Hv Curran

Differentiating the effects of centrally acting drugs on arousal and memory: an event-related potential study of scopolamine, lorazepam and diphenhydramine

Abstract The degree to which apparent amnesic effects of various centrally acting drugs are secondary to their effects on arousal remains a contentious issue. The present study uses two methods to dissociate memory and arousal effects of the cholinergic antagonist, scopolamine (SP), and the GABA-A/benzodiazepine receptor agonist, lorazepam (LZ). First, it compared their effects to those of an antihistamine, diphenhydramine (DPh), to provide an active control for arousal reduction. Second, it used the same measure – event-related potentials (ERPs) – as as a parallel index of both the arousal and cognitive effects of the drugs. Fifty participants were allocated to one of five parallel treatment groups (0.6 mg SP; 2 mg LZ; 25, 50 mg DPh; placebo). ERPs were recorded during a continuous word recognition task as well as during an “oddball” task. SP, LZ and 50 mg DPh produced a similar profile of effects on certain indices of arousal and on early components of ERPs. However, SP and LZ (but not DPh) produced marked impairments of episodic memory, and this pattern was similar to that on later components of ERPs. Memory impairments by SP and LZ were highly significant on retention in the continuous recognition task and further, no drug effects were found on response bias. Subsequent free recall was similarly very impaired by SP and LOR but not by the antihistamine. We conclude that benzodiazepines and anticholinergic drugs both reduce arousal and induce amnesia, but these effects are not interdependent. Our findings provide strong evidence for a dissociation between the effects on episodic memory and on arousal of these centrally acting compounds.

Dissociative effects of alcohol on recollective experience

This article reports a study comparing the effects of a single dose of alcohol with a matched placebo drink on recognition memory with and without conscious recollection. A double-blind, cross-over design was used with healthy volunteers who were all social drinkers. Processing depth at study was manipulated using generate versus read instructions. Conscious recollection at test was assessed using the remember-know-guess paradigm (Gardiner, 1988; Tulving, 1985). Alcohol significantly reduced conscious recollection (remember responses) but had no effect on recognition in the absence of conscious recollection (know responses). False alarms rates were low and unaffected by alcohol. Previous findings that generation effects are found only for remember responses were closely replicated. A further dissociation of the generation effect occurred between treatments in that deeper processing at study facilitated recognition on placebo but not on alcohol. That both alcohol and depth of processing produce dissociative effects on recollective experience provides further evidence that remembering and knowing reflect distinct memory systems.

Acute cannabis use causes increased psychotomimetic experiences in individuals prone to psychosis.

BACKGROUND Epidemiological evidence suggests a link between cannabis use and psychosis. A variety of factors have been proposed to mediate an individuals vulnerability to the harmful effects of the drug, one of which is their psychosis proneness. We hypothesized that highly psychosis-prone individuals would report more marked psychotic experiences under the acute influence of cannabis. METHOD A group of cannabis users (n=140) completed the Psychotomimetic States Inventory (PSI) once while acutely intoxicated and again when free of cannabis. A control group (n=144) completed the PSI on two parallel test days. All participants also completed a drug history and the Schizotypal Personality Questionnaire (SPQ). Highly psychosis-prone individuals from both groups were then compared with individuals scoring low on psychosis proneness by taking those in each group scoring above and below the upper and lower quartiles using norms for the SPQ. RESULTS Smoking cannabis in a naturalistic setting reliably induced marked increases in psychotomimetic symptoms. Consistent with predictions, highly psychosis-prone individuals experienced enhanced psychotomimetic states following acute cannabis use. CONCLUSIONS These findings suggest that an individuals response to acute cannabis and their psychosis-proneness scores are related and both may be markers of vulnerability to the harmful effects of this drug.

Attentional bias to incentive stimuli in frequent ketamine users

BACKGROUND The attention-grabbing properties of drugs to drug-using individuals have been well documented and recent research has begun to suggest that such attentional bias may be related to the severity of drug dependency. Dependence on ketamine has been reported anecdotally but no systematic study has investigated this phenomenon. We aimed to explore attentional biases to incentive stimuli in different populations of ketamine users. METHOD Using a dot-probe paradigm, attentional bias to both drug-related and money-related stimuli was investigated in 150 participants: 30 frequent ketamine users, 30 infrequent ketamine users, 30 ex-ketamine users, 30 poly-drug users and 30 non-drug-using controls. Two stimulus presentation times were used (200 and 2000 ms) to investigate whether attentional bias was as a result of an automatic or a more conscious attentional shift. Participants also rated the degree to which stimuli used in the dot-probe paradigm were pleasurable. RESULTS Frequent ketamine users demonstrated an attentional bias to both types of incentive stimuli only at the short stimulus presentation interval and this was significantly correlated with degree of ketamine use. No attentional biases were observed in any of the other groups. All groups rated money stimuli as more pleasurable than neutral stimuli. CONCLUSIONS These data support incentive models of drug use and demonstrate the ability of the attentional bias paradigm to discriminate recreational drug users from those with more dependent patterns of use. Ketamine is a potentially dependence-forming drug.

Scopolamine induces impairments in the recognition of human facial expressions of anger and disgust

RationaleRecent psychopharmacological studies lend support to the notion of partially dissociable neuronal systems dedicated to processing specific emotions. For example, GABA-ergic enhancement after an acute dose of the benzodiazepine, diazepam, produces specific impairments in anger and fear recognition. However, it is unclear if these impairments are a general property of benzodiazepines and other drugs that produce a similar profile of neurocognitive impairment to benzodiazepines, such as the anticholinergic, scopolamine.ObjectiveWe investigated the effects of scopolamine and the benzodiazepine, lorazepam, on emotion-recognition accuracy.MethodsA double-blind independent group design was used with 48 healthy volunteers to compare the effects of scopolamine and lorazepam with an inactive placebo on a commonly used emotion-recognition task. Control measures included an episodic memory task and subjective mood ratings.ResultsAnger and disgust recognition accuracy was impaired after scopolamine. In contrast, lorazepam produced no impairment in emotion-recognition despite producing similar levels of sedation and anterograde amnesia to scopolamine.ConclusionsScopolamine-induced cholinergic hypofunction selectively impaired the recognition accuracy of disgust and anger facial expressions. The effects of scopolamine on emotion-recognition are similar to those found in Huntington’s disease patients. Furthermore, the impairments in anger and fear recognition previously observed with diazepam do not appear to be a general property of benzodiazepines. This suggests that alterations in emotional processing involving changes in the ability to recognize threat-related emotions (particularly, fear and anger) may not be a principal mechanism underlying anxiolysis or paradoxical aggression seen with benzodiazepines.

Long-term effects of alprazolam on memory: a 3·5 year follow-up of agoraphobia/panic patients

BACKGROUND Benzodiazepines (BZs) can impair explicit memory after a single dose and also when taken repeatedly for treatment of anxiety disorders. A previous study with agoraphobia/panic patients found that the BZ alprazolam impaired memory during an 8-week treatment and residual impairments were still manifest several weeks after drug withdrawal (Curran et al. 1994). The present study followed up the same group of patients 3.5 years after treatment to determine whether those memory impairments persisted. METHOD Thirty-one patients, 15 who had originally been treated with alprazolam and 16 with placebo, were assessed on a battery of psychometric tests and self-rating scales. RESULTS Ex-alprazolam patients performed at the same levels as ex-placebo patients on the memory task and on other objective tests. Performance levels of both groups were similar to pre-treatment baselines, however there were differences in subjective ratings whereby ex-alprazolam patients rated themselves as less attentive and clear headed and more incompetent and clumsy than ex-placebo patients. CONCLUSIONS Explicit memory impairments found while patients were taking alprazolam and weeks after drug withdrawal did not persist 3.5 years later. We suggest that the memory impairments observed in our previous study weeks after withdrawal of alprazolam were not residual effects of alprazolam but rather were due to the drugs interference with practice effects on the tests and habituation of anxiety over repeated exposure to the test situation.

The effects of single doses of lorazepam on event-related potentials and cognitive function

Twelve healthy participants received double‐blind single doses of lorazepam 1 mg, 2 mg and placebo at weekly intervals using a Latin square design. Prior to administration and 2 h afterwards, a battery of tests was used to assess psychomotor and cognitive function and to elicit event‐related potentials (ERPs), concentrating on the P300 wave. This wave, elicited reliably using two paradigms (Rugg– Nagy and ‘oddball’), was prolonged in latency and reduced in amplitude in a dose‐related manner by lorazepam. Cognitive and psychomotor performance was impaired by the benzodiazepine. Subjective sedation was induced by the drug. However, no relationships were found between drug effects and the ERPs and on psychological functioning. It was concluded that the lack of correlation could reflect relatively low participant numbers or carry‐over effects of the medication.

Ecstasy (MDMA) Does Not Have Long-Term Effects on Aggressive Interpretative Bias: A Study Comparing Current and Ex-Ecstasy Users With Polydrug and Drug-Naive Controls

+/-3, 4-methylenedioxymethamphetamine (MDMA or ecstasy) remains a widely used recreational drug, which, in animals, can produce long-lasting changes to the brains serotonergic system. As serotonin has been implicated in human aggression, it is possible that ecstasy users are at risk of increased aggression even after prolonged abstention from the drug. The objective of this study was to indirectly assess aggression in current and abstinent ecstasy users using an information-processing paradigm that measures cognitive bias toward material with aggressive content. The task employed has previously shown increased aggressive bias 3-4 days after ecstasy use. An interpretative bias task was administered to 105 male participants: 26 ex-ecstasy users, 25 current ecstasy users, 29 polydrug using controls, and 25 drug-naive controls. Accuracy and response times to process and recognize ambiguous sentences were tested. There were no group differences in aggressive interpretative bias. All 4 groups processed neutral sentences faster than aggressive sentences and were subsequently faster and more confident in recognizing neutral compared with aggressive sentences. Further, self-ratings of aggression also showed no group differences, even though self-rated impulsivity was significantly higher in current ecstasy users than in drug-naive controls. The findings that all groups were biased toward neutral and away from aggressive interpretations of ambiguous sentences add to the existing body of knowledge in suggesting that increased aggression found in ecstasy users a few days after taking the drug is a transient phenomenon and not a long-term, persisting effect.

An investigation of the effects of benzodiazepine receptor ligands and of scopolamine on conceptual priming

Abstract Scopolamine and lorazepam both produce anterograde impairments of explicit memory but only lorazepam impairs implicit memory as assessed by perceptual priming tasks. The main aim of the two experiments reported in this article was to determine the effects of these drugs on conceptual priming. Experiment 1 compared the effects of lorazepam (1,2 mg PO) with scopolamine (0.3,0.6 mg SC) and placebo in a study with 60 healthy volunteers. Experiment 2 compared the separate and combined effects of lorazepam (2 mg PO) and flumazenil (2 mg IV) with placebo in a study with 48 healthy volunteers. We found that conceptual priming in category generation tasks was intact following lorazepam in both studies. This preservation of conceptual priming contrasted with lorazepam-induced impairments on explicit memory tasks. In conjunction with previous findings, these results are interpreted as providing further support for the notion that conceptual and perceptual priming are subserved by distinct memory systems, one based on the operations of semantic memory, the other possibly based on a perceptual representation system. That lorazepam impairs perceptual but not conceptual priming suggests that the neurochemical substrates of the two kinds of priming are distinct.

Benzodiazepine effects on memory tests : dependence on retrieval cues?

Acute effects of oral flunitrazepam (0.5 and 1 mg), nitrazepam (5 and 10 mg) and placebo were assessed on direct (free recall of words and prose, stem-cued recall) and indirect (stem and fragment completion) memory tasks. Fifty healthy volunteers took part in this double-blind, independent group study. The relative effects of the two benzodiazepines (BZs) on memory revealed a different pattern from their effects on alertness, indicating that their amnesic effects are not totally secondary to their sedative effects. The higher dose of flunitrazepam impaired free recall of words and prose but not cued recall, while neither drug affected the two indirect tasks. Differences in drug effects on the direct and indirect memory tasks were discussed in terms of resource demands of the various tests. We conclude that whether BZs impair performance on memory tasks depends more on the cues given at retrieval than the retrieval instructions (direct/indirect). The implications for this in terms of BZ amnestic effects are drawn out for contextual encoding deficits induced by BZs.