Prefrontal response and frontostriatal functional connectivity to monetary reward in abstinent alcohol-dependent young adults

Although altered function in neural reward circuitry is widely proposed in models of addiction, more recent conceptual views have emphasized the role of disrupted response in prefrontal regions. Changes in regions such as the orbitofrontal cortex, medial prefrontal cortex, and dorsolateral prefrontal cortex are postulated to contribute to the compulsivity, impulsivity, and altered executive function that are central to addiction. In addition, few studies have examined function in these regions during young adulthood, when exposure is less chronic than in typical samples of alcohol-dependent adults. To address these issues, we examined neural response and functional connectivity during monetary reward in 24 adults with alcohol dependence and 24 psychiatrically healthy adults. Adults with alcohol dependence exhibited less response to the receipt of monetary reward in a set of prefrontal regions including the medial prefrontal cortex, lateral orbitofrontal cortex, and dorsolateral prefrontal cortex. Adults with alcohol dependence also exhibited greater negative correlation between function in each of these regions and that in the nucleus accumbens. Within the alcohol-dependent group, those with family history of alcohol dependence exhibited lower mPFC response, and those with more frequent drinking exhibited greater negative functional connectivity between the mPFC and the nucleus accumbens. These findings indicate that alcohol dependence is associated with less engagement of prefrontal cortical regions, suggesting weak or disrupted regulation of ventral striatal response. This pattern of prefrontal response and frontostriatal connectivity has consequences for the behavior patterns typical of addiction. Furthermore, brain-behavior findings indicate that the potential mechanisms of disruption in frontostriatal circuitry in alcohol dependence include family liability to alcohol use problems and more frequent use of alcohol. In all, these findings build on the extant literature on reward-circuit function in addiction and suggest mechanisms for disrupted function in alcohol dependence. © 2014 Forbes et al

Effort-related functions of nucleus accumbens dopamine and associated forebrain circuits

Background Over the last several years, it has become apparent that there are critical problems with the hypothesis that brain dopamine (DA) systems, particularly in the nucleus accumbens, directly mediate the rewarding or primary motivational characteristics of natural stimuli such as food. Hypotheses related to DA function are undergoing a substantial restructuring, such that the classic emphasis on hedonia and primary reward is giving way to diverse lines of research that focus on aspects of instrumental learning, reward prediction, incentive motivation, and behavioral activation. Objective The present review discusses dopaminergic involvement in behavioral activation and, in particular, emphasizes the effort-related functions of nucleus accumbens DA and associated forebrain circuitry. Results The effects of accumbens DA depletions on food-seeking behavior are critically dependent upon the work requirements of the task. Lever pressing schedules that have minimal work requirements are largely unaffected by accumbens DA depletions, whereas reinforcement schedules that have high work (e.g., ratio) requirements are substantially impaired by accumbens DA depletions. Moreover, interference with accumbens DA transmission exerts a powerful influence over effort-related decision making. Rats with accumbens DA depletions reallocate their instrumental behavior away from food-reinforced tasks that have high response requirements, and instead, these rats select a less-effortful type of food-seeking behavior. Conclusions Along with prefrontal cortex and the amygdala, nucleus accumbens is a component of the brain circuitry regulating effort-related functions. Studies of the brain systems regulating effort-based processes may have implications for understanding drug abuse, as well as energy-related disorders such as psychomotor slowing, fatigue, or anergia in depression

Estado de saúde percebido e adesão farmacológica em pacientes submetidos à intervenção coronária percutânea

Os objetivos foram avaliar o estado de saúde percebido e a adesão farmacológica, e verificar a correlação entre essasmedidas em pacientes submetidos à intervenção coronária percutânea, após alta hospitalar. Trata-se de estudotransversal realizado no período de maio de 2011 a julho de 2012. Utilizaram-se os instrumentos SF-36 e Medidade Adesão aos Tratamentos, com 101 pacientes. Destes, 54 (53,5%) eram homens, a idade média era 59,5±10,3 e32 (32,7%) haviam passado por tratamento cardíaco prévio. Todos utilizavam medicamentos anti-hipertensivos;99 (98%) utilizavam antiagregantes plaquetários; 98 (97%), redutores de colesterol e 59 (58,4%), vasodilatadorescoronarianos. A média do número de medicamentos utilizados foi 6,8±2,1. A adesão farmacológica foi verificada em 98 (97%) pacientes. Os participantes apresentaram melhor estado de saúde nos componentes “Aspectos sociais” e “Capacidade funcional”. Constataram-se correlações positivas e de moderada magnitude entre as medidas de adesão e “Capacidade funcional”, “Estado geral de saúde” e “Aspectos sociais”. Houve correlação entre adesão farmacológica e estado de saúde percebido

Neuronal Glutathione Content and Antioxidant Capacity can be Normalized In Situ by N-acetyl Cysteine Concentrations Attained in Human Cerebrospinal Fluid

N-acetyl cysteine (NAC) supports the synthesis of glutathione (GSH), an essential substrate for fast, enzymatically catalyzed oxidant scavenging and protein repair processes. NAC is entering clinical trials for adrenoleukodystrophy, Parkinson’s disease, schizophrenia, and other disorders in which oxidative stress may contribute to disease progression. However, these trials are hampered by uncertainty about the dose of NAC required to achieve biological effects in human brain. Here we describe an approach to this issue in which mice are used to establish the levels of NAC in cerebrospinal fluid (CSF) required to affect brain neurons. NAC dosing in humans can then be calibrated to achieve these NAC levels in human CSF. The mice were treated with NAC over a range of doses, followed by assessments of neuronal GSH levels and neuronal antioxidant capacity in ex vivo brain slices. Neuronal GSH levels and antioxidant capacity were augmented at NAC doses that produced peak CSF NAC concentrations of ≥50 nM. Oral NAC administration to humans produced CSF concentrations of up to 10 μM, thus demonstrating that oral NAC administration can surpass the levels required for biological activity in brain. Variations of this approach may similarly facilitate and rationalize drug dosing for other agents targeting central nervous system disorders. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1007/s13311-015-0404-4) contains supplementary material, which is available to authorized users