Preclinical research into cognition enhancers
ABSTRACT The preclinical development of drugs to treat the cognitive symptoms of neuropsychiatric and neurological disorders is a formidable challenge. Evidence from a wide range of preclinical behavioral and neuropharmacological tests has formed the basis for predicting drug-induced cognition enhancement in normal volunteers and in patients with cognitive impairments. However, the limited validity of preclinical predictions of this enhancement in humans indicates that conventional screening for "broadly active" compounds represents a below-optimal research strategy. This article conceptualizes the evidence needed to improve the predictive validity of preclinical research designed to discover and characterize cognition enhancers. We suggest that the investigation of reciprocal relationships among molecular, cellular, behavioral and cognitive processes modulated by candidate drugs represents the core of such research. By contrast, the usefulness of simple and high-throughput screening tests for the detection of cognition enhancers might be restricted to advanced drug-finding programs that are guided by evidence of the modulation of neurocognitive relationships by cognition enhancers and that are informed by iterative preclinical-clinical cross-validation of research approaches. We stress the need for basic biopsychological research approaches in preclinical programs to find and characterize drugs to treat cognitive disorders.
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- "Increases in attentional effort are thought to be under the control of the " central executive " (Baddeley, 1986) and the anterior attention system (Posner, 1994; Posner and Dehaene, 1994), including frontal and parietal regions. Attentional effort is thought to engage top-down attentional control processes that are employed in order to carry out goal-directed behaviors (Sarter et al., 2006). The right MFG results in this study support the idea that this region is particularly sensitive to the attentional control demands of a given task and is engaged to a greater extent under more demanding conditions. "
ABSTRACT: Maintaining attention and performance over time is an essential part of many activities, and effortful cognitive control is required to avoid vigilance decrements and interference from distraction. Regions at or near right middle frontal gyrus (Brodmann's area (BA) 9), as well as in other prefrontal and parietal areas, are often activated in studies of sustained attention (e.g., Cabeza and Nyberg, 2000; Kim et al., 2006; Lim et al., 2010). This activation has often been interpreted as representing the engagement of cognitive control processes. However, such studies are typically implemented at one level of task difficulty, without an experimental manipulation of control demands. The present study used the distractor condition sustained attention task (dSAT), which has been used extensively in animals to determine the role of neuromodulator systems in attentional performance, to test the hypotheses that BA 9 is sensitive to changes in the demand for cognitive control and that this sensitivity reflects an increased engagement of attentional effort. Continuous arterial spin labeling (ASL) was used to measure neural activity in sixteen healthy, young adults performing a sustained attention task under standard conditions and under a distraction condition that provided an experimental manipulation of demands on cognitive control. The distractor impaired behavioral performance and increased activation in right middle frontal gyrus. Larger increases in right middle frontal gyrus activity were associated with greater behavioral vulnerability to the distractor. These findings indicate that while right middle frontal gyrus regions are sensitive to demands for attentional effort and control, they may not be sufficient to maintain performance under challenge. In addition, they demonstrate the sensitivity of ASL methods to variations in task demands, and suggest that the dSAT may be a useful tool for translational cross-species and clinical research.NeuroImage 01/2011; 54(2):1518-29. DOI:10.1016/j.neuroimage.2010.09.026 · 6.36 Impact Factor
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- "Attentional functions and capacities are key variables of cognitive performance (Sarter et al, 2005, 2006), and as such have been extensively targeted for drug-induced cognition enhancement. Cholinergic activity is necessary for the performance of attention tasks (eg McGaughy et al, 1996; for review see Sarter et al, 2005, 2006). The development of enzyme-coated microelectrodes allowing for the amperometric monitoring of real-time acetylcholine (ACh) release has revealed that brief (on the scale of seconds) increases in cholinergic activity (henceforth termed 'transients') mediate the detection of cues in attentional contexts (Parikh et al, 2007). "
ABSTRACT: Impairments in attention are a major component of the cognitive symptoms of neuropsychiatric and neurodegenerative disorders. Using an operant sustained attention task (SAT), including a distractor condition (dSAT), we assessed the putative pro-attentional effects of the selective alpha4beta2(*) nicotinic acetylcholine receptor (nAChR) agonist S 38232 in comparison with the non-selective agonist nicotine. Neither drug benefited SAT performance. However, in interaction with the increased task demands implemented by distractor presentation, the selective agonist, but not nicotine, enhanced the detection of signals during the post-distractor recovery period. This effect is consistent with the hypothesis that second-long increases in cholinergic activity ('transients') mediate the detection of cues and that nAChR agonists augment such transients. Electrochemical recordings of prefrontal cholinergic transients evoked by S 38232 and nicotine indicated that the alpha4beta2(*) nAChR agonist evoked cholinergic transients that were characterized by a faster rise time and more rapid decay than those evoked by nicotine. Blockade of the alpha7 nAChR 'sharpens' nicotine-evoked transients; therefore, we determined the effects of co-administration of nicotine and the alpha7 nAChR antagonist methyllycaconitine on dSAT performance. Compared with vehicle and nicotine alone, this combined treatment significantly enhanced the detection of signals. These results indicate that compared with nicotine, alpha4beta2(*) nAChR agonists significantly enhance attentional performance and that the dSAT represents a useful behavioral screening tool. The combined behavioral and electrochemical evidence supports the hypothesis that nAChR agonist-evoked cholinergic transients, which are characterized by rapid rise time and fast decay, predict robust drug-induced enhancement of attentional performance.Neuropsychopharmacology: official publication of the American College of Neuropsychopharmacology 02/2010; 35(6):1391-401. DOI:10.1038/npp.2010.9 · 7.83 Impact Factor
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- "To date, nootropic drug discovery efforts have focused on the enhancement of cholinergic, glutaminergic, and serotonergic neurotransmission and phosphodiesterase inhibition, and have had limited benefits (Sarter, 2006). Examples include the cholinesterase inhibitors and Nmethyl-d-aspartate (NMDA) agonists currently approved for the treatment of Alzheimer's disease, α-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) receptor agonists and nicotinic alpha 7 receptor agonists. "
ABSTRACT: Previously, utilizing a series of genome-wide association, brain imaging, and gene expression studies we implicated the KIBRA gene and the RhoA/ROCK pathway in hippocampal-mediated human memory. Here we show that peripheral administration of the ROCK inhibitor hydroxyfasudil improves spatial learning and working memory in the rodent model. This study supports the action of ROCK on learning and memory, suggests the potential value of ROCK inhibition for the promotion of cognition in humans, and highlights the powerful potential of unbiased genome-wide association studies to inform potential novel uses for existing pharmaceuticals.Behavioral Neuroscience 03/2009; 123(1):218-23. DOI:10.1037/a0014260 · 3.25 Impact Factor