Dual task performance after diazepam intake: can resource depletion explain the benzodiazepine-induced amnesia?

 It was tested whether a depletion in resources can account for the benzodiazepine-induced memory impairment. In two experiments, it was examined whether dividing attention had a disproportionately detrimental effect on learning semantically related and unrelated word pairs after diazepam intake. Word pairs had to be learned in both a single task condition and while performing a visual discrimination task concurrently (dual task condition). Moreover, the complexity of the visual discrimination task was manipulated systematically. Diazepam (15 mg, orally) or placebo was administered in a double-blind, between-subjects design. Subjects after diazepam intake were clearly impaired in learning unrelated word pairs, but not in learning related word pairs. Dividing attention in the dual task condition was associated with a reduction in learning unrelated word pairs, but this was not disproportionately reduced after diazepam intake. Moreover, the magnitude of resource depletion did not correlate with the severity of the diazepam-induced memory impairment. In general, the pattern of results does not support the hypothesis that a depletion of resources can explain the benzodiazepine-induced memory impairment. Received: 27 October 1997 / Final version: 18 December 1997     

Effects of diazepam or chronic alcohol treatment on spatial reversal learning in mice

Mice submitted to chronic alcohol consumption (CAC; 11 months) or to systemic diazepam administration were trained in a spatial reversal learning task. Although CAC-treated mice were able to learn the initial acquisition at normal rates, they were impaired during the first reversal of the discrimination and subsequent reversal sessions. In contrast, diazepam administration induced no deficits for any behavioral measure. In conclusion, CAC, but not diazepam administration, induces an exaggerated sensitivity to proactive interference. The two treatments spared, however, the development of the learning set curve. These results are congruent with clinical data showing that nondeclarative or implicit forms of memory processes are spared in diazepam-treated subjects or in chronic alcoholics.     

Diazepam-induced prospective memory impairment and its relation to retrospective memory, attention, and arousal

The amnestic effects of benzodiazepines are well documented on a variety of memory tasks. However, prospective memory (PM), or remembering to execute an action at a future time, has not been studied previously. This study examined the effect of diazepam on word list recall, PM, sustained attention, and subjective ratings of arousal. Forty-eight healthy participants, aged 19-35, received an average of 0.19 mg/kg oral diazepam or placebo in a double-blind manner. Retrospective memory and PM were assessed by free recall of unrelated word lists and by instructing participants to request a hidden belonging at the end of the session, respectively. Sustained attention was measured by multiple trials of a digit cancellation task, and subjective arousal was assessed by self-ratings of drowsiness. Diazepam impaired performance on all measures, including PM. Reduced PM performance was associated with decreased subjective arousal in the diazepam group but was unrelated to sustained attention. This is the first report of the effects of benzodiazepines on prospective remembering, and further supports the view that the arousal/attentional system is composed of partially independent subsystems that have differential relationships to memory.     

Interference effects on verbal memory function, following oral lorazepam

Previous studies have consistently reported deficits in verbal memory following oral lorazepam administration. The possible role of susceptibility to interference effects as a contributory mechanism in benzodiazepine amnesia has not been examined as an independent variable. In addition, most studies of benzodiazepine amnesia have not controlled for the possible confounding effects of alcohol consumption, recently reported to affect the degree of amnesia produced by lorazepam. The present study assessed the verbal memory capabilities of 24 low social drinkers (MAST score < 3) receiving either oral lorazepam (2 mg) or placebo. Interference effects on verbal memory were assessed using the Auditory herbal Learning Test, with either the interference word list (trial B) or a counting backwards task. Lorazepam significantly reduced the recall scores for list B, compared to the first presentation of list A, suggesting lorazepam may increase susceptibility to proactive interference. There was no drug effect on retroactive interference. With regard to recall per se, lorazepam impaired verbal learning for initial acquisition trials (trials 2 and 3) but not subsequent trials, where learning was comparable to the placebo. Lorazepam did not produce significant impairment in immediate and delayed recall trials. This pattern of recall does not conform to the classic profile of benzodiazepine-induced amnesia; potential explanations for this are discussed.     

Effects of diazepam on cognitive processes in normal subjects

The effects of 10 mg orally-administered diazepam on various aspects of cognition were examined in ten male subjects. Diazepam produced a subjective sense of cognitive impairment and impaired auditory vigilence, immediate recognition of twice presented words, and context-dependent free recall. There was a trend for a significant proportion of subjects to show impairment in delayed recognition of twice-presented words. There was no impairment of context-independent semantic memory, or of subjects' ability to judge how well they had performed on the free recall task. In fact, subjects' subjective sense of cognitive impairment was correlated with their performance on context-dependent memory tasks.     

Effects on memory following a single oral dose of diazepam

The effects of diazepam on learning and memory were investigated in a double-blind study of 28 Uruguayan university women who were randomly assigned to four treatments, seven subjects each: placebo, 0.1, 0.2, and 0.3 mg/kg diazepam orally. Subjects were presented with five uncategorized and categorized word lists, a 12-digit number list, and a tonal discrimination test, before and up to 200 min after treatment. Immediate and delayed recall were tested. Performance of the 0.1 mg/kg diazepam group did not show significant differences from placebo in any of the tests. For the 0.2 dose group, marginal impairments were noted at 60 min followed by full recovery at 190 min. On the contrary, 0.3 mg/kg diazepam produced significant impairments on immediate and delayed recall, with marginal impairments still evident at 190 min. The finidng that diazepam did not impair performance on a tonal discrimination test provided some evidence that memory impairments did not result from failures in general alertness.     

Separating intentional inhibition of prepotent responses and resistance to proactive interference in alcohol-dependent individuals

Background

Impulsivity is a hallmark of addictive behaviors. Addicts’ weakened inhibition of irrelevant prepotent responses is commonly thought to explain this association. However, inhibition is not a unitary mechanism. This study investigated the efficiency of overcoming competition due to irrelevant responses (i.e., inhibition of a prepotent response) and overcoming competition in memory (i.e., resistance to proactive interference) in sober and recently detoxified alcohol-dependent individuals.

Methods

Three cognitive tasks assessing the inhibition of a prepotent response (Hayling task, anti-saccade task and Stroop task) and two tasks tapping into the capacity to resist proactive interference (cued recall, Brown-Peterson variant) were administered to 30 non-amnesic recently detoxified alcohol-dependent individuals and 30 matched healthy participants without alcohol dependency. In addition, possible confounds such as verbal updating in working memory was assessed.

Results

Alcohol-dependent subjects performed worse than healthy participants on the three cognitive tasks assessing the inhibition of irrelevant prepotent responses but group performance was similar in the tasks assessing overcoming proactive interference in memory, updating of working memory and abstract reasoning.

Conclusions

These findings suggest that alcohol-dependence is mainly associated with impaired capacity to intentionally suppress irrelevant prepotent response information. Control of proactive interference from memory is preserved. Theoretical and clinical implications are discussed.     

Diazepam and memory: evidence for spared memory function

The effects of diazepam on several tests of memory were investigated in a double-blind study of 24 healthy young adults. Following a single oral administration of 0.3 mg/kg diazepam or placebo, subjects in the diazepam group showed marked impairment in immediate free recall of words as compared to placebo control subjects. However, diazepam-treated subjects demonstrated performance benefits from prior exposure to the same words on tests of memory priming using word completion and category-generation tasks. The two types of memory tests differ in their demand for conscious recollection. Tests of free recall have explicit (declarative) memory demands whereas the priming test places only implicit (procedural) demands upon memory. The results demonstrate that diazepam spares some forms of memory as does amnesia induced by neurological impairment.     

Using a computer model to explore impairments of acquisition processes following ingestion of diazepam

Hypotheses about the information processes impaired in diazepam-induced amnesia were tested by fitting the output from a computer simulation of list learning to observed serial position curves and to overt rehearsal protocols. Twenty-four subjects received an average weight-relative dosage of 0.18 mg/kg oral diazepam; 24 subjects received placebo. Immediate free recall of 16-word lists was examined at 2- and 8-s presentation times. Subjects receiving diazepam recalled significantly fewer words than placebo subjects (diazepam=6.77 ± 2.39 words; placebo=9.29 ± 1.42 words); their memory impairment was greater at the 8-s than 2-s presentation time. Tests of nonlinear regression models based on computer simulations of list learning performance were consistent with the hypothesis that diazepam reduces rehearsal capacity and disrupts the formation or utilization of contextual and inter-item associations. Among these causes of diazepam-induced amnesia, the disruption of contextual associations appears most important. The results further suggest that quantitative modeling of memory data may complement traditional methods of inferring relationships between brain processes and cognitive dysfunction in amnesic states.Bold letters represent model parameters     

Profiles of cognitive dysfunction in chronic amphetamine and heroin abusers.

Groups of subjects whose primary drug of abuse was amphetamine or heroin were compared, together with age- and IQ-matched control subjects. The study consisted of a neuropsychological test battery which included both conventional tests and also computerised tests of recognition memory, spatial working memory, planning, sequence generation, visual discrimination learning, and attentional set-shifting. Many of these tests have previously been shown to be sensitive to cortical damage (including selective lesions of the temporal or frontal lobes) and to cognitive deficits in dementia, basal ganglia disease, and neuropsychiatric disorder. Qualitative differences, as well as some commonalities, were found in the profile of cognitive impairment between the two groups. The chronic amphetamine abusers were significantly impaired in performance on the extra-dimensional shift task (a core component of the Wisconsin Card Sort Test) whereas in contrast, the heroin abusers were impaired in learning the normally easier intra-dimensional shift component. Both groups were impaired in some of tests of spatial working memory. However, the amphetamine group, unlike the heroin group, were not deficient in an index of strategic performance on this test. The heroin group failed to show significant improvement between two blocks of a sequence generation task after training and additionally exhibited more perseverative behavior on this task. The two groups were profoundly, but equivalently impaired on a test of pattern recognition memory sensitive to temporal lobe dysfunction. These results indicate that chronic drug use may lead to distinct patterns of cognitive impairment that may be associated with dysfunction of different components of cortico-striatal circuitry.     

Auditory verbal learning in drug-free Ecstasy polydrug users

Drug-free Ecstasy polydrug users have shown impairment on tasks of verbal working memory and memory span. Current research aims to investigate how these deficits may affect the learning of verbal material by administration of the Auditory Verbal Learning Task (AVLT) (Rey, 1964). The task provides a learning curve by assessing immediate memory span over multiple trials. Learning strategies are further analysed by tendencies to confabulate as well as demonstrate either proactive or retroactive interference elicited by a novel 'distractor' list. Three groups completed the task: two groups of 14 Ecstasy users (short- and long-term) and one group of 14 polydrug controls. Compared with controls both Ecstasy groups recalled significantly fewer words and made more confabulation errors on the initial three recall trials as well as a delayed recall trial. Long-term users demonstrated increased confabulation on the initial trials and the novel 'distractor7' trial, compared with short-term users. Only following repeated presentations were both short- and long-term users shown to perform at control levels. As such, deficits in verbal learning may be more related to storage and/or retrieval problems than problems associated with capacity per se. No interference errors were demonstrated by either of the Ecstasy groups. However, a high level of intrusion errors may indicate selective working memory problems associated with longer-term use of the drug. Copyright 2001 John Wiley & Sons, Ltd.     

An analysis of the learning deficit following hyoscine administration to man

1. Twelve volunteer subjects completed a free-recall word learning test, a number-colour association test, and a scanning task after the following treatments: saline 1 ml, hyoscine 0.4 mg, or atropine 0.6 mg, administered by intravenous injection.2. Performance on all three tests was not significantly impaired after atropine.3. Performance on the two learning tests but not on the scanning task, was significantly impaired after hyoscine.4. Analysis of the results of the free-recall word learning test indicates that impairment of learning following hyoscine does not affect recall over intervals of a few seconds, but affects that portion of the learning curve which has been attributed to long-term (or secondary) rather than short-term (or primary) memory.5. The results suggest that hyoscine 0.4 mg may impair learning processes, without significantly depressing other psychological functions, and that the impairment of learning following hyposcine does not affect recall over intervals memory.     

Diazepam and learning: Assessment of acquisition deficits

Subjects treated with diazepam (0.3 mg/kg) showed significant reductions in performance on multiple-trial free recall, paired-associate learning, and serial learning tasks compared to placebo control subjects. The free recall task showed the largest drug effect with diazepam subjects failing in six acquisition trials to attain the level of performance achieved by placebo subjects on the first trial. Serial position curves in the serial learning task were changed by the diazepam treatment from their usual skewed form to symmetrical functions. Results indicate that diazepam exerts its greatest memory influence on the acquisition of new information.     

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.     

Differential effects of the anxiolytic drugs, diazepam and buspirone, on memory function.

The effects of the anxiolytic drugs diazepam (5 mg) or buspirone (5 or 10 mg) were studied in comparison with placebo on memory function in 39 subjects diagnosed with generalized anxiety disorder. Neither drug altered the immediate recall of a list of 16 nouns or impaired digit span, a second test of immediate memory. Diazepam selectively impaired the recall of nouns after a 20 min delay when compared with placebo. In contrast, neither dose of buspirone altered the delayed recall of the word list. The implications of such different effects of anxiolytic drugs on memory function for the clinical treatment of anxiety are discussed.     

Selective dissociations of sedation and amnesia following ingestion of diazepam

Forty-eight healthy volunteers received 0.2 mg/kg oral diazepam or a placebo in a double-blind manner. The effect of the drug on memory was assessed by the free recall of unrelated word lists, and arousal was assessed by subjective ratings of drowsiness, multiple trials of a digit cancellation task, and the rate at which subjects rehearsed aloud items from the word lists. As expected, diazepam, depressed both memory functioning and all three measures of arousal. However, within the diazepam group, rehearsal rate was the only arousal measure that correlated with performance on the recall task. When looking at change scores, or the degree to which performance deteriorated from baseline to the diazepam condition, digit cancellation reduction was the only arousal measure that correlated with recall deterioration. Analyses also revealed that the three arousal measures did not correlate with each other. Results support the view that the arousal/attentional system is composed of partially independent subsystems with varying relationships to memory functioning.     

Toward a neuropsychology of memory in schizophrenia.

Three brain regions that have been the focus of recent interest in the neuropathology of schizophrenia include the frontal lobes, the basal ganglia, and the temporal lobes. We tested patients with chronic schizophrenia on three memory tasks, the successful performance of which depends on the integrity of each of these three brain regions. Comparisons between chronic schizophrenic patients and normal control subjects yielded the following results: (a) patients were impaired in remembering the temporal order of previously presented events; (b) patients were impaired on a motor task of procedural learning; and (c) patients showed normal priming effects in an implicit memory task despite their recall deficit in an explicit memory task. The significance of these findings lies in their relation to neuropsychological findings in patients with dysfunction in frontal cortical, basal ganglia, and medial temporal lobe structures.     

Further consideration of the learning impairment after aceperone in the marmoset: Effects of the drug on shape and colour discrimination and on an alternation task

Ten marmosets (Callithrix jacchus) learned to discriminate between pairs of small grey objects differing only in shape or small plain plaques differing only in colour, in a Wisconsin General Test Apparatus. Each day, each animal was presented with three consecutive visual discrimination problems in the order shape-colour-shape or colour-shape-colour. After aceperone, an α-noradrenergic antagonist, animals were impaired at learning the first but not the subsequent tasks of each trio. These results suggest that the previously observed impairment [10] on the first of a pair of object discrimination tasks after aceperone is a consequence of disruption of a mechanism common to both shape and colour discrimination learning. The fact that there is no impairment on task 2 in a dimension differing from task 1 suggests that the deficit is not one of attending to, or switching attention to, the appropriate visual dimension. Three further marmosets were trained to perform an alternation task and tested under aceperone. No impairment in performance was seen, suggesting that a variety of cognitive skills other than stimulus-reward association were intact. We conclude that the impairment following aceperone is a dysfunction of processes involved in association formation, but that it is one which is manifest only when the animal is faced with a type of task which has not recently been performed and that it can be overcome with persistence even when the animal encounters novel stimuli.     

Distinct contributions of glutamate and dopamine receptors to temporal aspects of rodent working memory using a clinically relevant task

RATIONALE: Understanding the mechanistic basis of working memory, the capacity to hold representation "on line," is important for delineating the processes involved in higher cognitive functions and the pathophysiology of thought disorders. OBJECTIVES: We compared the contribution of glutamate and dopamine receptor subtypes to temporal aspects of working memory using a modified rodent spatial working memory task that incorporates important elements of clinical working memory tasks. METHODS: A discrete paired-trial variable-delay T-maze task was used. Initial characterization studies indicated that performance on this task is stable at seconds-long retention intervals, is sensitive to retention interval and proactive interference, and is dependent on the integrity of the medial prefrontal cortex. RESULTS: Consistent with clinical findings, low dose amphetamine (0.25 mg/kg) produced a delay-dependent improvement in performance, while higher doses impaired performance at all retention intervals. D1 receptor blockade produced the predicted dose- and delay-dependent impairment. D2 receptor blockade had no effect. Activation of metabotropic glutamate 2/3 (mGluR2/3) receptors, which in the prefrontal cortex inhibits the slow asynchronous phase of glutamate release, also produced a delay-dependent impairment. Low doses of an AMPA/kainate antagonist had effects similar to the mGluR2/3 agonist. In contrast, NMDA receptor antagonist-induced impairment was memory load-insensitive, resulting in chance-level performance at all retention intervals. CONCLUSIONS: These findings suggest that activation of NMDA receptors is necessary for the formation of mnemonic encoding while modulatory components involving slow asynchronous release of glutamate and phasic release of dopamine contribute to the active maintenance of information during the delay period.     

Diazepam produces disinhibitory cognitive effects in male volunteers

Rationale Diazepam has well known amnestic and sedative effects but effects on fronto-executive function remain largely uninvestigated, especially on neuropsychologically validated tests of risk taking and orbitofrontal cortex function.Objectives We aimed to determine the impact of diazepam on a variety of executive tasks.Methods The effects of 5, 10 and 20 mg of diazepam on a battery of neuropsychological tests were investigated using a randomised, double blind, placebo-controlled design. Seventy-five adult men were recruited. The Rogers et al. (1999b) test of risk-taking was given along with tasks from the CANTAB battery.Results Diazepam impaired performance on the Tower of London test of planning, without influencing visual pattern recognition memory. Subjects who had taken diazepam made more risky choices on the risk-taking task. On two speeded reaction time tasks diazepam impaired discrimination sensitivity and increased the bias to respond.Conclusions In contrast to the well-known sedative effects of diazepam, we demonstrate disinhibitory effects on two speeded reaction time tasks. Our results show that diazepam can impair performance on reaction time tasks both by impairing sensitivity and by increasing the bias to respond. Furthermore diazepam impaired performance on tests of planning and risky decision making that depend predominantly on dorsolateral and orbitofrontal regions of the prefrontal cortex, respectively.