Proactive interference and temporal context encoding after diazepam intake

 Two experiments were designed to test whether the memory impairment induced by benzodiazepines (BZDs) is due to impaired memory for temporal context. In both experiments, subjects were administered either diazepam (15 mg oral) or placebo, and a standard BZD impairment on prose recall as well as a decreased subjective arousal was found. Key tasks to explore temporal context memory were an A-B A-C proactive interference paradigm and a list discrimination task. Initial learning of both groups on these tasks was broadly matched. In experiment 1, diazepam did not increase susceptibility to proactive interference using semantically related words. However, in experiment 2, using unrelated word pairs, diazepam markedly increased the number of prior list intrusions. Furthermore, after diazepam intake, subjects were clearly impaired in learning unrelated word pairs. Subjects after diazepam intake were not impaired in the list discrimination task. We conclude that (1) diazepam impairs the forming of new associations, whether this is the formation of links between two or more targets or between targets and context, (2) a temporal context encoding deficit cannot account for a broader diazepam-induced memory impairment. Received: 18 March 1997 / Final version: 24 July 1997     

Effects of post-trial administration of nicotine on human memory: evaluating the conditions for improving memory

In the studies reported here, we investigated the effects of nicotine on memory for unrelated word lists. Nicotine was delivered through cigarette smoking, and memory performance was assessed using both intentional and incidental recall tasks, and employing an additional, indirect measure of memory. We report the results of four experiments in which we manipulated 1) the intake of nicotine using nicotine-containing and nicotine-free cigarettes, 2) the associative aspects of the word-sets, by unrelated words and category words and by instructing subjects to use an associative mnemonic strategy, 3) the opportunity for rehearsal between the presentation and recall, and 4) the time of nicotine administration, post- or pre-trial. We found a positive effect of post-trial nicotine on memory in the incidental recall task, as indicated by enhanced repetition priming, but no effect of nicotine on either immediate recall or pronunciation times (experiments 1 and 2). In experiment 3 we examined the effects of post-trial nicotine using associative and unrelated word-lists, when volunteers were instructed to use an associative mnemonic strategy. We found no main effect of nicotine, but when volunteers were distracted from rehearsal, related words were recalled better than unrelated words. Experiment 4 was a positive control for the timing of nicotine administration within our experimental design, and this showed that pre-trial nicotine not only improved free recall but differentially enhanced the recall of category words over unrelated words. We conclude that nicotine does modulate memory, that associative aspects of verbal memory in particular are sensitive to modulation by nicotine, and that the effects are more reliably observed with pre-trial than with post-trial administration. The conditions under which post-trial effects can be observed remain unclear.     

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 cigarette smoking and 12-h abstention on working memory during a serial-probe recognition task

Nicotine has been shown to affect attentional and mnemonic processes. However, whether these effects are due to changes in perceptual and/or motor aspects of the tasks is not at all clear. This study tested the hypothesis that nicotine from cigarette smoking has differential effects on perceptual and motor processes, as reflected by event-related potentials (ERPs) and reaction times (RTs), respectively, and that perceptual effects may be specific to changes in working memory. ERPs, RTs and performance accuracy were recorded from smokers and nonsmokers during a serial-probe recognition memory task in which lists of words or “memory sets” were followed by a probe word that was either in-set or out-of-set. Smokers were tested in a “smoking” and a 12-h “deprived” condition. Smoking-smokers and deprived-smokers exhibited fast RTs to in-set and out-of-set probes relative to a group of nonsmokers. They exhibited even faster RTs when the in-set probe word matched the first or last item in the memory set. Thus, smokers as a group showed enhanced primacy and recency effects suggesting that smoking specifically facilitates processes related to the motor output aspects of working memory. Different effects characterized the electrophysiology. Larger P300s were recorded to in-set compared to out-of-set probes by both subject groups. Smoking smokers exhibited enhanced P300s to both types of probes. When smokers abstained for 12 h (deprived smokers), the differences in P300 amplitude were reduced but not eliminated. Smoking smokers exhibited faster P300 latencies to in-set probes, while deprived smokers showed delayed latencies relative to nonsmokers. Primacy and recency P300 effects characterized nonsmokers and deprived smokers. However, this relationship was reversed in the Smoking condition. These results support the hypotheses that nicotine has distinct effects on memory-related perceptual and motor aspects of working memory. The increase in efficiency of the memory search with nicotine is consistent with the functional role of the cholinergic system in maintaining a state “appropriate for efficient information processing.” Received: 12 April 1997/Final version: 4 March 1998     

Initial nicotine sensitivity in humans as a function of impulsivity

Rationale  Impulsivity is related to greater risk of nicotine dependence, perhaps by enhancing sensitivity to nicotine’s reinforcing and rewarding effects during initial smoking experiences. Objective  We examined the influence of impulsivity characteristics on acute sensitivity to nicotine reward, reinforcement, and other effects in 131 young adult nonsmokers. Materials and methods  Participants engaged in four sessions: the first three to assess dose–response effects of nasal spray nicotine (0, 5, 10 μg/kg) on reward, as well as mood, physiological, and performance effects, and the fourth to assess nicotine reinforcement using a choice procedure. Five impulsivity factors, derived from factor analysis of self-report (e.g., Barratt Impulsivity Scale, Sensation-Seeking Scale, Novelty seeking) and computer (stop–go, delay discounting, probability discounting) measures of impulsivity, were labeled “novelty seeking”, “response disinhibition”, “extraversion”, “inhibition”, and “probability/delay discounting”. Results  The associations of novelty seeking with nicotine reinforcement and reward tended to move in opposite directions by sex, generally being directly related in men but inversely or unrelated in women. Similarly, response disinhibition was associated with reward and some mood responses to nicotine that differed by sex. Extraversion was inversely associated with nicotine reinforcement. Characteristics loading on to the other impulsivity factors had little association with nicotine sensitivity. Conclusions  These results are preliminary, but they suggest that characteristics broadly related to impulsivity, especially novelty seeking and response disinhibition, are associated with initial sensitivity to some effects of acute nicotine, including reinforcement and reward, and may do so differentially between men and women.     

An investigation into the effects of nicotine gum on short-term memory

Using a between-subjects 2 × 2 × 2 factorial design, 60 smokers and 60 non-smokers (equal number of males and females) performed a short-term memory task requiring delayed free recall of a visually presented supraspan word list. Using a double-blind procedure, half the subjects chewed nicotine gum and the other half chewed placebo gum prior to performing the memory task. Results support previous research findings which show that nicotine significantly improves short-term memory. Sex differences were also investigated, but findings showed no significant differences between male and female subjects. Methodological considerations are discussed and directions for future research are suggested. Received: 12 November 1997/Final version: 13 May 1998     

Distinguishing between attentional and amnestic effects in information processing: the separate and combined effects of scopolamine and nicotine on verbal free recall

An important issue in our understanding of cholinergic modulation of information processing is the extent to which drug-induced changes affect memory processes per se or simply the attentional processes required for effective acquisition of information. In this study, we examined the separate and combined effects of scopolamine and nicotine on verbal free recall. A single dose of nicotine improved recall performance on supraspan lists (30 words), but not on short lists (10 words). The same dose of nicotine had no effect on the scopolamine-induced recall deficits observed for both 30 and 10 word lists. The results are discussed in terms of the independence of attention and memory processes and the specificity of action of these two cholinergic compounds.     

Effects of cotinine on information processing in nonsmokers

 Cotinine, the major proximate metabolite of nicotine, is present in smokers in higher concentrations and for a longer time than nicotine, yet its effects on information processing have not previously been reported. We studied the cognitive effects of cotinine in non-smokers. Sixteen subjects were tested on three doses of cotinine (0.5, 1.0, and 1.5 mg cotinine base/kg), and placebo, on a choice reaction time (RT) task and on a verbal recall task with short and long lists. Cotinine significantly impaired recall on the long list and displayed non-significant but generally consistent dose-related slowing of RT and N100 latency. The acute effects of cotinine were small, and probably do not account for the cognitive deficits observed in tobacco withdrawal, although the cognitive effects of chronic cotinine administration need to be investigated. Received: 2 January 1997/Final version: 22 June 1997     

Oxygen administration selectively enhances cognitive performance in healthy young adults: a placebo-controlled double-blind crossover study

It was recently demonstrated that oxygen administration can improve performance on a simple word recall task in healthy young adults. This study was aimed at determining the impact of various durations of oxygen administration on a wider range of cognitive measures. This was achieved using the Cognitive Drug Research computerised test battery, and employing a double-blind, placebo-controlled crossover design. Over a period of 7 weeks, 20 participants were trained and subsequently assessed on the test battery under several durations of oxygen inhalation; air administered in an identical fashion served as a control. The results provided support for our earlier work in that increases were found in both immediate and delayed word recall. In addition, oxygen administration significantly improved performance on several measures of attention and vigilance. Simple reaction time, choice reaction time, digit vigilance reaction time and picture recognition reaction time were improved in a manner which depended on the duration of oxygen inspired. With the exception of word recall, no significant improvements were found for any measure of accuracy, nor were word recognition, digit memory scanning, or spatial memory improved. These results are discussed in the context of stages of information processing and are consistent with the hypothesis that cognitive performance is “fuel-limited” and can be differentially augmented by increasing the availability of the brain’s metabolic resources. Received: 7 July 1997/Final version: 22 December 1997     

Effects of a benzodiazepine on free recall of semantically related words

Although it is widely known that benzodiazepines impair episodic memory, few studies have investigated their effects upon specific processes involved in free recall. This study evaluated the acute effects of flunitrazepam (1.0 mg; 1.3 mg) and placebo in healthy volunteers on immediate and delayed free recall of word lists considering serial positions as well as semantic relations between words inserted in the middle of the lists (e.g. milk-cheese-butter). Flunitrazepam promoted a global amnestic effect, impairing recall in all serial positions except the last words (recency effect). Primacy and recency effects were preserved as indexed, respectively, by larger recall of the first and last words in relation to adjacent items. Facilitation in recall of semantically related words was not impaired by the drug when compared to recall in adjacent positions, in spite of a dose-dependent diminution of the number of words recalled also in mid-list positions. Flunitrazepam-induced deficits were interpreted as impairment in the formation of new associations between items, or groups of items in the case of related words, and context.     

Nicotine discrimination and self-administration in humans as a function of smoking status

Nicotine’s discriminative stimulus effects may be critical to understanding reinforcement of tobacco smoking. It is not known whether regular nicotine exposure produces tolerance or sensitivity to these effects. In this study, male and female smokers (n = 11) and never-smokers (n = 10) were trained to discriminate 20 μg/kg nicotine by nasal spray from placebo (0) on day 1. On day 2, both groups were tested on generalization of this discrimination across intermittent presentations of 0, 3, 6, 12, and 20 μg/kg nicotine in random order. Quantitative and quantal behavioral discrimination tasks, used in previous research, were employed. On day 3, subjects were instructed to self-administer sprays from the 20 μg/kg nicotine versus 0 bottles in a concurrent-choice procedure. All but one subject (female smoker) learned reliably to discriminate 20 μg/kg nicotine from placebo (≥ 80% correct) on day 1. Nicotine-appropriate responding on day 2 was attenuated in smokers versus never-smokers at 20 μg/kg on the quantitative task and at 12 μg/kg on the quantal task, suggesting tolerance. There was no difference in responding at other doses. Smokers also showed attenuated responses on the subjective measure of “head rush”, which was associated with discrimination responding in both groups. Nicotine self-administration was significantly greater in smokers versus never-smokers, who self-administered nicotine below chance levels, and was inversely related to discrimination behavior in never-smokers but unrelated in smokers. Women smokers showed less change in nicotine-appropriate responding across generalization doses, reported less confidence in discriminating training doses during acquisition on day 1, and tended to self-administer less nicotine on day 3. These results indicate that smokers may become tolerant to the discriminative stimulus effects of nicotine, perhaps promoting increased use. Received: 1 October 1996/Final version: 28 January 1997     

A further study of FTC yield and nicotine absorption in smokers

The relationship between nicotine yield as determined by the FTC method and nicotine absorption was examined in 72 smokers in a more rigorous repetition of a previous study of 33 smokers. For this study, 113 smokers evenly distributed across four FTC “tar” yield ranges were recruited; only 72 demonstrated reasonable compliance with the study criteria with regard to sample collections and cigarette brand style consistency. Subjects recorded the number of cigarettes smoked daily and collected a 24-h urine sample and a saliva sample on 3 consecutive days. Nicotine absorption was determined by monitoring urinary excretion of nicotine and its metabolites. In addition, saliva samples were monitored for cotinine using radioimmunoassay (RIA). The correlation of the relationship for nicotine absorbed per cigarette was positive and significant (r = 0.31, P = 0.008) but weaker than in the previous study. Only smokers in the highest yield range showed any statistical difference from smokers in the lower ranges. Our results suggest that FTC nicotine yield is weakly related to nicotine absorption and that smoker-controlled factors exert a great influence on the amount of nicotine absorbed by smokers. Compensation is substantial but incomplete for the minority (by market share) of smokers at the low end of the yield scale. It is uncertain how well any alternative set of machine parameters would predict nicotine absorption for the majority of smokers, even if it were more predictive for the small number of smokers at the lower yield part of the range. Received: 5 March 1997/Final version: 19 December 1997     

Evidence of cellular nicotinic receptor desensitization in rats exhibiting nicotine-induced acute tolerance

Rationale Individuals vary in their susceptibility to nicotine addiction. However, there is little evidence that behavioral sensitivity to nicotine is dependent upon the functional state of nicotinic cholinergic receptors (nAChRs). Objective To determine the relationship between in vivo pharmacological desensitization (in other words, acute tolerance) and brain regional nAChR function. Methods Male Sprague–Dawley rats, trained to discriminate nicotine (0.4 mg/kg free base) from saline in a two-lever drug discrimination task, were tested for the development of acute tolerance. Rats were injected with 0.4 mg/kg nicotine, tested for nicotine discrimination for 2 min, then injected with the same dose of nicotine 90 min, 180 min, and 270 min after the first injection and tested for nicotine discrimination after each injection. These subjects were separated into two groups, desensitizers (DZ) and nondesensitizers (NDZ), based upon performance in the repetitive dosing drug discrimination paradigm. The sensitivity of nAChRs in specific brain regions of these two groups was assessed by the use of an ⁸⁶Rb⁺ efflux assay using synaptosomes prepared from the frontal cortex, hippocampus, striatum, and “thalamus,” which included the midbrain and hypothalamus as well as the thalamus. Results The nicotine-induced increase in ⁸⁶Rb⁺ efflux was significantly greater in NDZ as compared to DZ in the “thalamus.” There was no statistically significant difference in the effects of nicotine in the frontal cortex, hippocampus, and striatum of these two groups. A significant correlation was observed between thalamic ⁸⁶Rb⁺ efflux and the rate of behavioral desensitization of individual rats. Conclusion These findings are consistent with the concept that the production of acute tolerance by nicotine in vivo correlates directly with its ability to induce nAChR desensitization at the cellular level.     

Cognitive performance effects of subcutaneous nicotine in smokers and never-smokers

In a double-blind placebo-controlled cross-over study the effects of two doses of subcutaneous nicotine and saline were compared on a range of performance measures in 18 abstaining smokers and 18 never-smokers. Each subject received two injections (40 min apart) of saline, 0.3 mg nicotine, or 0.6 mg nicotine in a balanced order over three sessions. Performance was assessed before and after the injections on nine tests [news recall, Sternberg memory task, finger tapping, logical reasoning, rapid visual information processing (RVIP), long-term word recognition, digit recall, Stroop test, and critical flicker fusion threshold]. In the abstinent smokers, nicotine produced significantly faster correct responses on the logical reasoning test, more target hits, faster reaction times and improved sensitivity on the RVIP task, and more correct responses on word recognition. In never-smokers, nicotine produced faster reaction times on the RVIP and digit-recall tasks, although in the latter case this was at the expense of fewer correct responses. There were no significant differences between the two groups’ responses to nicotine but smokers performed worse than never-smokers prior to injections, even controlling for background characteristics. These results are consistent with other recent research suggesting a primary effect of nicotine in enhancing cognitive performance.     

Both nicotine and mecamylamine block dizocilpine-induced explosive jumping behavior in mice: psychiatric implications

Dizocilpine (MK-801) administration to an outbred strain of NIH Swiss mice elicits discrete episodes of explosive jumping behavior designated as “popping.” This behavior may serve as a useful preclinical paradigm for the screening of potentially novel antipsychotic medications. Both nicotine and mecamylamine, a nicotinic antagonist, dose-dependently blocked dizocilpine-induced popping. The data suggest that nicotine may be of therapeutic benefit in the treatment of schizophrenia and that some of its effects may be mediated by non-nicotinic receptors. Received: 17 December 1997/Final version: 10 March 1998     

Facilitation of memory by post-trial administration of nicotine: evidence for an attentional explanation

In human studies, reported performance improvements with post-trial administration of nicotine have all involved associative learning (Mangan and Golding 1983; Colrain et al. 1992; Warburton et al. 1992). In this study, post-trial nicotine, obtained through smoking a cigarette, improved free recall of lists of unrelated words under conditions which limited the opportunity for associative learning. However, the nicotine-induced advantage was not observed when volunteers were required to complete a secondary (attention) task during the post-trial period in which they smoked. The results suggest that post-trial effects depend on the opportunity for stimulus processing after input, and that nicotine improves performance by increasing the attentional resources available for such strategic processing.     

Moxonidine and cognitive function: interactions with moclobemide and lorazepam

Objective: Moxonidine represents a new generation of centrally acting antihypertensive drugs. It binds to I₁-imidazoline receptors and exerts its antihypertensive activity through a reduction in systemic vascular resistance, while cardiac output remains unchanged or even increases slightly. Moxonidine is prescribed for the treatment of mild to moderate hypertension. Typical doses are 0.4 to 2.0 mg given as one dose in the morning or as divided doses in the morning and evening. Methods: The effects of moxonidine 0.4 mg once daily in combination with moclobemide or lorazepam were investigated in two, double-blind, randomised, placebo-controlled, two-way crossover studies in a total of 48 healthy volunteers. Safety assessments were made in each study and included pre- and post-study measurement of blood pressure, heart rate, ECG, haematology, blood biochemistry, and urinalysis, and recording of adverse events. Results: In the first study, moxonidine alone was found to produce small but statistically significant impairments of vigilance detection speed at 4 h and 6 h. Lowering of subjective alertness was also observed. Repeat dosing with moxonidine produced an impairment of memory scanning performance. These findings were not reproduced in the second study, in which moxonidine alone produced an improvement in immediate word recall at 4 h and 6 h. No interactions were observed when moxonidine was co-administered with moclobemide. Moxonidine, when co-administered with lorazepam, produced interactions with three tasks requiring high levels of attention: choice, simple reaction time and digit vigilance performance; memory tasks; immediate word recall, delayed word recall accuracy; and visual tracking. A total of 47 adverse events were reported in study 1. Moxonidine produced a slight decrease of systolic and diastolic blood pressure. In study 2, a total of 55 adverse events were reported. In both trials, the most frequently reported events were tiredness and dryness of mouth, the latter occurring only under the moxonidine treatment. There were no clinically relevant changes observed in blood pressure, pulse rate, and laboratory tests in either study, nor was there any evidence of any interaction between moxonidine and either moclobemide or lorazepam. Conclusion: Moxonidine was found to be safe and well tolerated in healthy volunteers. However, the impairments on attentional tasks were greater when moxonidine was co-administered with lorazepam 1 mg. These effects should be considered when moxonidine is co-dosed with lorazepam, although they were smaller than would have been produced by a single dose of lorazepam 2 mg. Received: 3 June 1996 / Accepted in revised form: 18 February 1997     

Effects of cotinine on cigarette self-administration

Previous studies have shown that cotinine, a metabolite of nicotine, antagonizes some of the effects of nicotine. One study showed that cotinine eliminates the beneficial effects of the nicotine patch in reducing cigarette withdrawal symptoms. The purpose of this study was to examine the effects of various doses of cotinine on cigarette self-administration. Subjects were randomly assigned to one of three doses of cotinine fumarate (40, 80 and 160 mg) and placebo, each for a period of 10 days, in a randomized order. Outcome variables included measures of nicotine intake and subjective responses to smoked cigarettes. Results showed no differences in the number of cigarettes smoked, carbon monoxide levels, and weights of cigarette butts across the various doses of cotinine and placebo. However, higher nicotine serum levels were observed in the 160 mg cotinine fumarate condition compared to placebo and to 40 mg cotinine fumarate. No systematic effects of cotinine on subjective responses to cigarettes were observed. Cotinine appears potentially to have a selective modulatory effect on nicotine withdrawal symptoms but not on cigarette smoking. Received: 2 September 1997 / Final version: 30 December 1997     

A comparison of the attentional and consolidation hypotheses for the facilitation of memory by nicotine

Studies examining facilitation of human memory by the administration of nicotine have given equivocal results and it has been argued that the positive findings on memory may have resulted indirectly from an effect on attention, rather than from a direct effect on memory storage. This study compared the attentional and the mnemonic hypotheses directly, by using both immediate and delayed recall tasks in a verbal free recall study, in which volunteers smoked on a fixed regime during presentation of a 32 word list (namely, one puff after each of eight 4-word blocks). The serial position curve for immediate recall demonstrated a significant improvement on the later blocks of the list (an attentional effect) when volunteers smoked a nicotine-containing cigarette. However, improved performance was found for items at the beginning of the list on the delayed recall measure and this improvement was significant on the first block of 4 words. Since nicotine input had been takenafter presentation of this information, the results demonstrate post-learning facilitation of memory by nicotine.     

Subjective and cardiovascular effects of intravenous nicotine in smokers and non-smokers

The present study assessed the subjective and cardiovascular effects of intravenous nicotine in smokers and nonsmokers. Nonsmokers (n = 5) and smokers (n = 5) were administered a single dose of nicotine (0.75 or 1.5 mg) or saline on each of 3 days. The nicotine doses were given in ascending order in a double-blind fashion. Although smokers and nonsmokers manifested significant increases in systolic and diastolic blood pressure and heart rate 1 min after administration of all active test doses, the difference between peak heart rate and that measured at later times was greater in nonsmokers than in smokers. Nonsmokers and smokers also differed in subjective self-reports. In response to items on visual analogue scales indicative of positive effects (e.g., “good effects,”“like drug,”“use again,” and “feel energetic”), smokers but not nonsmokers reported high scores (> 40) after nicotine injection. In addition, responses on the MBG and LSD subscales of the Addiction Research Center Inventory indicated that smokers experienced positive subjective effects after the test doses, whereas nonsmokers experienced disorientation. The fact that intravenous nicotine was not associated with positive subjective effects in nonsmokers indicates that repeated exposure is required to establish positive reinforcing effects of nicotine. Received: 11 August 1995 /Final version: 30 May 1996