic alcoholic. Excitatory amino acid transporter 1 staining in non-alcoholic, non-smoking control cases were obtained as a confluent band in cortical layer II and sparsely in deeper cortical layers. Excitatory amino acid transporter 1 immunoreactivity overlapped partially with glial fibrillary acidic protein labelling. In chronic alcoholics, excitatory amino acid transporter 1 staining in the area between the cortical layer II and VI was significantly increased. At withdrawal, glutamate levels may reach toxic levels in the cortex. The increase in cells expressing excitatory amino acid transporter 1 throughout the cortical layers may indicate a protective measure of this brain region in the chronic alcoholic. Additionally, layer specific expression of midkine and excitatory amino acid transporter 1 in the prefrontal cortex of the healthy individual may implicate a specialised role of these astrocytes.

Alcohol and tobacco are drugs of abuse which are legal to sell and consume in most western societies. Addiction to these two substances has major social and health implications worldwide. The brain structure known to mediate addictive behaviour is the dopaminergic mesocorticolimbic system. Dopaminegic neurons arise from the ventral tegmental area, project to the nucleus accumbens and interact with the amygdala and the prefrontal cortex. Chronic alcoholism elicits marked damage in the prefrontal cortex with significant loss of neurons and glia. The key components of addiction, tolerance and dependence, are thought to be the result of semipermanent adaptive changes in gene expression. Gene expression profiling of the mesocorticolimbic system from human alcoholics and alcohol-dependent animals has revealed highly region-specific alterations. How these molecular changes result in the development of alcohol dependence in humans is not fully understood. Complicating factors in human alcoholism include a high comorbidity with smoking, socioeconomic factors and the prevalence of underlying psychological pathologies. Gene expression profiling of the prefrontal cortex of six alcoholics and six controls resulted in the identification of functional gene groups sensitive to alcoholism. Mitochondrial function was found down regulated while mRNA levels of genes involved in stress response and cell protection were elevated. These results correlate with the pathology of the prefrontal cortex in chronic alcoholism. Some of the control cases used for gene expression profiling were later identified as chronic smokers, while all of the alcoholics were heavy smokers. To date the heavy co-morbidity of alcoholism with smoking has not been taken into account. Thus the expression of selected genes were investigated by realtime PCR in an extended case set of non-smoking alcoholics, smoking alcoholics, smoking non-alcoholics and non-smoking, non-alcoholics. This study revealed that alcoholism itself had a significant impact on the expression of midkine, the high affinity glial glutamate transporter, member 1 and the tissue inhibitor of the metalloproteinase 3. Heavy smoking itself led to a small but significant elevation of MDK mRNA levels as well as an increase in variation of excitatory amino acid transporter 1 and metalloproteinase inhibitor, member 3 expression. Apolipoprotein D however was induced by chronic smoking but not by alcohol dependence. These results highlight the need of careful case selection in future studies on gene expression in the human alcoholic brain. Peptide antibodies were produced to midkine and a polyclonal antibody against the excitatory amino acid transporter 1 was obtained from a collaborating laboratory. Western blots utilizing these antibodies revealed a marked increase in midkine and excitatory amino acid transporter 1 protein in alcoholics compared to non-smoking and non-drinking controls. In coronal sections of human prefrontal cortex of alcoholics and non-smoking non-drinking controls, immunofluorescence of midkine was obtained from nuclei throughout the layers of the cortex and from the cell bodies of a distinct set of astrocytes in cortical layer II. Double staining with glial fibrillary acidic protein revealed that a portion of midkine-positive nuclei were localised in glial cells. There was no difference in immunostaining of alcohol and control sections with midkine. In summary these results indicate that midkine protein is induced in the prefrontal cortex of the chronic alcoholic. However, this increase in protein may not be strong enough to be visualised by immunohistochemistry. Midkine induction may be reflective of reparative processes in the prefrontal cortex of the chronic alcoholic. Excitatory amino acid transporter 1 staining in non-alcoholic, non-smoking control cases were obtained as a confluent band in cortical layer II and sparsely in deeper cortical layers. Excitatory amino acid transporter 1 immunoreactivity overlapped partially with glial fibrillary acidic protein labelling. In chronic alcoholics, excitatory amino acid transporter 1 staining in the area between the cortical layer II and VI was significantly increased. At withdrawal, glutamate levels may reach toxic levels in the cortex. The increase in cells expressing excitatory amino acid transporter 1 throughout the cortical layers may indicate a protective measure of this brain region in the chronic alcoholic. Additionally, layer specific expression of midkine and excitatory amino acid transporter 1 in the prefrontal cortex of the healthy individual may implicate a specialised role of these astrocytes.

Alcohol and tobacco are drugs of abuse which are legal to sell and consume in most western societies. Addiction to these two substances has major social and health implications worldwide. The brain structure known to mediate addictive behaviour is the dopaminergic mesocorticolimbic system. Dopaminegic neurons arise from the ventral tegmental area, project to the nucleus accumbens and interact with the amygdala and the prefrontal cortex. Chronic alcoholism elicits marked damage in the prefrontal cortex with significant loss of neurons and glia. The key components of addiction, tolerance and dependence, are thought to be the result of semipermanent adaptive changes in gene expression. Gene expression profiling of the mesocorticolimbic system from human alcoholics and alcohol-dependent animals has revealed highly region-specific alterations. How these molecular changes result in the development of alcohol dependence in humans is not fully understood. Complicating factors in human alcoholism include a high comorbidity with smoking, socioeconomic factors and the prevalence of underlying psychological pathologies. Gene expression profiling of the prefrontal cortex of six alcoholics and six controls resulted in the identification of functional gene groups sensitive to alcoholism. Mitochondrial function was found down regulated while mRNA levels of genes involved in stress response and cell protection were elevated. These results correlate with the pathology of the prefrontal cortex in chronic alcoholism. Some of the control cases used for gene expression profiling were later identified as chronic smokers, while all of the alcoholics were heavy smokers. To date the heavy co-morbidity of alcoholism with smoking has not been taken into account. Thus the expression of selected genes were investigated by realtime PCR in an extended case set of non-smoking alcoholics, smoking alcoholics, smoking non-alcoholics and non-smoking, non-alcoholics. This study revealed that alcoholism itself had a significant impact on the expression of midkine, the high affinity glial glutamate transporter, member 1 and the tissue inhibitor of the metalloproteinase 3. Heavy smoking itself led to a small but significant elevation of MDK mRNA levels as well as an increase in variation of excitatory amino acid transporter 1 and metalloproteinase inhibitor, member 3 expression. Apolipoprotein D however was induced by chronic smoking but not by alcohol dependence. These results highlight the need of careful case selection in future studies on gene expression in the human alcoholic brain. Peptide antibodies were produced to midkine and a polyclonal antibody against the excitatory amino acid transporter 1 was obtained from a collaborating laboratory. Western blots utilizing these antibodies revealed a marked increase in midkine and excitatory amino acid transporter 1 protein in alcoholics compared to non-smoking and non-drinking controls. In coronal sections of human prefrontal cortex of alcoholics and non-smoking non-drinking controls, immunofluorescence of midkine was obtained from nuclei throughout the layers of the cortex and from the cell bodies of a distinct set of astrocytes in cortical layer II. Double staining with glial fibrillary acidic protein revealed that a portion of midkine-positive nuclei were localised in glial cells. There was no difference in immunostaining of alcohol and control sections with midkine. In summary these results indicate that midkine protein is induced in the prefrontal cortex of the chronic alcoholic. However, this increase in protein may not be strong enough to be visualised by immunohistochemistry. Midkine induction may be reflective of reparative processes in the prefrontal cortex of the chronic alcoholic. Excitatory amino acid transporter 1 staining in non-alcoholic, non-smoking control cases were obtained as a confluent band in cortical layer II and sparsely in deeper cortical layers. Excitatory amino acid transporter 1 immunoreactivity overlapped partially with glial fibrillary acidic protein labelling. In chronic alcoholics, excitatory amino acid transporter 1 staining in the area between the cortical layer II and VI was significantly increased. At withdrawal, glutamate levels may reach toxic levels in the cortex. The increase in cells expressing excitatory amino acid transporter 1 throughout the cortical layers may indicate a protective measure of this brain region in the chronic alcoholic. Additionally, layer specific expression of midkine and excitatory amino acid transporter 1 in the prefrontal cortex of the healthy individual may implicate a specialised role of these astrocytes.

Alcohol and tobacco are drugs of abuse which are legal to sell and consume in most western societies. Addiction to these two substances has major social and health implications worldwide. The brain structure known to mediate addictive behaviour is the dopaminergic mesocorticolimbic system. Dopaminegic neurons arise from the ventral tegmental area, project to the nucleus accumbens and interact with the amygdala and the prefrontal cortex. Chronic alcoholism elicits marked damage in the prefrontal cortex with significant loss of neurons and glia. The key components of addiction, tolerance and dependence, are thought to be the result of semipermanent adaptive changes in gene expression. Gene expression profiling of the mesocorticolimbic system from human alcoholics and alcohol-dependent animals has revealed highly region-specific alterations. How these molecular changes result in the development of alcohol dependence in humans is not fully understood. Complicating factors in human alcoholism include a high comorbidity with smoking, socioeconomic factors and the prevalence of underlying psychological pathologies. Gene expression profiling of the prefrontal cortex of six alcoholics and six controls resulted in the identification of functional gene groups sensitive to alcoholism. Mitochondrial function was found down regulated while mRNA levels of genes involved in stress response and cell protection were elevated. These results correlate with the pathology of the prefrontal cortex in chronic alcoholism. Some of the control cases used for gene expression profiling were later identified as chronic smokers, while all of the alcoholics were heavy smokers. To date the heavy co-morbidity of alcoholism with smoking has not been taken into account. Thus the expression of selected genes were investigated by realtime PCR in an extended case set of non-smoking alcoholics, smoking alcoholics, smoking non-alcoholics and non-smoking, non-alcoholics. This study revealed that alcoholism itself had a significant impact on the expression of midkine, the high affinity glial glutamate transporter, member 1 and the tissue inhibitor of the metalloproteinase 3. Heavy smoking itself led to a small but significant elevation of MDK mRNA levels as well as an increase in variation of excitatory amino acid transporter 1 and metalloproteinase inhibitor, member 3 expression. Apolipoprotein D however was induced by chronic smoking but not by alcohol dependence. These results highlight the need of careful case selection in future studies on gene expression in the human alcoholic brain. Peptide antibodies were produced to midkine and a polyclonal antibody against the excitatory amino acid transporter 1 was obtained from a collaborating laboratory. Western blots utilizing these antibodies revealed a marked increase in midkine and excitatory amino acid transporter 1 protein in alcoholics compared to non-smoking and non-drinking controls. In coronal sections of human prefrontal cortex of alcoholics and non-smoking non-drinking controls, immunofluorescence of midkine was obtained from nuclei throughout the layers of the cortex and from the cell bodies of a distinct set of astrocytes in cortical layer II. Double staining with glial fibrillary acidic protein revealed that a portion of midkine-positive nuclei were localised in glial cells. There was no difference in immunostaining of alcohol and control sections with midkine. In summary these results indicate that midkine protein is induced in the prefrontal cortex of the chronic alcoholic. However, this increase in protein may not be strong enough to be visualised by immunohistochemistry. Midkine induction may be reflective of reparative processes in the prefrontal cortex of the chronic alcoholic. Excitatory amino acid transporter 1 staining in non-alcoholic, non-smoking control cases were obtained as a confluent band in cortical layer II and sparsely in deeper cortical layers. Excitatory amino acid transporter 1 immunoreactivity overlapped partially with glial fibrillary acidic protein labelling. In chronic alcoholics, excitatory amino acid transporter 1 staining in the area between the cortical layer II and VI was significantly increased. At withdrawal, glutamate levels may reach toxic levels in the cortex. The increase in cells expressing excitatory amino acid transporter 1 throughout the cortical layers may indicate a protective measure of this brain region in the chronic alcoholic. Additionally, layer specific expression of midkine and excitatory amino acid transporter 1 in the prefrontal cortex of the healthy individual may implicate a specialised role of these astrocytes.

Alcohol and tobacco are drugs of abuse which are legal to sell and consume in most western societies. Addiction to these two substances has major social and health implications worldwide. The brain structure known to mediate addictive behaviour is the dopaminergic mesocorticolimbic system. Dopaminegic neurons arise from the ventral tegmental area, project to the nucleus accumbens and interact with the amygdala and the prefrontal cortex. Chronic alcoholism elicits marked damage in the prefrontal cortex with significant loss of neurons and glia. The key components of addiction, tolerance and dependence, are thought to be the result of semipermanent adaptive changes in gene expression. Gene expression profiling of the mesocorticolimbic system from human alcoholics and alcohol-dependent animals has revealed highly region-specific alterations. How these molecular changes result in the development of alcohol dependence in humans is not fully understood. Complicating factors in human alcoholism include a high comorbidity with smoking, socioeconomic factors and the prevalence of underlying psychological pathologies. Gene expression profiling of the prefrontal cortex of six alcoholics and six controls resulted in the identification of functional gene groups sensitive to alcoholism. Mitochondrial function was found down regulated while mRNA levels of genes involved in stress response and cell protection were elevated. These results correlate with the pathology of the prefrontal cortex in chronic alcoholism. Some of the control cases used for gene expression profiling were later identified as chronic smokers, while all of the alcoholics were heavy smokers. To date the heavy co-morbidity of alcoholism with smoking has not been taken into account. Thus the expression of selected genes were investigated by realtime PCR in an extended case set of non-smoking alcoholics, smoking alcoholics, smoking non-alcoholics and non-smoking, non-alcoholics. This study revealed that alcoholism itself had a significant impact on the expression of midkine, the high affinity glial glutamate transporter, member 1 and the tissue inhibitor of the metalloproteinase 3. Heavy smoking itself led to a small but significant elevation of MDK mRNA levels as well as an increase in variation of excitatory amino acid transporter 1 and metalloproteinase inhibitor, member 3 expression. Apolipoprotein D however was induced by chronic smoking but not by alcohol dependence. These results highlight the need of careful case selection in future studies on gene expression in the human alcoholic brain. Peptide antibodies were produced to midkine and a polyclonal antibody against the excitatory amino acid transporter 1 was obtained from a collaborating laboratory. Western blots utilizing these antibodies revealed a marked increase in midkine and excitatory amino acid transporter 1 protein in alcoholics compared to non-smoking and non-drinking controls. In coronal sections of human prefrontal cortex of alcoholics and non-smoking non-drinking controls, immunofluorescence of midkine was obtained from nuclei throughout the layers of the cortex and from the cell bodies of a distinct set of astrocytes in cortical layer II. Double staining with glial fibrillary acidic protein revealed that a portion of midkine-positive nuclei were localised in glial cells. There was no difference in immunostaining of alcohol and control sections with midkine. In summary these results indicate that midkine protein is induced in the prefrontal cortex of the chronic alcoholic. However, this increase in protein may not be strong enough to be visualised by immunohistochemistry. Midkine induction may be reflective of reparative processes in the prefrontal cortex of the chronic alcoholic. Excitatory amino acid transporter 1 staining in non-alcoholic, non-smoking control cases were obtained as a confluent band in cortical layer II and sparsely in deeper cortical layers. Excitatory amino acid transporter 1 immunoreactivity overlapped partially with glial fibrillary acidic protein labelling. In chronic alcoholics, excitatory amino acid transporter 1 staining in the area between the cortical layer II and VI was significantly increased. At withdrawal, glutamate levels may reach toxic levels in the cortex. The increase in cells expressing excitatory amino acid transporter 1 throughout the cortical layers may indicate a protective measure of this brain region in the chronic alcoholic. Additionally, layer specific expression of midkine and excitatory amino acid transporter 1 in the prefrontal cortex of the healthy individual may implicate a specialised role of these astrocytes.