title: Dopaminergic modulation of probabilistic reasoning and overconfidence in errors: a double-blind study. Modulation of memory and visuospatial processes by biperiden and rivastigmine in elderly healthy subjects Effect of aspirin on hypothalamic–pituitary–adrenal function and on neuropsychological performance in healthy adults: a pilot study Use of illicit and prescription drugs for cognitive or mood enhancement among surgeons The effects of single-dose fexofenadine, diphenhydramine, and placebo on cognitive performance in flight personnel. Effects of acute cortisol administration on autobiographical memory in patients with major depression and healthy controls Lack of effects of guanfacine on executive and memory functions in healthy male volunteers Levodopa increases memory encoding and dopamine release in the striatum in the elderly Levodopa: Faster and better word learning in normal humans Catechol O-Methyltransferase Val158Met Polymorphism is Associated with Cognitive Performance in Nondemented Adults Evidence That a Positive Modulator of AMPA-Type Glutamate Receptors Improves Delayed Recall in Aged Humans Antiparkinsonian drug-induced sleepiness: a double-blind placebo-controlled study of L-dopa, bromocriptine and pramipexole in healthy subjects. Guanfacine and Clonidine, Alpha2-Agonists, Improve Paired Associates Learning, but not Delayed Matching to Sample, in Humans
abstract: INTRODUCTION Reasoning biases such as jumping to conclusions ( JTC ) and overconfidence in errors have been well replicated in patients with delusions . However , their relation to dopaminergic activity , central to pathophysiologic models of psychosis , has not yet been investigated . This study aim ed to examine the effects of a dopaminergic agonist ( L-dopa ) and a dopaminergic antagonist ( haloperidol ) on the JTC bias and overconfidence in errors after single-dose administration in healthy individuals . METHODS The study used a r and omized , double-blind , placebo-controlled , 3-way crossover design . Participants were 36 healthy individuals aged 18 - 36 years . The variables of interest were draws to decision and probability threshold to decision on a computerized variant of the beads task and the number of high-confident incorrect responses on a visual memory task . RESULTS There were no significant effects of substance on draws to decision and probability threshold to decision . A significant effect emerged for high-confident incorrect responses in the memory task ; pairwise comparisons indicated a significant reduction of the number of high-confident incorrect responses after administration of haloperidol vs l-dopa and placebo . CONCLUSIONS This is the first study to investigate the direct effects of dopaminergic drugs on reasoning biases . The JTC bias and overconfidence in errors showed a differential pattern of dopaminergic modulation , suggesting that they represent different facets of reasoning abnormalities that interact with each other to produce delusions in susceptible individuals Rationale The central cholinergic system is implicated in cognitive functioning . The dysfunction of this system is expressed in many diseases like Alzheimer 's disease , dementia of Lewy body , Parkinson 's disease and vascular dementia . In recent animal studies , it was found that selective cholinergic modulation affects visuospatial processes even more than memory function . Objective In the current study , we tried to replicate those findings . In order to investigate the acute effects of cholinergic drugs on memory and visuospatial functions , a selective anticholinergic drug , biperiden , was compared to a selective acetylcholinesterase-inhibiting drug , rivastigmine , in healthy elderly subjects . Methods A double-blind , placebo-controlled , r and omised , cross-over study was performed in 16 healthy , elderly volunteers ( eight men , eight women ; mean age 66.1 , SD 4.46 years ) . All subjects received biperiden ( 2 mg ) , rivastigmine ( 3 mg ) and placebo with an interval of 7 days between them . Testing took place 1 h after drug intake ( which was around Tmax for both drugs ) . Subjects were presented with tests for episodic memory ( wordlist and picture memory ) , working memory tasks ( N-back , symbol recall ) and motor learning ( maze task , pursuit rotor ) . Visuospatial abilities were assessed by tests with high visual scanning components ( tangled lines and Symbol Digit Substitution Test ) . Results Episodic memory was impaired by biperiden . Rivastigmine impaired recognition parts of the episodic memory performance . Working memory was non-significantly impaired by biperiden and not affected by rivastigmine .  Motor learning as well as visuospatial processes were impaired by biperiden and improved by rivastigmine . Conclusions These results implicate acetylcholine as a modulator not only of memory but also of visuospatial abilities Rationale Hypothalamic – pituitary – adrenal axis dysregulation predicts poor clinical and biochemical response to antidepressants . Antiglucocorticoids have therapeutic benefits but most have a troublesome adverse event profile . Aspects of neuropsychological performance , notably working memory , are susceptible to corticosteroid modulation and are impaired in depression . Aspirin has been shown to attenuate the adrenocorticotropic hormone ( ACTH ) and cortisol response to physiological challenge suggesting its potential to act as an augmenting agent in depression . Objectives To examine the effect of sub-acute ( 300 mg daily for 7 days ) aspirin pre-treatment on the cortisol awakening response and the effect of acute ( 600 mg ) and sub-acute aspirin on the neuroendocrine and neuropsychological response to the arginine vasopressin analogue , desmopressin . Results We demonstrated that aspirin pre-treatment did not attenuate the cortisol or ACTH response to desmopressin but , as hypothesised , significantly reduced the cortisol awakening response and improved working memory . Conclusions Further studies to examine the impact of aspirin on neuropsychological performance and HPA axis function are warranted Background Surgeons are usually exposed to high workloads leading to fatigue and stress . This not only increases the likelihood of mistakes during surgery but also puts pressure on surgeons to use drugs to counteract fatigue , distress , concentration deficits , burnout or symptoms of depression . The prevalence of surgeons taking pharmacological cognitive enhancement ( CE ) or mood enhancement ( ME ) drugs  has not been systematic ally assessed so far . Methods Surgeons who attended five international conferences in 2011 were surveyed with an anonymous self-report question naire ( AQ ) regarding the use of prescription or illicit drugs for CE and ME and factors associated with their use . The R and omized Response Technique ( RRT ) was used in addition . The RRT guarantees a high degree of anonymity and confidentiality when a person is asked about stigmatizing issues , such as drug abuse . Results A total of 3,306 question naires were distributed and 1,145 entered statistical analysis ( response rate : 36.4 % ) . According to the AQ , 8.9 % of all surveyed surgeons confessed to having used a prescription or illicit drug exclusively for CE at least once during lifetime . As one would expect , the prevalence rate assessed by RRT was approximately 2.5-fold higher than that of the AQ ( 19.9 % ; 95 % confidence interval ( CI ) , 15.9 % to 23.9 % , N = 1,105 ) . An even larger discrepancy between the RRT and AQ was observed for the use of antidepressants with a 6-fold higher prevalence ( 15.1 % ; 95 % CI , 11.3 % to 19.0 % , N = 1,099 ) as compared to 2.4 % with the AQ . Finally , logistic regression analysis revealed that pressure to perform at work ( odds ratio ( OR ) : 1.290 ; 95 % CI , 1.000 to 1.666 ; P = 0.05 ) or in private life ( OR : 1.266 ; 95 % CI , 1.038 to 1.543 ; P = 0.02 ) , and gross income ( OR : 1.337 ; 95 % CI , 1.091 to 1.640 ; P = 0.005 ) , were positively associated with the use of drugs for CE or ME . Conclusions The use of illicit and prescription drugs for CE or ME is an underestimated phenomenon among surgeons which is generally attributable to high workload , perceived workload , and private stress . Such intake of drugs is associated with attempts to counteract fatigue and loss of concentration . However , drug use for CE may lead to addiction and to overestimation of one ’s own capabilities , which can put patients at risk . Coping strategies should be taught during medical education BACKGROUND Sedation and functional impairments are side effects associated with the use of first-generation antihistamines that preclude their use in aviation . Selected second-generation antihistamines do not have such side effects and have been proposed for use in aircrew . METHODS Forty-two healthy naval aviation personnel served as subjects in this double-blind , r and omized , placebo-controlled crossover study . Subjective drowsiness , cognitive performance , and vigilance were measured under three conditions : 180 mg fexofenadine ( F ) , 50 mg diphenhydramine ( D ) as a positive control , or placebo ( P ) . RESULTS Subjects receiving F vs. D tended to have a faster mean hit reaction time ( adjusted mean difference + /- SE , -10.5 + /- 6.8 ms , p = 0.127 ) . Subjects performed faster and better with F vs. D on measures of omission errors and commission errors ( p < 0.05 ) . Variable symbol digit coding delayed recall accuracy was better for F vs. D ( p = 0.023 ) , and approached significance for shifting attention and divided attention tasks ( p = 0.062 and p = 0.057 , respectively ) . Subjects reported significantly more drowsiness ( p < 0.005 ) with D than F. CONCLUSIONS Diphenhydramine administration result ed in significant psychomotor decrements compared with fexofenadine , while the effects of fexofenadine were similar to placebo . These results provide additional support for the safe use of fexofenadine by aviation personnel OBJECTIVE Overgeneral autobiographical memory has become a well established phenomenon within major depressive disorder ( MDD ) . Neuroendocrinologically , MDD is often characterized by a dysregulation of the hypothalamic-pituitary-adrenal ( HPA ) axis , i.e. hypercortisolemia and reduced feedback sensitivity . In healthy participants cortisol administration has been found to impair autobiographical memory retrieval . The purpose of this study was to compare the effects of acute cortisol administration on autobiographical memory in MDD patients with the effects observed in healthy controls . We hypothesized that in contrast to healthy control subjects acute cortisol administration would not affect autobiographical memory performance in MDD due to reduced central glucocorticoid sensitivity . METHODS In a placebo-controlled , double-blind crossover study , 16 patients with MDD and 16 healthy control subjects received a placebo or 10 mg of hydrocortisone orally before autobiographical memory testing ( AMT ) . RESULTS In the placebo condition depressed patients performed poorer than controls . After hydrocortisone intake , healthy subjects reported significantly fewer specific memories on the AMT compared to placebo treatment . In contrast , memory specificity of MDD patients was not affected by hydrocortisone treatment . CONCLUSIONS The present findings replicate previous findings of impaired autobiographical memory retrieval after hydrocortisone treatment in healthy subjects and of impaired AMT performance in depressed patients . We speculate that the missing acute impairing effect of hydrocortisone on autobiographical memory in depressed patients might reflect reduced central glucocorticoid sensitivity . However alternative explanations can not be ruled out Rationale Guanfacine is an α2-adrenergic receptor agonist that has been shown to have beneficial effects on working memory and attentional functions in monkeys and in patients with attention deficit hyperactivity disorder . Objectives The aim of this study was to further investigate the cognitive-enhancing properties of guanfacine using an established battery of tasks measuring executive and memory functions . Methods Sixty healthy male volunteers were r and omised into three groups . Cognitive testing was performed from + 2 to + 4 h after double-blind administration of a single oral dose of 1 or 2 mg of guanfacine or placebo .  Results Systolic blood pressure was significantly reduced by both doses of guanfacine at the end of the testing session . There were no statistically significant effects on any of the cognitive measures . Two trend effects were observed with poorer performance on digit span backward and slower ‘ Go ’ reaction times after guanfacine . Conclusion This study found no improvement of prefrontal memory or executive functions  after guanfacine . Negative effects on blood pressure and trend effects on digit span backward and go reaction time indicate a mild sedative effect of guanfacine at these doses , possibly via mechanisms of autoreceptor down-regulation Normal aging is associated with a decrease in dopaminergic function and a reduced ability to form new motor memories with training . This study examined the link between both phenomena . We hypothesized that levodopa would ( a ) ameliorate aging-dependent deficits in motor memory formation , and ( b ) increase dopamine availability at the dopamine type 2-like ( D2 ) receptor during training in task-relevant brain structures . The effects of training plus levodopa ( 100 mg , plus 25 mg carbidopa ) on motor memory formation and striatal dopamine availability were measured with [(11)C]raclopride ( RAC ) positron emission tomography ( PET ) . We found that levodopa did not alter RAC-binding potential at rest but it enhanced training effects on motor memory formation as well as dopamine release in the dorsal cau date nucleus . Motor memory formation during training correlated with the increase of dopamine release in the cau date nucleus . These results demonstrate that levodopa may ameliorate dopamine deficiencies  in the elderly by replenishing dopaminergic presynaptic stores , actively engaged in phasic dopamine release during motor training Dopamine is a potent modulator of learning and has been implicated in the encoding of stimulus salience . Repetition , however , as required for the acquisition and reacquisition of sensorimotor or cognitive skills ( e.g. , in aphasia therapy ) , decreases salience . We here tested whether increasing brain levels of dopamine during repetitive training improves learning success . Forty healthy humans took  100 mg of the dopamine precursor levodopa or placebo daily for 5 days in a r and omized double‐blind and parallel‐group design . Ninety minutes later on each day , subjects were trained on an  artificial vocabulary using a high‐frequency repetitive approach . Levodopa significantly enhanced the speed , overall success , and long‐term retention of novel word learning in a dose‐dependent manner . These findings indicate new ways to potentiate learning in a variety of domains if conventional training alone fails The catechol O-methyltransferase ( COMT ) gene is essential in the metabolic degradation of dopamine in the prefrontal cortex . In the present study , we examined the effect of a Val158Met polymorphism in the COMT gene on individual differences and changes in cognition ( executive functions and visuospatial ability ) in adulthood and old age . The participants were 292 nondemented men ( initially aged 35 - 85 years ) from a r and om sample of the population ( i.e. , the Betula study ) tested at two occasions with a 5-year interval .  Confirmatory factor analyses were used to test the underlying structure of three indicators of executive functions ( verbal fluency , working memory , and Tower of Hanoi ) . Associations between COMT , age , executive functioning , and visuospatial ( block design ) tasks were examined using repeated- measures analyses of variance . Carriers of the Val allele ( with higher enzyme activity ) compared with carriers of the Met/Met genotype ( with low enzyme activity ) performed worse on executive functioning and visuo-spatial tasks . Individuals with the Val/Val genotype declined in executive functioning over the 5-year period , whereas carriers of the Met allele remained stable in performance . An Age COMT interaction for visuospatial ability located the effect for middle-aged men only . This COMT polymorphism is a plausible c and i date gene for executive functioning and fluid intelligence in nondemented middle-aged and older adults Elderly subjects ( 65 - 76 years ) were tested for recall of nonsense syllables prior to and after oral administration of 1-(quinoxalin-6 ylcarbonyl)piperidine ( CX516 ) , a central ly active drug that enhances currents mediated by AMPA-type glutamate receptors . A significant and positive drug effect was found for delayed ( 5 min ) recall at 75 min posttreatment ; average scores for the highest dose group were more than twofold greater than for the placebo group . The drug had no evident influence on heart rate or self- assessment of several psychological variables AIMS To assess the sleepiness induced by pramipexole , a D2/D3-dopamine receptor agonist commonly used in Parkinson 's disease and restless legs syndrome , without the problem of the confounding factors related to the disease . METHODS Placebo , bromocriptine ( 2.5 mg ) , L-dopa ( 100 mg ) and pramipexole ( 0.5 mg ) were administered in a single oral dose on four separate days , with at least a 2-week wash-out period in a r and omized cross-over design . Induced somnolence was assessed using Multiple Sleep Latency Test ( MSLT ) and subjective scaling of vigilance .  Twelve male subjects ( 26.3 + /- 5.5 years old ) without anxiety , mood , sleep or sedation disorders were enrolled . RESULTS Pramipexole significantly reduced mean sleep latency compared with placebo 3 h 30 min [ -6.1 min ( -9.8 , -2.4 ) , P = 0.002 ] and 5 h 30 min [ -5.6 min ( -7.7 , -3.5 ) , P = 0.003 ] after administration . In addition , the total duration of sleep during the tests was higher with pramipexole than with placebo [ + 6.0 min ( 2.3 , 9.7 ) , P < 0.001 ] . These differences were not observed with L-dopa and bromocriptine in comparison with placebo . The induced sleepiness was not associated with an increase in subjective somnolence scaling , indicating that this adverse event may occur without prior warning . CONCLUSIONS These results show that a single oral dose of pramipexole induces sleepiness as assessed by MSLT in healthy young subjects , independent of disease-related sleep dysfunction The present study compares the effects of two alpha2-agonists , clonidine ( 0.5 , 2 , and 5 μg/kg , PO ) and guanfacine ( 7 and 29 μg/kg , PO ) in young healthy volunteers on their performance in visual paired associates learning ( PAL ) and delayed matching to sample ( DMTS ) visual short-term recognition memory tests . In the PAL test , clonidine 2 and guanfacine 29 μg/kg improved the subjects ’ performance . In the DMTS test , clonidine at 5 μg/kg delay-dependently impaired performance accuracy , and at 2 and 5 μg/kg it also slowed responses . Guanfacine had no effect on DMTS test performance . Clonidine 5 and guanfacine 29 μg/kg equally increased subjective feelings of sedation and reduced blood pressure . The results suggest that both clonidine and guanfacine facilitated PAL learning by improving “ frontal strategies , ” but only clonidine disrupted “ mnemonic processing ” decreasing DMTS accuracy . The greater selectivity of guanfacine for alpha2A-adrenoceptor subtype may explain the different profile of action of the drugs
target: In conclusion , a number of new active drugs were found to improve some cognitive functions , in particular verbal episodic memory .
background: Pharmacological cognitive enhancement refers to improvement in cognitive functions after drug use in healthy individuals .
  This popular topic attracts attention both from the general public and the scientific community .
  The objective was to explore innovative mechanisms of psychostimulant 's action , whose potential effectiveness was assessed in r and omized placebo-controlled trials ( RCTs ) .