Attention-modulating effects of cognitive enhancers

Department of Psychiatry and Behavioral Sciences, Duke University Medical Center, NC 27710, USA.
Pharmacology Biochemistry and Behavior (Impact Factor: 2.78). 02/2011; 99(2):146-54. DOI: 10.1016/j.pbb.2011.02.008
Source: PubMed


Attention can be readily measured in experimental animal models. Animal models of attention have been used to better understand the neural systems involved in attention, how attention is impaired, and how therapeutic treatments can ameliorate attentional deficits. This review focuses on the ways in which animal models are used to better understand the neuronal mechanism of attention and how to develop new therapeutic treatments for attentional impairment. Several behavioral test methods have been developed for experimental animal studies of attention, including a 5-choice serial reaction time task (5-CSRTT), a signal detection task (SDT), and a novel object recognition (NOR) test. These tasks can be used together with genetic, lesion, pharmacological and behavioral models of attentional impairment to test the efficacy of novel therapeutic treatments. The most prominent genetic model is the spontaneously hypertensive rat (SHR). Well-characterized lesion models include frontal cortical or hippocampal lesions. Pharmacological models include challenge with the NMDA glutamate antagonist dizocilpine (MK-801), the nicotinic cholinergic antagonist mecamylamine and the muscarinic cholinergic antagonist scopolamine. Behavioral models include distracting stimuli and attenuated target stimuli. Important validation of these behavioral tests and models of attentional impairments for developing effective treatments for attentional dysfunction is the fact that stimulant treatments effective for attention deficit hyperactivity disorder (ADHD), such as methylphenidate (Ritalin®), are effective in the experimental animal models. Newer lines of treatment including nicotinic agonists, α4β2 nicotinic receptor desensitizers, and histamine H₃ antagonists, have also been found to be effective in improving attention in these animal models. Good carryover has also been seen for the attentional improvement caused by nicotine in experimental animal models and in human populations. Animal models of attention can be effectively used for the development of new treatments of attentional impairment in ADHD and other syndromes in which have attentional impairments occur, such as Alzheimer's disease and schizophrenia.

Download full-text


Available from: Edward D Levin,
28 Reads
  • Source
    • "In light of this hypothesis, acute MK-801 treatment has been widely adopted as a model for an acute schizophrenia episode in rats. In the present study, we successfully established a rat model of MK-801 in which cognitive impairment could be detected through behavioral tests (Levin et al., 2011), while the toxicity of MK-801 induced the cognitive Fig. 2. MK-801 suppression of long-term potential (LTP). Olanzapine (OLZ) but not haloperidol reversed impaired LTP in the hippocampus. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Schizophrenia patients exhibit a wide range of impairments in cognitive functions. Clinically, atypical antipsychotic drugs (AAPs) such as olanzapine (OLZ) have a therapeutic effect on memory function among schizophrenia patients rather than typical antipsychotics, e.g., haloperidol. To date, however, little is known about the neuroplasticity mechanism underlying the effect of AAPs on the impairment of cognitive functions. Here, we treated schizophrenia rat models with a systematic injection of MK-801 (0.1mg/kg) and chose the drug OLZ as a tool to investigate the mechanisms of AAPs when used to alter cognitive function. The results showed that the systematic administration of MK-801 results in the impairment of spatial learning and memory as well as spatial working memory in a Morris water maze task. OLZ but not HAL improved these MK-801-induced cognitive dysfunctions. After MK-801 application, the hippocampal LTP was profoundly impaired. In conjunction with the results of the behavioral test, the administration of OLZ but not of HAL resulted in a significant reversal effect on the impaired LTP induced via MK-801 application. Furthermore, we found that OLZ but not HAL can upregulate the phosphorylation of GluR1 Ser845. These data suggest that the therapeutic effect of OLZ on cognitive dysfunctions may be due to its contribution to synaptic plasticity via the ability to upregulate the state of GluR1 Ser845 phosphorylation. We therefore suggest that the upregulated state of GluR1 Ser845 phosphorylation may be a promising target for developing novel therapeutics for treating schizophrenia.
    Schizophrenia Research 09/2014; 159(2-3). DOI:10.1016/j.schres.2014.07.054 · 3.92 Impact Factor
  • Source
    • "Attendance at the objects area and time spent in Copyright © 2013 SciRes. JBBS the area by an animal exploring novel environment is generally considered as measures of an attention directed to the objects [20] [24] [25]. 2) Total time in maze until an animal completes 12 visits to arms, i.e. when it returns to central partition from the arm entered on 12th visit. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Treatment of attention deficit hyperactivity disorder with medications is helpful in less than 60% of cases suggesting the necessity of development of novel drugs. The most accepted animal model of the disease is outbred spontaneously hy-pertensive rat strain. It was recently found in a novel enrichment discrimination test that the rat strain includes atten-tionally-low and -high phenotypes and clinically efficient drug for the treatment of the disorder atomoxetine is capable of ameliorating the enrichment discrimination by the attentionally-low rats. The present study aimed to test the generali-ty of these findings in outbred CD-1 mice assessed in the same experimental design. The frequency distribution of the en-richment discrimination ratio differed from the curve expected under the normality hypothesis and had a bimodal shape suggesting the existence of attentionally-low and -high mouse phenotypes. Atomoxetine (3 mg/kg, orally, once daily for 4 days) selectively enhanced enrichment discrimination in mice of attentionally-low phenotype only. The present results generalize and extend findings previously reported in spontaneously hypertensive rats and suggest that the present model could be useful in studies of the neurobiological mechanisms of attention deficiency in rodents and for screening of novel drug candidates for treatment of attention deficit disorder.
    Journal of Behavioral and Brain Science 05/2013; 3(02):210-216. DOI:10.4236/jbbs.2013.32022
  • Source
    • "There is no necessary training other than the initial exposure session. The main drawback of the NOR test is that its specificity for assessing attention is more limited than in the operant methods [3]. Other factors, such as changes in novelty preference, sensory function, or memory, must be independently evaluated to determine whether changes in performance can be ascribed to altered attention. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Selective attention can be assessed with the novel object recognition test (NOR). In the standard version of this test the selection of objects to be used is critical. We created a modified version of NOR, the virtual object recognition test (VORT) in mice, where the 3D objects were replaced with highly discriminated geometrical shapes and presented on two 3.5-inch widescreen displays. No difference in the discrimination index (from 5min to 96h of inter-trial) was found between NOR and VORT. Scopolamine and mecamylamine decreased the discrimination index. Conversely, the discrimination index increased when nicotine was given to mice. No further improvement in the discrimination index was observed when nicotine was injected in mice presented with highly discriminable shapes. To test the possibility that object movements increased mice's attention in the VORT, different movements were applied to the same geometrical shapes previously presented. Mice were able to distinguish among different movements (horizontal, vertical, oblique). Notably, the shapes previously found not distinguishable when stationary were better discriminated when moving. Collectively, these findings indicate that VORT, based on virtual geometric simple shapes, offers the possibility to obtain rapid information on amnesic/pro-amnestic potential of new drugs. The introduction of motion is a strong cue that makes the task more valuable to study attention.
    Behavioural brain research 01/2013; 242(1). DOI:10.1016/j.bbr.2012.12.040 · 3.03 Impact Factor
Show more