Because GABA A receptors containing α2 subunits are highly represented in areas of the brain, such as nucleus accumbens (NAcc), frontal cortex, and amygdala, regions intimately involved in signaling motivation and reward, we hypothesized that manipulations of this receptor subtype would influence processing of rewards. Voltageclamp recordings from NAcc medium spiny neurons of mice with α2 gene deletion showed reduced synaptic GABA A receptor-mediated responses. Behaviorally, the deletion abolished cocaine's ability to potentiate behaviors conditioned to rewards (conditioned reinforcement), and to support behavioral sensitization. In mice with a point mutation in the benzodiazepine binding pocket of α2-GABA A receptors (α2H101R), GABAergic neurotransmission in medium spiny neurons was identical to that of WT (i.e., the mutation was silent), but importantly, receptor function was now facilitated by the atypical benzodiazepine Ro 15-4513 (ethyl 8-amido-5,6-dihydro-5-methyl-6-oxo-4H-imidazo [1,5-a] [1,4] benzodiazepine-3-carboxylate). In α2H101R, but not WT mice, Ro 15-4513 administered directly into the NAcc-stimulated locomotor activity, and when given systemically and repeatedly, induced behavioral sensitization. These data indicate that activation of α2−GABA A receptors (most likely in NAcc) is both necessary and sufficient for behavioral sensitization. Consistent with a role of these receptors in addiction, we found specific markers and haplotypes of the GABRA2 gene to be associated with human cocaine addiction.GABRA2 | behavioral sensitization | nucleus accumbens | mutant mouse | human genetics

Cocaine addiction involves a number of medical, psychological and social problems. Understanding the genetic aetiology of this disorder will be essential for design of effective treatments. Dopaminebeta hydroxylase (DbH) catalyzes the conversion of dopamine to norepinephrine and could, therefore, have an influence on both cocaine action and the basal sensitivity of neurotransmitter systems to cocaine. Recently, the -1021C>T polymorphism have been found to strongly correlated with individual variation in plasma DbH activity. To test the influence of this polymorphism on the susceptibility of cocaine addiction, we decided to genotype it in a sample of 689 cocaine addicts and 832 healthy individuals. Genotypic and allelic analyses did not show any evidence of association with cocaine addiction, even after correcting for the effect of population stratification and other possible confounders. Our results do not support a major role of the -1021C>T polymorphism or the gene itself in the development of cocaine addiction but further examination of other variants within this gene will be necessary to completely rule out an effect. FindingsCocaine is one of the most powerfully addictive of the drugs of abuse. The number of cocaine users is estimated at some 13 million worldwide [1]. From those, 15-16% will become addicted within 10 years of first cocaine use [2]. Twin and family studies have demonstrated that cocaine addiction has a strong genetic component but the exact basis of the heritable factors that have a significant contribution to this phenotype remain unclear [3].Cocaine's potent actions in blocking the uptake by neuronal plasma membrane transporters for dopamine (DAT), serotonin (SERT), and norepinephrine (NET) are well known [4]. Studies in transgenic mice indicate that both DAT and SERT can mediate cocaine's rewarding effects, but the DAT may play the more important role [5]. On the other hand, mice lacking norepinephrine transporter demonstrated prolonged clearance of NE, elevated extracellular levels of this catecholamine and were behaviourally hypersensitive to cocaine and amphetamine, as measured by locomotor stimulation and conditioned place preference [6]. Similarly, double knockouts of both SERT and NET showed dramatically enhanced cocaine place preference [7].

Psychosis is the most ineffable experience of mental disorder. We provide here the first co‐written bottom‐up review of the lived experience of psychosis, whereby experts by experience primarily selected the subjective themes, that were subsequently enriched by phenomenologically‐informed perspectives. First‐person accounts within and outside the medical field were screened and discussed in collaborative workshops involving numerous individuals with lived experience of psychosis as well as family members and carers, representing a global network of organizations. The material was complemented by semantic analyses and shared across all collaborators in a cloud‐based system. The early phases of psychosis (i.e., premorbid and prodromal stages) were found to be characterized by core existential themes including loss of common sense, perplexity and lack of immersion in the world with compromised vital contact with reality, heightened salience and a feeling that something important is about to happen, perturbation of the sense of self, and need to hide the tumultuous inner experiences. The first episode stage was found to be denoted by some transitory relief associated with the onset of delusions, intense self‐referentiality and permeated self‐world boundaries, tumultuous internal noise, and dissolution of the sense of self with social withdrawal. Core lived experiences of the later stages (i.e., relapsing and chronic) involved grieving personal losses, feeling split, and struggling to accept the constant inner chaos, the new self, the diagnosis and an uncertain future. The experience of receiving psychiatric treatments, such as inpatient and outpatient care, social interventions, psychological treatments and medications, included both positive and negative aspects, and was determined by the hope of achieving recovery, understood as an enduring journey of reconstructing the sense of personhood and re‐establishing the lost bonds with others towards meaningful goals. These findings can inform clinical practice, research and education. Psychosis is one of the most painful and upsetting existential experiences, so dizzyingly alien to our usual patterns of life and so unspeakably enigmatic and human.

Genetic factors play a role in the vulnerability to cocaine dependence. The reinforcing properties of cocaine are related to the dopaminergic system, and, in particular, the dopamine receptors have been linked to the reward mechanisms. The present study examines the role of the variants TaqI A of the dopamine D2 receptor gene and BalI of the dopamine D3 receptor gene in a Brazilian sample consisting of 730 cocaine dependents and 782 healthy controls. The studied polymorphisms did not show any difference in allelic frequencies or genotypic distribution between the groups. Our data do not support a role for the dopamine D2 receptor gene TaqI A and dopamine D3 receptor gene BalI gene polymorphisms in the susceptibility to cocaine dependence in a Brazilian sample.

Phenomenological psychopathology is a body of scientific knowledge on which the clinical practice of psychiatry is based since the first decades of the twentieth century, a method to assess the patient's abnormal experiences from their own perspective, and more importantly, a science responsible for delimiting the object of psychiatry. Recently, the frontiers of phenomenological psychopathology have expanded to the productive development of therapeutic strategies that target the whole of existence in their actions. In this article, we present an overview of the current state of this discipline, summing up some of its key concepts, and highlighting its importance to clinical psychiatry today. Phenomenological psychopathology understands mental disorders as modifications of the main dimensions of the life-world: lived time, lived space, lived body, intersubjectivity, and selfhood. Psychopathological symptoms are the expression of a dialectical modification of the proportions of certain domains of the life-world or of the lived experience. The far-reaching relevance of the concepts of proportion and dialectics for the clinical agenda is explored. The article presents two contemporary models for clinical practice based on phenomenological psychopathology: Dialectical-proportional oriented approach and Person-centered dialectic approach (P.H.D. method). The main characteristics of these approaches are considered, as well as the new perspectives they bring to the challenges of psychiatric care in the twentieth-first century.

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Examina a evolução das leis e normas da República brasileira relativas ao padecimento mental, demarcando três períodos. No período inicial (1890-1910), caracterizado pela introdução do tema da patologia mental no campo das preocupações do Estado, o interesse fundamental foi o reconhecimento e a preservação dos direitos dos portadores dessas patologias; nesse período, a alteração mental é entendida em termos de neuropatologia. No período de ampliação da ação estatal (1911-1945) permanecem os interesses observados no período anterior; a interpretação de adoecimento mental não sofre alterações substanciais, a despeito do alargamento de sua abrangência. No período do desenvolvimentismo brasileiro (1946-1982), marcado por uma descontinuidade em relação aos períodos anteriores, prevalece um espírito econômico-desenvolvimentista, expresso na vigorosa ampliação do parque hospitalar e amparado por um pensamento humanista de tons conservadores; mantém-se o interesse na proteção dos portadores de doenças mentais.

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