Modulation of memory and visuospatial processes by biperiden and rivastigmine in elderly healthy subjects

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, randomised, 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 T _max 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.     

Dissociations in the expression of the sedative effects of triazolam

Fifteen normal volunteers were administered 0.250, 0.375, and 0.500 mg of triazolam and placebo in a double-blind repeated measures cross-over design. Subjects demonstrated dose-dependent impairments in free recall, a test of explicit memory requiring awareness and reflection, and sedation as assessed by objective behavioral measures (the digit symbol substitution task) and subjective visual analogue scales. The sedative drug response did not account for the impairment in free recall. Differences in performance of the two tests of sedation indicated that the effect of this drug on reflective processes accounts for impairment in episodic memory and the inability to track the sedative effects of this drug at the higher doses tested in this study.     

Interaction between effects of caffeine and lorazepam in performance tests and self-ratings

In 18 normal volunteers, lorazepam (2.5 mg) compared with placebo significantly impaired performance in a verbal learning task, in the digit-symbol substitution test, and in symbol copying and number cancellation tasks. These impairments were found equally in subjects with high and low state anxiety and in subjects with high and low trait anxiety. Caffeine citrate (125 to 500 mg) significantly improved performance on the digit-symbol substitution test when given alone and reduced the lorazepam impairment. In the symbol copying test caffeine counteracted the lorazepam impairment. Lorazepam produced a significant loss of appetite and made the subjects feel significantly more dizzy, physically and mentally tired, withdrawn and tranquil, and significantly less anxious. Caffeine citrate (500 mg) counteracted the lorazepam effect of reducing anxiety and making the subjects feel more relaxed.     

Allopregnanolone impairs episodic memory in healthy women

OBJECTIVE: Allopregnanolone is an endogenous neuroactive steroid that, through its binding to the gamma-aminobutyric acid (GABA) A receptor, has GABA-active properties. Animal studies indicate that allopregnanolone administration results in diminished learning and memory impairment. The aim of the current study was to investigate the effect of intravenously administered allopregnanolone on episodic memory, semantic memory, and working memory in healthy women. MATERIALS AND METHODS: Twenty-eight healthy women were included in the study. The participants were scheduled for the memory tests twice in the follicular phase. During the test sessions, an intravenous allopregnanolone and placebo infusion were administered in a double-blinded, randomized order at intervals of 48 h. Before and 10 min after the allopregnanolone/placebo injections, memory tasks were performed. RESULTS: The study demonstrated that allopregnanolone impaired episodic memory in healthy women. There was a significant difference between pre- and postallopregnanolone injection episodic memory scores (p < 0.05), whereas there was no change in episodic memory performance following the placebo injections. There was also a significant difference between allopregnanolone and placebo postinjection episodic memory scores (p < 0.05). There were no effects of allopregnanolone on the semantic memory task or working memory task. CONCLUSION: Intravenous allopregnanolone impairs episodic memory in healthy women, but there is a high degree of individual variability.     

A comparison of the effects of a secondary task and lorazepam on cognitive performance

In order to test whether the lorazepam-induced impairments in a variety of cognitive tasks were similar to those of divided attention, the effects of lorazepam (2.5 mg) in healthy volunteers were compared with those requiring subjects to perform an additional task (detecting silences superimposed onto classical music). Neither treatment impaired implicit memory or judgements of frequency. Both treatments impaired performance in tests of speed, lorazepam having the greatest effect on number cancellation and the additional task having the greatest effect on simple reaction time. Both treatments impaired performance in a coding task, in a test of explicit episodic memory and in judgements of recency (indicating impaired coding of contextual information). Lorazepam significantly reduced performance in a word completion task, but this was unimpaired in the group performing the additional task. In general, the pattern of results suggests that there are similarities between the effects of divided attention and lorazepam treatment, and that lorazepam-induced cognitive impairments are not restricted to explicit tests of episodic memory.     

Memory impairments in humans after acute tryptophan depletion using a novel gelatin-based protein drink

Acute tryptophan depletion (ATD) can be used to decrease serotonin levels in the brain. Traditionally, ATD has been established by administering amino acid (AA) mixtures and studies using this method showed that serotonin is involved in learning and memory processes. This study used a recently developed gelatin-based protein drink to examine whether it 1) is superior to the traditional AA method in controlling the tryptophan levels in the placebo condition, 2) impairs long-term memory and 3) differentially affects episodic and spatial memory. Sixteen healthy subjects participated in a double-blind, placebo-controlled study. Memory was assessed using a visual verbal learning test and an object relocation task (spatial memory). Tryptophan ratio significantly decreased after ATD and did not significantly increase in the placebo condition. Delayed recall in the verbal learning test and delayed relocation of objects to positions in the spatial task were impaired after ATD. Spatial short-term memory, however, improved. The current results indicate that the tryptophan levels were essentially neutral in the placebo condition compared with those in the traditional AA mixture. Our study provides further evidence that impairment in long-term episodic and elementary spatial memory after ATD is related to lowered tryptophan levels in plasma.     

The class I metabotropic glutamate receptor antagonist, AIDA, improves short-term and impairs long-term memory in a spatial task for rats.

Effects of the class I selective metabotropic glutamate receptor antagonist, 1-aminoindan-1,5-dicarboxylic acid (AIDA), on spatial procedural learning and episodic short-term memory of rats were investigated in an appetitively reinforced 3-choice delayed match-to-position task. First, an acute intraperitoneal injection of AIDA (2 mg/kg) was given 20 min before a single training session of 20 trials using repeated reward position in one alcove out of three. AIDA caused facilitated short-term acquisition within such a session compared to saline treated controls. Secondly, injections were given before each of ten sessions (48 h intervals) also using constant reward position. The results showed AIDA induced inhibition of procedural between-session acquisition. Finally, the use of reward positions in a non-repetitive but trial-specific version of the 3-choice test revealed a facilitating effect of AIDA on episodic short-term memory.     

Effects of repeated cortisol administration on brain potential correlates of episodic memory retrieval

RATIONALE: Neuropsychological impairments in depressive illness may be secondary to hypercortisolaemia. Cortisol administration to healthy subjects impairs episodic memory, though how this is mediated is unknown. OBJECTIVES: To examine the effects of 1 week's administration of cortisol on the neural correlates of episodic memory in healthy subjects. METHODS: Fourteen healthy men were treated with oral cortisol (hydrocortisone 20 mg) or placebo twice daily for 1 week, in a double blind, crossover fashion. Event related potentials (ERPs) were recorded during a well-validated source memory task. Subjects listened to words spoken in a male or female voice. At test, old and new words were presented visually; subjects judged whether words were old or new, and if old, the gender of the voice at study. RESULTS: Response times were significantly speeded by cortisol. A significant reduction in recognition accuracy with cortisol was found for the second study occasion. ERP recordings with placebo showed greater positivity over left parietal and right frontal scalp areas for ERPs to items given correct source judgements versus correctly rejected new items. In comparison, cortisol increased ERP voltage between 500 and 1400 ms post-stimulus and this effect interacted with item type and electrode site, being diffusely distributed for correct rejections but of a lesser magnitude frontally for old items accorded a correct source judgement. CONCLUSIONS: Repeated cortisol administration leads to a qualitative change in the neural correlates of episodic memory retrieval in healthy subjects. This change may contribute to cognitive impairments seen in illnesses characterised by hypercortisolaemia.     

Caffeine and diazepam: Separate and combined effects on mood,memory, and psychomotor performance

The effects of caffeine and diazepam on several mood, cognitive, learning, memory, and psychomotor tasks were investigated in a double-blind study of 108 young healthy adults who were randomly assigned to nine treatments; oral administration of caffeine (0, 3 and 6 mg/kg), diazepam (0, 0.15, and 0.30 mg/kg) and their combinations. Subjects completed a battery of tasks once before and twice after administration of the drugs. Caffeine alone showed no effects on cognitive, learning, and memory performance, but impaired fine motor coordination and increased anxiety and tenseness. Diazepam alone produced sedation, lowered other ratings of subjective moods, and impaired cognitive, learning, and memory performance. The two drugs did not antagonize the effects of each other, except in the symbol cancellation task.     

Haloperidol increases false recognition memory of thematically related pictures in healthy volunteers

Dopamine can modulate long‐term episodic memory. Its potential role on the generation of false memories, however, is less well known. In a randomized, double‐blind, placebo‐controlled experiment, 24 young healthy volunteers ingested a 4‐mg oral dose of haloperidol, a dopamine D₂‐receptor antagonist, or placebo, before taking part in a recognition memory task. Haloperidol was active during both study and test phases of the experiment. Participants in the haloperidol group produced more false recognition responses than those in the placebo group, despite similar levels of correct recognition. These findings show that dopamine blockade in healthy volunteers can specifically increase false recognition memory.     

Effects of tryptophan depletion on brain potential correlates of episodic memory retrieval

RATIONALE: Neuropsychological impairments in depressive illness may be secondary to proposed serotonergic abnormalities. Acute tryptophan depletion (ATD) in healthy subjects impairs episodic memory, but the mechanism of this is unclear. OBJECTIVES: To examine the effects of ATD on the neural correlates of episodic memory retrieval in healthy subjects. METHODS: Fourteen healthy men were given an amino acid cocktail drink with or without tryptophan, in a double blind, crossover design. Event related potentials (ERPs) were recorded during a well-validated episodic memory task performed 5 h after drink ingestion. Subjects listened to words spoken in a male or female voice. At test, old and new words were presented visually; subjects judged whether words were old or new, and if old, the gender of the voice at study. RESULTS: ATD led to an 84+/-5% reduction in plasma free tryptophan concentrations, and significantly impaired episodic memory recall. ERP recordings demonstrated previously reported left parietal and right frontal "old/new" differences for ERPs to items associated with accurate episodic memory retrieval versus correctly rejected new items. ATD increased ERP voltage between 500 and 1400 ms post-stimulus particularly over posterior regions of the scalp, but there was no interaction with item type. Topographical analysis of the old/new difference revealed no significant treatment by site interaction. CONCLUSIONS: ATD impairs episodic memory recall with no effect on the magnitude or topography of the neural correlates of retrieval in healthy subjects. This suggests that the effects of ATD on recall may reflect an impairment of memory encoding and/or consolidation.     

The memory-enhancing effects of Ginseng and Ginkgo biloba in healthy volunteers

Rationale The use of herbal remedies, such as Ginkgo biloba and Ginseng, for improving cognitive performance has become increasingly popular during recent years. Several previous studies have indicated that administration of Ginkgo biloba and Ginseng may improve aspects of learning and memory in healthy volunteers. These results, however, are generally not supported by well-controlled clinical studies. Also, positive results have often been reported from studies investigating effects related to short-term, chronic administration of the extract. Nonetheless, both Ginkgo biloba and Ginseng are marketed as having the capacity to enhance cognitive functions, such as memory and learning, in the long term.Objective This study aimed at investigating whether the use of Ginkgo biloba and Ginseng for a long period of time has positive effects on performance on learning and memory.Methods Community-dwelling volunteers (n=3500) from The Betula prospective cohort study: memory, health, and aging were included in the study.Results It was found that the use of neither Ginkgo biloba (n=40) nor Ginseng (n=86) was associated with enhanced memory performance in any of the eight memory tests examined, relative to control groups either using or not using nutritional supplements.Conclusions These findings indicate that use of Ginkgo biloba or Ginseng does not provide any quantifiable beneficial effects on memory performance in the long-term in healthy adult volunteers.     

Does potency determine amnestic effects of benzodiazepines? A dose-response comparison of flunitrazepam and nitrazepam

This study was designed to explore whether differences in the psychomotor, subjective and memory effects of different benzodiazepines (BDZ) relate to differences in their potencies. Two BDZs with similar kinetics but different potencies were compared. Flunitrazepam (0.5 and 1.0mg, nitrazepam (5 and 10mg) or placebo were administered to 50 healthy volunteers in a double-blind, parallel group design. Subjects completed a test battery before and 1.5h post-treatment. The higher dose of the more potent BDZ, flunitrazepam, impaired episodic memory in relation to placebo. In contrast, differences in psychomotor and subjective effects between BDZ were less clear. We conclude that a main caveat to the conclusion that potency plays a role in determining BDZ amnestic effects is the possible contribution of sedation and differential task sensitivities to apparent differential effects of BDZ compounds.     

Role of the mesotelencephalic dopamine system in learning and memory processes in the rat

The effects of lesioning the ventral tegmental area or substantia nigra pars reticulata by means of bilateral microinjections of two doses of kainic acid (50 ng/250 nl and 100 ng/500 nl) or 6-hydroxydopamine (8 microg/4 microl) were investigated to clarify the role of the mesotelencephalic dopamine system in learning and memory processes. Our findings suggest that ventral tegmental area and substantia nigra dopaminergic neurons play an important role in retention of both short-term memory, tested in the Y-maze task and long-term memory evaluated with the multi-trial passive avoidance test, without affecting memory acquisition. As compared to short-term memory, long-term memory is more susceptible to the decreased dopamine level in nervous structures involved in processing and storage of information.     

Caffeine attenuates scopolamine-induced memory impairment in humans

Caffeine consumption can be beneficial for cognitive functioning. Although caffeine is widely recognized as a mild CNS stimulant drug, the most important consequence of its adenosine antagonism is cholinergic stimulation, which might lead to improvement of higher cognitive functions, particularly memory. In this study, the scopolamine model of amnesia was used to test the cholinergic effects of caffeine, administered as three cups of coffee. Subjects were 16 healthy volunteers who received 250 mg caffeine and 2 mg nicotine separately, in a placebo-controlled double-blind cross-over design. Compared to placebo, nicotine attenuated the scopolamine-induced impairment of storage in short-term memory and attenuated the scopolamine-induced slowing of speed of short-term memory scanning. Nicotine also attenuated the scopolamine-induced slowing of reaction time in a response competition task. Caffeine attenuated the scopolamine-induced impairment of free recall from short- and long-term memory, quality and speed of retrieval from long-term memory in a word learning task, and other cognitive and non-cognitive measures, such as perceptual sensitivity in visual search, reading speed, and rate of finger-tapping. On the basis of these results it was concluded that caffeine possesses cholinergic cognition enhancing properties. Caffeine could be used as a control drug in studies using the scopolamine paradigm and possibly also in other experimental studies of cognitive enhancers, as the effects of a newly developed cognition enhancing drug should at least be superior to the effects of three cups of coffee.     

Comparative amnesic and sedative effects of lorazepam and oxazepam in healthy volunteers

Oxazepam and its chlorinated derivative, lorazepam, have similar half-lives but differing potencies. This study compared the effects of these two benzodiazepines with a placebo on memory, mood and psychomotor function. Thirty six volunteers took part in a double-blind, independent groups design. Subjects completed a battery of tests before and 2.5 h after drug administration. Lorazepam 2 mg produced more profound subjective and motor sedation than oxazepam 30 mg, and this in turn produced a similar, global pattern of impairments across a wide range of tasks. However, lorazepam produced greater decrements than oxazepam on a task involving episodic memory even when sedative effects were partialled out. We suggest that this finding may reflect either differential task sensitivities or a contribution of priming to performance on the explicit memory task.     

Effects of a single dose of cortisol on the neural correlates of episodic memory and error processing in healthy volunteers

Rationale. Neuropsychological impairments seen in depression may be secondary to hypercortisolaemia. Repeated cortisol administration impairs episodic memory with an alteration in event-related potentials (ERPs) recorded during information retrieval. It is unclear whether such ERP effects are specific to episodic memory, or whether repeated cortisol administration is required. Objective. To investigate the effect of a single dose of hydrocortisone on the neural correlates of episodic memory and error detection. Methods. Twenty healthy subjects were treated with hydrocortisone (100 mg) or placebo orally, in a double-blind, two-way crossover study. ERPs were recorded during an episodic memory and a Stroop task, 1–3 h following the medication. Results. Cortisol increased error rates during the Stroop task but had no effect on episodic memory. The magnitude of ERPs associated with incorrect response in the Stroop task between −250 ms and +500 ms post-response was increased by cortisol, with no effect on correct-response ERPs. There was no effect of cortisol on episodic memory-retrieval-dependent ERPs. Conclusions. Cortisol can impair not only episodic memory but also processes involved in error detection. In contrast to repeated cortisol administration, a single dose of cortisol does not alter the behavioural performance or the electrophysiological correlates of episodic memory. However, it increases error rates in a choice response task with associated quantitative changes in incorrect-response ERPs. This probably reflects an alteration in anterior cingulate cortex activity. Such changes may contribute to the neuropsychological impairment seen in depression. This study also demonstrates the utility of ERPs for investigating the effect of neuroendocrine manipulations on the neural correlates of neuropsychological function. Electronic Publication     

Zolpidem and triazolam do not affect the nocturnal sleep-induced memory improvement

Rationale It is widely accepted that sleep facilitates memory consolidation. Hypnotics (e.g., benzodiazepines), which reportedly increase sleep efficiency but also modify sleep architecture, could affect memory improvement that occurs during sleep. Objectives The present study examined the effects of single doses of two short half-life hypnotics, zolpidem and triazolam, on sleep-induced improvement of memory. Methods Twenty-two healthy volunteers participated in this randomized, double-blind, crossover study. All subjects received a single oral dose of zolpidem (10 mg), triazolam (0.25 mg) or placebo at 9 p.m. and slept for 7.5±0.2 h. The effect of sleep on memory was investigated by comparing the performance of this group of volunteers with a group of 21 subjects in wakefulness condition. Declarative memory was evaluated by using a free-recall test of ten standard word and seven nonword lists. Subjects memorized the word and nonword lists 1 h before dosing and they were asked to recall the memorized lists 10 h after dosing. Digit symbol substitution test (DSST) and forward and backward digit tests were also given 1 h before and 10 h after dosing. Results Subjects who slept remembered more nonwords than those in wakefulness condition, but they did not recall significantly more standard words. Neither zolpidem nor triazolam affected the enhanced nonword recall observed after sleep. Finally, none of the hypnotics affected the improvement in the DSST performance of subjects who slept. Conclusions The hypnotics tested did not interfere with the nocturnal sleep-induced improvement of memory.     

Acute effects of opioids on memory functions of healthy men and women

Introduction Although several psychotropic drugs can acutely induce an anterograde impairment of memory which impedes new learning, they do not produce retrograde impairments, reducing memory for information learned prior to the drug being administered. However, both anterograde and retrograde memory impairments have been reported following an acute dose of morphine in palliative care patients (Kamboj et al., Pain 117:388–395, 2005). Objective The present study was designed to determine: (1) whether similar amnestic effects would be found after a single oral dose of either morphine or oxycodone in healthy volunteers, (2) how generalisable such effects were across a broader range of memory tasks and (3) whether men and women showed a differential response. Materials and methods A double-blind, placebo-controlled crossover design was used with 18 participants (nine men, nine women) who were administered 10 mg morphine, 5 mg oxycodone and placebo on three separate test days. Results On a working memory task, subtle impairments were found in women following both opioids whilst in men only following morphine. On an episodic memory task, women made significantly more source attribution errors after oxycodone and men made more after placebo. Most gender differences were weight related and a range of other measures showed no drug-induced impairments. Conclusion We conclude that these standard doses of opioids have only marginal effects on memory. If these findings can be extrapolated to patients with pain, then clinicians can feel confident in prescribing them on an outpatient basis without impacting on patients’ daily functioning.     

Memory formation for an appetitive visual discrimination task in young chicks

The three-phase model of memory formation in young chicks proposed by Gibbs and Ng [7] was based on a single trial passive avoidance task. Some methodological and interpretative problems associated with this task are not encountered in appetitive visual discrimination tasks. Using such a task, it is shown that 2 mM KCl induces amnesia at 10 min, ouabain at 30 min and cycloheximide at 60 min after learning. These findings are consistent with those for the single trail passive avoidance task and confirm the generality of a model of memory formation in young chicks entailing a short-term phase, a sodium pumo-dependent labile phase, and a long-term, protein synthesis-dependent phase.