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- Bilbao, Ainhoa, et al.
(författare)
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Loss of the Ca2+/calmodulin-dependent protein kinase type IV in dopaminoceptive neurons enhances behavioral effects of cocaine
- 2008
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Ingår i: Proceedings of the National Academy of Sciences of the United States of America. - : National Academy of Sciences; 1999. - 0027-8424 .- 1091-6490. ; 105:45, s. 17549-17554
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Tidskriftsartikel (refereegranskat)abstract
- The persistent nature of addiction has been associated with activity-induced plasticity of neurons within the striatum and nucleus accumbens (NAc). To identify the molecular processes leading to these adaptations, we performed Cre/loxP-mediated genetic ablations of two key regulators of gene expression in response to activity, the Ca2+/calmodulin-dependent protein kinase IV (CaMKIV) and its postulated main target, the cAMP-responsive element binding protein (CREB). We found that acute cocaine-induced gene expression in the striatum was largely unaffected by the loss of CaMKIV. On the behavioral level, mice lacking CaMKIV in dopaminoceptive neurons displayed increased sensitivity to cocaine as evidenced by augmented expression of locomotor sensitization and enhanced conditioned place preference and reinstatement after extinction. However, the loss of CREB in the forebrain had no effect on either of these behaviors, even though it robustly blunted acute cocaine-induced transcription. To test the relevance of these observations for addiction in humans, we performed an association study of CAMK4 and CREB promoter polymorphisms with cocaine addiction in a large sample of addicts. We found that a single nucleotide polymorphism in the CAMK4 promoter was significantly associated with cocaine addiction, whereas variations in the CREB promoter regions did not correlate with drug abuse. These findings reveal a critical role for CaMKIV in the development and persistence of cocaine-induced behaviors, through mechanisms dissociated from acute effects on gene expression and CREB-dependent transcription.
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| 2. |
- Wittchen, Hans-Ulrich, et al.
(författare)
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The need for a behavioural science focus in research on mental health and mental disorders
- 2014
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Ingår i: International Journal of Methods in Psychiatric Research. - : Wiley-Blackwell. - 1049-8931 .- 1557-0657. ; 23, s. 28-40
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Tidskriftsartikel (refereegranskat)abstract
- Psychology as a science offers an enormous diversity of theories, principles, and methodological approaches to understand mental health, abnormal functions and behaviours and mental disorders. A selected overview of the scope, current topics as well as strength and gaps in Psychological Science may help to depict the advances needed to inform future research agendas specifically on mental health and mental disorders. From an integrative psychological perspective, most maladaptive health behaviours and mental disorders can be conceptualized as the result of developmental dysfunctions of psychological functions and processes as well as neurobiological and genetic processes that interact with the environment. The paper presents and discusses an integrative translational model, linking basic and experimental research with clinical research as well as population-based prospective-longitudinal studies. This model provides a conceptual framework to identify how individual vulnerabilities interact with environment over time, and promote critical behaviours that might act as proximal risk factors for ill-health and mental disorders. Within the models framework, such improved knowledge is also expected to better delineate targeted preventive and therapeutic interventions that prevent further escalation in early stages before the full disorder and further complications thereof develop. In contrast to conventional personalized medicine that typically targets individual (genetic) variation of patients who already have developed a disease to improve medical treatment, the proposed framework model, linked to a concerted funding programme of the Science of Behaviour Change, carries the promise of improved diagnosis, treatment and prevention of health-risk behaviour constellations as well as mental disorders.
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