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Ramos BP, Arnsten AF. Adrenergic pharmacology and cognition: focus on the prefrontal cortex. Pharmacol Ther 113: 523-536

Department Neurobiology, Yale Medical School, New Haven, CT 06520-8001, USA.
Pharmacology [?] Therapeutics (Impact Factor: 7.75). 04/2007; 113(3):523-36. DOI: 10.1016/j.pharmthera.2006.11.006
Source: PubMed

ABSTRACT Norepinephrine (NE) has widespread projections throughout the brain, and thus, is ideally positioned to orchestrate neural functions based on arousal state. For example, NE can increase "signal/noise" ratio in the processing of sensory stimuli, and can enhance long-term memory consolidation in the amygdala and hippocampus through actions at alpha-1 and beta adrenoceptors. Over the last 20 years, NE has also been shown to play a powerful role in regulating the working memory and attention functions of the prefrontal cortex (PFC). Moderate levels of NE released under control conditions strengthen prefrontal cortical functions via actions at post-synaptic alpha-2A adrenoceptors with high affinity for NE, while high levels of NE release during stress impair PFC cortical functions via alpha-1 and possibly beta-1 receptors with lower affinity for NE. Thus, levels of NE determine whether prefrontal cortical or posterior cortical systems control our behavior and thought. Understanding these receptor mechanisms has led to new intelligent treatments for neuropsychiatric disorders associated with PFC dysfunction.

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    • "β-AR expression in the hippocampus is well documented (Hillman et al., 2005). Furthermore, noradrenergic signaling through a1-AR has also been linked to behavioral effects (Smiałowska et al., 1994) and also prefrontal cortical function regulation (Ramos and Arnsten, 2007) which further illustrates a1-AR's implication in cognition and the possibility of its targeting in disease in which loss of cognitive functions is observed such as AD (Ghanemi, 2014a; Mufson et al., 2005). On the other hand, ARs have been linked to some metabolic and cellular processes including glycogen formation, oxidative metabolism (stimulation of a2-ARs), glutamate uptake (a1-ARs stimulation), glycogenolysis and increased Na+, K+ ATPase activity (β-ARs activation ) (Hertz et al., 2010). "
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    ABSTRACT: Adrenergic receptors belong to the family of the G protein coupled receptors that represent important targets in the modern pharmacotherapies. Studies on different physiological and pathophysiological prop-erties of the adrenergic system have led to novel evidences and theories that suggest novel possible targeting of such system in a variety of pathologies and disorders, even beyond the classical known therapeutic possibilities. Herein, those advances have been illustrated with selected concepts and different ex-amples. Furthermore, we illustrated the applications and the therapeutic implications that such findings and advances might have in the contexts of experimental pharmacology, therapeutics and clinic. We hope that the content of this work will guide researches devoted to the adrenergic aspects that combine neu-rosciences with pharmacology.
    Neuropeptides 11/2014; 49. DOI:10.1016/j.npep.2014.11.003 · 2.55 Impact Factor
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    • "Under physiological conditions, cortisol, in conjunction with epinephrine and norepinephrine, prepares an individual for the " fight or flight response " , enabling rapid shifting of blood flow toward large skeletal muscles and permitting an individual to flee threatening situations. Cortisol also plays a significant role in memory processes (Tollenaar et al., 2009), with areas of the brain important for memory (e.g., hippocampus, prefrontal cortex, amygdala) expressing high levels of GC receptors (Ramos and Arnsten, 2007). In the hippocampal region, excessive GCs levels have been linked to a significant reduction in neurogenesis (Liu et al., 2003), suppression of LTP in excitatory synapses (Setiawan et al., 2007), cell death through apoptosis (Zhao et al., 2007), and extensive dendritic reorganization in the prefrontal cortex (Cook and Wellman, 2004). "
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    ABSTRACT: While the relationship between increased physical activity and cognitive ability has been conjectured for centuries, only recently have the mechanisms underlying this relationship began to emerge. Convergent evidence suggests that physical activity offers an affordable and effective method to improve cognitive function in all ages, particularly the elderly who are most vulnerable to neurodegenerative disorders. In addition to improving cardiac and immune function, physical activity alters trophic factor signaling and, in turn, neuronal function and structure in areas critical for cognition. Sustained exercise plays a role in modulating anti-inflammatory effects and may play a role in preserving cognitive function in aging and neuropathological conditions. Moreover, recent evidence suggests that myokines released by exercising muscles affect the expression of brain-derived neurotrophic factor synthesis in the dentate gyrus of the hippocampus, a finding that could lead to the identification of new and therapeutically important mediating factors. Given the growing number of individuals with cognitive impairments worldwide, a better understanding of how these factors contribute to cognition is imperative, and constitutes an important first step toward developing non-pharmacological therapeutic strategies to improve cognition in vulnerable populations.
    Frontiers in Cellular Neuroscience 06/2014; DOI:10.3389/fncel.2014.00170 · 4.18 Impact Factor
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    • "Third, chronic as well as acute stress – in addition to its well established effects on hippocampus-dependent declarative memory – exerts strong effects on cognitive control processes, presumably via influences of stress hormones and catecholamines (noradrenaline, dopamine) on prefrontal neurotransmission (for review see Arnsten, 2009). These stress-related modulations appear to induce a shift of behavioural control from a goal-directed ( " top-down " ) to an affective-habitual ( " bottom-up " ) mode dominated by the amygdale and basal ganglia (Ramos and Arnsten, 2007; Wang et al., 2007; Wingard and Packard, 2008). In addition, recent evidence indicates that acute social stress also shifts the balance between cognitive flexibility and stability towards increased tonic goal shielding and reduced context-sensitive adaptation of cognitive control (Plessow et al., 2011a, 2011b). "
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    ABSTRACT: Disadvantageous decision-making and impaired volitional control over actions, thoughts, and emotions are characteristics of a wide range of mental disorders such as addiction, eating disorders, depression, and anxiety disorders and may reflect transdiagnostic core mechanisms and possibly vulnerability factors. Elucidating the underlying neurocognitive mechanisms is a precondition for moving from symptom-based to mechanism-based disorder classifications and ultimately mechanism-targeted interventions. However, despite substantial advances in basic research on decision-making and cognitive control, there are still profound gaps in our current understanding of dysfunctions of these processes in mental disorders. Central unresolved questions are: (i) to which degree such dysfunctions reflect transdiagnostic mechanisms or disorder-specific patterns of impairment; (ii) how phenotypical features of mental disorders relate to dysfunctional control parameter settings and aberrant interactions between large-scale brain systems involved in habit and reward-based learning, performance monitoring, emotion regulation, and cognitive control; (iii) whether cognitive control impairments are consequences or antecedent vulnerability factors of mental disorders; (iv) whether they reflect generalized competence impairments or context-specific performance failures; (v) whether not only impaired but also chronic over-control contributes to mental disorders. In the light of these gaps, needs for future research are: (i) an increased focus on basic cognitive-affective mechanisms underlying decision and control dysfunctions across disorders; (ii) longitudinal-prospective studies systematically incorporating theory-driven behavioural tasks and neuroimaging protocols to assess decision-making and control dysfunctions and aberrant interactions between underlying large-scale brain systems; (iii) use of latent-variable models of cognitive control rather than single tasks; (iv) increased focus on the interplay of implicit and explicit cognitive-affective processes; (v) stronger focus on computational models specifying neurocognitive mechanisms underlying phenotypical expressions of mental disorders. Copyright © 2013 John Wiley & Sons, Ltd.
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