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At least 19 recordsLinked to original sources

PubMed1996

Neuronal mechanisms mediating drug-induced cognition enhancement: cognitive activity as a necessary intervening variable.

The conceptual foundations of a research aimed at the determination of potential neuronal, neuropharmacological, and behavioral/cognitive mechanisms mediating drug-induced cognition enhancement are discussed. The available evidence justifies a focus on attentional processes as a target for drug-induced cognition enhancement. Neuropharmacological mechanisms that may mediate drug-induced enhancement of attentional functions are proposed to interact necessarily with attention-associated neuronal activity. The elements of a transsynaptic approach to increase the excitability of basal forebrain cholinergic neurons and hence, attentional functions are discussed. Experimental tests of this hypothesis require the demonstration of interactions between cognition-induced increases in the activity of cortical cholinergic afferents and the effects of putative cognition enhancers. The available data illustrate that the effects of benzodiazepine receptor (BZR) agonists and inverse agonists on cortical acetylcholine (ACh) efflux interact with the state of activity in this system. The feasibility, potential heuristic power, and the experimental and conceptual problems of studies attempting to simultaneously assess drug effects on behavioral/cognitive abilities, ACh efflux, and neuronal activity have been revealed by an experiment intended to correlate performance in a task measuring sustained attention with medial prefrontal ACh efflux and medial prefrontal single-unit activity. The rational development of a psychopharmacology of cognition enhancers requires a union among behavioral/cognitive pharmacology, neuropharmacological and electrophysiological approaches.

Acetylcholine↗

PubMedDate not supplied

D-cycloserine, a novel cognitive enhancer, improves spatial memory in aged rats.

D-cycloserine, a partial agonist of the NMDA receptor-associated glycine site, can enhance cognition. The present experiment examines the behavioral effects of D-cycloserine on cognitive deficits in male Fischer-344 rats, 24 months old. Rats 24 months old (n = 42) received either vehicle or one of 3 doses of D-cycloserine prior to testing. Young rats, 4 months old (n = 13), received vehicle prior to testing. Place discrimination and repeated acquisition were tested in the water maze and a variety of sensorimotor tasks were given. Aging impaired performance in all tasks. D-cycloserine improved performance in place discrimination and repeated acquisition. No doses affected sensorimotor function. These results support the hypothesis that D-cycloserine has cognition enhancing properties and that it may be useful in treating disorders involving cognitive impairment.

Aging↗

PubMed1985

The effects of various cognition-enhancing drugs on in vitro rat hippocampal synaptosomal sodium dependent high affinity choline uptake.

The purpose of the present study was to compare the effect of seven drugs, that have been reported to enhance cognitive functions, on rat hippocampal cholinergic neuronal activity. The latter was assessed by measuring the effects of the drugs on in vitro sodium-dependent high affinity choline uptake (HACU) into rat hippocampal synaptosomes 30 minutes after their in vivo administration. 3,4-Diaminopyridine (0.1 mg/kg IP), like pramiracetam (44 and 88 mg/kg IP), increased HACU with higher or lower doses being ineffective. Centrophenoxine (100 mg/kg IP) decreased HACU. Piracetam (100 and 500 mg/kg IP), aniracetam (10-200 mg/kg PO), lysine vasopressin (0.005-0.05 mg/kg IM) and 4-aminopyridine (0.01-3.0 mg/kg IP) were ineffective. The results indicate that 3,4-diaminopyridine and centrophenoxine, like pramiracetam may be increasing cognitive function in part by affecting hippocampal cholinergic neuronal activity. In addition, the findings indicate the usefulness of using in vitro HACU as a biochemical measurement to assess the potential effect of cognitive-enhancing drugs on cholinergic neuronal activity in vivo.

Adrenocorticotropic Hormone↗

PubMed2004

Asiatic acid derivatives enhance cognitive performance partly by improving acetylcholine synthesis.

Thirty-six semi-synthesized derivatives of asiatic acid were examined to determine if they had cognitive-enhancing activity in a passive avoidance test. Among the compounds tested, AS-2, AS-2-9-006 and AS-9-006 significantly alleviated scopolamine-induced memory impairment at doses of 1 and 10 mg kg(-1). Furthermore, AS-2 and AS-2-9-006 (1 mg kg(-1) administered four times daily) enhanced cognitive performance as determined in a water maze test. These three asiatic acid derivatives did not show any significant effect on the learning process in active avoidance tests. AS-2, AS-2-9-006 and AS-9-006 enhanced cholineacetyltransferase activity in a cholinergic neuroblastoma cell line, S-20Y, in-vitro. Therefore, AS-2, AS-2-9-006 and AS-9-006 may have therapeutic value in alleviating certain memory impairment observed in dementia.

Acetylcholine↗

PubMed2004

The cognitive-enhancing properties of modafinil are limited in non-sleep-deprived middle-aged volunteers.

Modafinil is a selective wakefulness-promoting agent that has been shown to enhance cognitive performance under conditions of sleep deprivation but which has equivocal effects in normal young volunteers. In a double-blind parallel group design study, 45 non-sleep-deprived middle-aged volunteers (20 men and 25 women, aged 50-67 years) were randomly allocated to receive two capsules containing placebo, 100 or 200 mg modafinil, and 3 h later they completed 100 mm visual analogue scales of mood and bodily symptoms, before and after an extensive battery of cognitive tests [pen and paper and the Cambridge Neuropsychological Test Automated Battery (CANTAB)]. There were no significant treatment-associated changes in ratings of mood or bodily symptoms and no significant effects on most of the cognitive tests used in this study. The group treated with modafinil (200 mg) was significantly faster in a simple colour naming of dots and also significantly better in a test of constructional ability (Clock Drawing Test) compared with the placebo group. However, subjects in the 200-mg group also made significantly more total errors in the Intra/Extradimensional Set Shift (ID/ED) task than both the other groups. Thus, this study found limited evidence of cognitive-enhancing properties of modafinil in healthy middle-aged volunteers.

Aged↗

PubMed1990

Problems in the search for cognition enhancers.

Drugs which enhance cognition may benefit the two largest groups of psychiatric patients who have been bypassed during the psychopharmacological revolution of the past 35 years: those with development mental disabilities and those with brains ravaged by senile dementias. But who among us would not benefit from such a drug, if indeed it could enhance normal performance? Establishing suitable animal models for developing such drugs has been a major problem. Lesioning experiments dictate the answers as well as the questions, delimiting the type of drug to remedy the defect. Other lesions which are less specific, such as anoxia or deficiency of some vitamin or metabolite, may not have particular relevance to the clinical situation. The best animal models would employ learning paradigms that mimic the problems encountered by the disabled patient. Testing new compounds in the clinic also has problems. Subjects should not be so deteriorated to require a miracle drug to show any effect. The characteristic variability in function of such patients must be taken into account, to assure that any changes are not simply within the normal range of variability. Thus, we may need a new kind of statistical approach to analyzing data, based more on individual responses than on group means. Finally, the end-points should be based on an improved quality of life both for patients and their caretakers. We need a different set of measurement criteria. Despite these difficulties the search for drugs which enhance cognition should not be delayed. The payoffs of success will be high for everyone.

Alzheimer Disease↗

PubMed1999

Acute effect of KA-672, a putative cognitive enhancer, on neurotransmitter receptor binding in mouse brain.

7-Methoxy-6-[3-[4-(2-methoxyphenyl)piperazin-1-yl]propoxy]-3,4-dim ethyl-2H-1-benzopyran-2-one hydro-chloride (KA-672), structurally related to naturally occurring coumarins, has been described as a potential drug for enhancing cognitive functions. However, a detailed characterization of the pharmacological profile of KA-672 in vivo is still lacking. Quantitative neurotransmitter receptor autoradiography was used as a tool to screen for KA-672-induced changes in a number of transmitter receptors including cholinergic, noradrenergic, glutamatergic, GABAergic, and serotonergic subtypes throughout the brain. Two hours following treatment of mice with 1 mg/kg KA-672 per os, slight increases of nicotinic and M1-muscarinic cholinergic receptor binding, of alpha2-and beta-adrenoceptor as well as 5-HT1A receptors in various cerebral cortical regions were observed, whereas 5-HT2A binding sites were strikingly increased throughout the brain following KA-672 treatment. In contrast, (+/-)-alphaamino-3-hydroxy-5-methylisoxazole-4-propionic acid receptor binding was significantly decreased in some cortical regions after drug treatment. No effects of KA-672 treatment on N-methyl-D-aspartate, kainate, GABA(A) and benzodiazepine receptor as well as M2-muscarinic cholinergic and high-affinity choline uptake binding were observed. As interactions between the cholinergic, noradrenergic and serotonergic neurotransmission have been stressed to play important roles in realizing learning and memory events, the cognition-enhancing effects of KA-672 may be due to this complex in vivo pharmacological profile of KA-672.

Animals↗

PubMed1990

The development of behavioral tests to assess the effects of cognitive enhancers.

The search for drugs that enhance cognition requires the development of behavioral tests for animals. These tests must be able to identify potentially therapeutic drugs and reject ineffective drugs. A reference compound for cognitive enhancement does not exist, and may not be a reasonable goal. Therefore, a coherent conceptual and experimental framework is needed to organize the various research endeavors in this area. This paper proposes a framework to assist in the development and evaluation of specific behavioral tests. It requires explicit identification of the goals of the research, the cognitive process, the neural systems involved in the process, the selectivity and sensitivity of tasks that measure the process, the validity of the behavioral tasks as a model to predict the effects of the drug in humans.

Alzheimer Disease↗

PubMed2001

SCH 57790, a selective muscarinic M(2) receptor antagonist, releases acetylcholine and produces cognitive enhancement in laboratory animals.

The present studies were designed to assess whether the novel muscarinic M(2) receptor antagonist 4-cyclohexyl-alpha-[4[[4-methoxyphenyl]sulphinyl]-phenyl]-1-piperazineacetonitrile (SCH 57790) could increase acetylcholine release in the central nervous system (CNS) and enhance cognitive performance in rodents and nonhuman primates. In vivo microdialysis studies show that SCH 57790 (0.1-10 mg/kg, p.o.) produced dose-related increases in acetylcholine release from rat hippocampus, cortex, and striatum. SCH 57790 (0.003-1.0 mg/kg) increased retention times in young rat passive avoidance responding when given either before or after training. Also, SCH 57790 reversed scopolamine-induced deficits in mice in a passive avoidance task. In a working memory operant task in squirrel monkeys, administration of SCH 57790 (0.01-0.03 mg/kg) improved performance under a schedule of fixed-ratio discrimination with titrating delay. The effects observed with SCH 57790 in behavioral studies were qualitatively similar to the effects produced by the clinically used cholinesterase inhibitor donepezil, suggesting that blockade of muscarinic M(2) receptors is a viable approach to enhancing cognitive performance.

Acetylcholine↗

PubMed2002

Design and study of piracetam-like nootropics, controversial members of the problematic class of cognition-enhancing drugs.

Cognition enhancers are drugs able to facilitate attentional abilities and acquisition, storage and retrieval of information, and to attenuate the impairment of cognitive functions associated with head traumas, stroke, age and age-related pathologies. Development of cognition enhancers is still a difficult task because of complexity of the brain functions, poor predictivity of animal tests and lengthy and expensive clinical trials. After the early serendipitous discovery of first generation cognition enhancers, current research is based on a variety of working hypotheses, derived from the progress of knowledge in the neurobiopathology of cognitive processes. Among other classes of drugs, piracetam-like cognition enhancers (nootropics) have never reached general acceptance, in spite of their excellent tolerability and safety. In the present review, after a general discussion of the problems connected with the design and development of cognition enhancers, the class is examined in more detail. Reasons for the problems encountered by nootropics, compounds therapeutically available and those in development, their structure activity relationships and mechanisms of action are discussed. Recent developments which hopefully will lead to a revival of the class are reviewed.

Acetylcholine↗

PubMed2004

AMPA receptor modulators as cognitive enhancers.

AMPA (alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid)-type glutamate receptors mediate fast excitatory transmission throughout the central nervous system. Positive modulation of these receptors can potentially enhance cognition by, firstly, offsetting losses of glutamatergic synapses; secondly, promoting synaptic plasticity; and thirdly, increasing the production of trophic factors. The advent of small molecules that selectively enhance AMPA receptors in the brain made it possible to test these hypotheses. Preclinical experiments indicate that the compounds accelerate the encoding of memory and have positive effects on models of cognitive dysfunction. Initial results with human subjects are also positive. AMPA receptor modulators thus represent an entirely new approach to cognitive enhancement and the treatment of diverse brain disorders.

Humans↗

PubMed1996

Cognition enhancers in age-related cognitive decline.

A review of recently published studies on the effect of cognition enhancers in non-demented human study participants is presented. The heterogeneity of the therapeutic target, age-associated cognitive decline, can be improved by separately treating groups in whom age-extrinsic factors may underlie cognitive pathology. Standardisation of cognitive assessments is necessary, since many different tests are applied to answer the same question. Modelling cognitive dysfunction, either by pharmacological or nonpharmacological means, in humans is highly recommended since it allows hypotheses to be tested in a clearly operationalised way. Predictive validity of the currently applied models for the clinical situation remains a problem, however. The scopolamine (hyoscine) model has, to a reasonable extent, predictive validity for the cholinergic agents. The results of 67 single-dose studies and 30 multiple-dose studies are summarised. All single-dose studies and 14 multiple-dose studies were carried out in young or elderly human volunteers. In 45 of 81 volunteer studies, models of cognitive dysfunction were employed. The scopolamine model was the most used (n = 21); the other studies induced cognitive dysfunction by means of benzodiazepines (8), hypoxia (7), alcohol (5) and sleep-deprivation (4). The remaining 16 multiple-dose studies were clinical trials of a duration varying between 2 weeks and 1 year (average duration was 14 weeks). In these trials, the effects of cognition enhancers were assessed in elderly people in whom impairment of memory, psychomotor performance or cognitive function was determined. These included age-associated memory impairment (AAMI) and age-associated cognitive decline (AACD). There were many studies in which the cognition enhancing properties of substances in humans were reliably demonstrated. The cognition enhancing properties of substances that are widely used, such as caffeine, nicotine and vitamins, may already be active against AACD. New developments such as serotonin (5-hydroxytryptamine3; 5-HT3) antagonists and N-methyl-D-aspartate (NMDA) antagonists have provided marginal and disappointing results in AAMI. There is no cognition enhancer that has reliably and repeatedly been demonstrated to be efficacious for the treatment of AACD. However, this situation may change as the selectivity, specificity and adverse effect profiles of substances that are being developed for the treatment of AD may be expected to be improved in the future.

Aged↗

PubMed1996

Chronic, post-injury administration of D-cycloserine, an NMDA partial agonist, enhances cognitive performance following experimental brain injury.

The purpose of this study was to determine the effect of augmenting NMDA receptor activation on cognitive deficits produced by traumatic brain injury (TBI). Specifically, D-cycloserine (DCS), a partial agonist of the NMDA-associated glycine site, was tested as a potential cognitive enhancer. Rats were injured using lateral fluid percussion TBI (2.8 +/- .10 atm). On days 1-15 post-injury, animals were injected (i.p.) with vehicle (n = 8), 10 mg/kg (n = 9), or 30 mg/kg (n = 8) of DCS. Sham-injured animals treated with either vehicle (n = 8) or 30 mg/kg of DCS (n = 8) were used for comparison. On days 11-15 post-injury, cognitive function was assessed using the Morris water maze (MWM). Results indicate that the 30 mg/kg dose of DCS significantly attenuated memory deficits as compared to injured vehicle-treated animals (P < 0.01). Analysis also revealed that performance of the injured-DCS (30 mg/kg) group was not significantly different from sham-injured animals treated with vehicle (P > 0.10). In contrast, the 10 mg/kg dose of DCS was ineffective in reducing injury-induced memory deficits. DCS (30 mg/kg) also significantly improved the spatial memory of sham-injured animals when compared with sham-injured animals treated with vehicle (P < 0.05). In conclusion, chronic, post-injury enhancement of the NMDA receptor is an effective strategy for ameliorating TBI-associated cognitive deficits.

Animals↗

PubMed1988

Cognitive enhancing agents: current status in the treatment of Alzheimer's disease.

Extensive recent literature on drugs used to enhance cognitive functioning, reflects the growing social problem of dementia. Many clinical trials have been undertaken with variable success. In most cases the disorder studied has been Alzheimer's disease. The pharmacological approach has been designed to rectify the presumed pathophysiological processes characteristic of the condition. Agents tested include cerebral vasodilators, cerebral metabolic enhancers, nootropics, psychostimulants, neuropeptides and neurotransmitters with a special emphasis on drugs used to enhance cholinergic function. Ethical and practical issues concerning clinical drug trials in dementia will be discussed.

Alzheimer Disease↗

PubMed2004

5alpha-reduced androgens may have actions in the hippocampus to enhance cognitive performance of male rats.

Androgens may improve cognitive performance; however, these effects and mechanisms of androgens are not well understood. Whether testosterone's (T) effects on cognitive performance are mediated by its 5alpha-reduced, non-aromatizable metabolite dihydrotestosterone (DHT) and/or its 3alpha-hydroxysteroid dehydrogenase (3alpha-HSD) reduced metabolite 3alpha-androstanediol (3alpha-diol), was investigated. In Experiment 1, male rats that were gonadally intact, or gonadectomized (GDX) and DHT-replaced with a silastic capsule, had better performance in the inhibitory avoidance task, and higher plasma DHT and 3alpha-diol levels, compared to GDX rats. In Experiments 2-4, intra-hippocampal indomethacin, a 3alpha-HSD inhibitor, to intact or DHT-replaced, but not GDX, rats decreased performance in the inhibitory avoidance task and reduced hippocampal 3alpha-diol levels compared to that observed in rats with control implants. Thus, the 5alpha-reduced androgen DHT has cognitive-enhancing effects, independent of E(2), which are attenuated by a 3alpha-HSD inhibitor, indomethacin. These results suggest that 5alpha-reduced androgens may have actions in the hippocampus to improve cognitive performance.

3-Oxo-5-alpha-Steroid 4-Dehydrogenase↗

PubMedDate not supplied

Enhancing cognition in the intellectually intact.

As science learns more about how the brain works, and fails to work, the possibility for developing "cognition enhancers" becomes more plausible. And the demand for drugs that can help us think faster, remember more, and focus more keenly has already been demonstrated by the market success of drugs like Ritalin, which tames the attention span, and Prozac, which ups the competitive edge. The new drug Aricept, which improves memory, most likely will join them. Whether such drugs are good for individuals, or for society, is an open question, one that demands far more public discussion.

Brain Diseases↗

PubMed2005

Does modafinil enhance cognitive performance in young volunteers who are not sleep-deprived?

In a double-blind, parallel groups study, 60 healthy student volunteers (29 men and 31 women, aged 19-22 years) were randomly allocated to receive placebo, 100 or 200 mg modafinil. Two hours later, in the early evening, they completed an extensive cognitive battery. The 3 groups did not differ in self-ratings of sleepiness or tiredness before the testing session, and there were no treatment-associated changes in these or in mood ratings during the tests. Modafinil was without effect in several tests of reaction time and attention, but the 200-mg group was faster at simple color naming of dots and performed better than placebo in the Rapid Visual Information Processing test of sustained attention. Modafinil was without effect on spatial working memory, but the 100-mg group performed better in the backward part of the digit span test. Modafinil was without effect on verbal short-term memory (story recall), but 100 mg improved digit span forward, and both doses improved pattern recognition, although this was accompanied by a slowing of response latency in the 200-mg group. There were no significant effects of modafinil compared with placebo in tests of long-term memory, executive function, visuospatial and constructional ability, or category fluency. These results suggest that the benefits of modafinil are not clearly dose-related, and those from 100 mg are limited to the span of immediate verbal recall and short-term visual recognition memory, which is insufficient for it to be considered as a cognitive enhancer in non-sleep-deprived individuals.

Adult↗

PubMed2005

Regulatable acetylcholine-producing fibroblasts enhance cognitive performance.

Regulatable gene therapy systems provide a method to alter neurotransmitter levels in vivo. We developed a rodent fibroblast cell line expressing the choline acetyltransferase (ChAT) cDNA that is silenced by doxycycline (DOX) administration. The ability of the cell line to improve cognition was tested by grafting after cholinergic lesions. Ibotenic acid was injected bilaterally into the nucleus basalis of rats, which were distributed into three groups. One group received no treatment, while the second group received cortical transplants (Graft). The third group received identical grafts but was treated with DOX to turn off ChAT expression (Graft/DOX). An unlesioned group served as control. Water maze acquisition was significantly better in the Graft group compared to the Graft/DOX group, an effect also seen in the retention and spatial probe trials. However, cognitive enhancement was restricted to spatial tasks, as inhibitory avoidance or open-field activity measures were unchanged. Molecular and biochemical analyses confirmed that DOX regulated transgene transcription and ACh levels. This study demonstrates that regulatable gene therapy has therapeutic value for single-gene disorders and also provides a mechanism to deliver small molecules in a spatiotemporal pattern to delineate the role of these compounds in discrete behavioral tasks.

Acetylcholine↗