Effects Of Lorazepam Research Articles

GABAergic control of novelty stress-responsive epigenetic and gene expression mechanisms in the rat dentate gyrus

The activity of dentate gyrus granule neurons is under a strong GABAergic tonic inhibitory control which contributes to the sparse activation pattern of these neurons after environmental stimuli. Previously, we reported that in sparse dentate gyrus neurons such stimuli evoke Ser-10 (S10) phosphorylation and Lys-14 (K14) acetylation in the nucleosomal protein histone H3 (H3S10p-K14ac) resulting in the induction of c-Fos. We hypothesized that GABA is an important modulator of novelty stress-evoked epigenomic mechanisms in rat dentate neurons. As reported previously, exposure to novelty (30 min in new cage) evoked a significant increase in H3S10p-K14ac-and c-Fos-positive neuron numbers in the dentate gyrus. Pre-treatment of rats with the benzo Lorazepam, an indirect GABA-A receptor agonist, had no effects on baseline levels of H3S10p-K14ac and c-Fos but dose-dependently inhibited the novelty-induced epigenomic effects. At the applied doses (0.1–0.3 mg/kg), Lorazepam's effects on behavior were mainly anxiolytic-like. To examine the effects of attenuated GABAergic inhibition on dentate granule neurons we applied the partial inverse GABA-A agonist FG-7142. This drug profoundly enhanced baseline levels as well as novelty-induced increases in the number of H3S10p-K14ac- and c-Fos-positive dentate neurons. Furthermore, FG-7142 evoked behavior in the novel cage congruous with increased anxiety and hyper-vigilance. Interestingly, the FG-7142-evoked enhancements in epigenomic changes were completely blocked by the NMDA receptor antagonist MK-801. We conclude that GABA tonically controls epigenomic responses to psychologically salient events in dentate gyrus granule neurons. Furthermore, GABA appears to exert its controller activity through modulation of NMDA receptor function. These findings may be of significance for the elucidation of anxiety disorders especially PTSD.

One milligram of lorazepam does not decrease anxiety induced by CCK-4 in healthy volunteers: Investigation of neural correlates with BOLD MRI

Benzodiazepine effects on cholecystokinin tetrapeptide (CCK-4)-induced panic attack (PA) in humans are incompletely characterized, in particular on the neurofunctional level. This work explores the effects of lorazepam on brain activity and behavioral and physiological symptoms related to CCK-4-induced PA in healthy volunteers. Twenty-one male volunteers received 1 mg of lorazepam or placebo orally, 2 hours before an injection of 0.9% saline solution followed by 50 µg of CCK-4 during functional magnetic resonance imaging (fMRI) and heart rate recording. Panic attacks were defined using the panic symptom scale (PSS). In addition, the Y1-STAI (state anxiety) and the Bond & Lader Visual Analogue Scale (VAS) were used. Eleven subjects were classified as panickers. CCK-4 induced behavioral anxiety and cardiovascular effects along with cerebral activation in anxiety-related brain regions. Overall, lorazepam did not significantly modify the anxiogenic and cardiovascular effects of CCK-4. Regarding CCK-4-induced brain activation, lorazepam did not reduce activity in the insulae and cingulate gyrus of panickers. One milligram of lorazepam was not sufficient to reverse strong panicogenic effects, but decreased brain activity in the case of mild anxiety.

Rupatadine does not potentiate the CNS depressant effects of lorazepam: randomized, double-blind, crossover, repeated dose, placebo-controlled study

The main objective was to assess whether benzodiazepine intake when rupatadine plasma concentrations were at steady-state would increase the CNS depressant effects. Rupatadine is a new H(1)-antihistamine which also inhibits platelet activating factor (PAF) release and has been shown to be clinically effective at doses of 10 mg. Sixteen healthy young volunteers took part in a crossover, randomized, double-blind, placebo controlled trial comprising two experimental periods (repeated administration for 7 days of rupatadine 10 mg or placebo as single oral daily doses, separated by a washout of 14 days). On days 5 and 7, according to a fully balanced design, a single oral dose of lorazepam 2 mg or placebo was added. CNS effects were evaluated on these days by seven objective tests of psychomotor performance and eight subjective visual analogue scales (VAS) at pre-dose and several times after drug intake. Four treatment conditions were evaluated: placebo, rupatadine 10 mg, lorazepam 2 mg and rupatadine 10 mg + lorazepam 2 mg. Significant CNS effects, either impairment of psychomotor performance or subjective sedation, were observed when lorazepam was administered, either alone or in combination with steady state concentrations of rupatadine. No significant differences were found between these two conditions. In addition, rupatadine was not different from placebo. All treatments were well tolerated. Repeated doses of rupatadine (10 mg orally) did not enhance the CNS depressant effects of lorazepam (2 mg orally, single dose) either in objective psychomotor tasks or in subjective evaluations.

The effects of lorazepam on extrastriatal dopamine D 2/3-receptors—A double-blind randomized placebo-controlled PET study

Lorazepam is a widely used anxiolytic drug of the benzodiazepine class. The clinical actions of benzodiazepines are thought to be mediated via specific allosteric benzodiazepine binding sites and enhancement of GABAergic neurotransmission in the brain. However, the indirect effects of benzodiazepines on other neurotransmitter systems have not been extensively studied. Previous experimental evidence suggests that benzodiazepines inhibit striatal dopamine release by enhancing the GABAergic inhibitory effect on dopamine neurons whereas very little is known about cortical or thalamic γ-amino-butyric (GABA)–dopamine interactions during benzodiazepine administration. We explored the effects of lorazepam (a single 2.5 mg dose) on cortical and thalamic D 2/3 receptor binding using Positron-Emission Tomography (PET) and the high-affinity D 2/3-receptor ligand [ 11C]FLB 457 in 12 healthy male volunteers. We used a randomized, double-blind and placebo-controlled study design. Dopamine D 2/D 3 receptor binding potential was measured with the reference tissue method in several extrastriatal D 2-receptor areas including frontal, parietal, temporal cortices and thalamus. The main subjective effect of lorazepam was sedation. Lorazepam induced a statistically significant decrease of D 2/D 3 receptor BP ND in medial temporal and dorsolateral prefrontal cortex (DLPFC) that was also confirmed by a voxel-level analysis. The sedative effect of lorazepam was associated with a decrease in D 2/D 3 receptor BP ND in the DLPFC. In conclusion, lorazepam decreased [ 11C]FLB 457 binding in frontal and temporal cortex, suggesting that cortical GABA–dopamine interaction may be involved in the central actions of lorazepam in healthy volunteers. The correlation between lorazepam-induced sedation and D 2/D 3 receptor binding potential (BP) change further supports this hypothesis.

Effects of Lorazepam and Citalopram on Human Defensive Reactions: Ethopharmacological Differentiation of Fear and Anxiety

Drugs that are clinically effective against generalized anxiety disorder preferentially alter rodent risk assessment behavior, whereas drugs that are clinically effective against panic disorder preferentially alter rodent flight behavior. The theoretical principle of "defensive direction" explains the pattern of associations between emotion and defensive behavior in terms of the differing functional demands arising from cautious approach to threat (anxiety) versus departure from threat (fear), offering the prospect that clinically important emotions may be explained using a single rubric of defense. We used a within-subjects, placebo-controlled, design to test this theory, measuring the effects of citalopram and lorazepam on the defensive behavior of 30 healthy adult male humans. We indexed human defensive behavior with a translation of an active avoidance task used to measure rodent defense and found that lorazepam significantly reduced the intensity of defensive behavior during approach to threat (hypothetically anxiety-related) but not departure from threat (hypothetically fear-related). Contrary to prediction, citalopram did not affect either form of defensive reaction. Since lorazepam is a drug with well established anxiety reducing properties, these data support the hypothesis that anxiety is an emotion elicited by threat stimuli that require approach. These data also contribute to the validation of a novel human analog of an established experimental model of rodent fear and anxiety.

Table of Contents

AbstractStudy Examines Impact of Treatment on Prodromal Symptom Progression in YouthTargeted Naltrexone Reduces Alcohol Use Among Male Problem DrinkersRhabdomyolysis After Clozapine and Lithium TreatmentMetabolic Assessment of Adjunctive Aripiprazole in MDDCognitive Effects of Lorazepam in APOE ε4 CarriersProdromal Treatment StudiesElevated Rate of Adverse Events With QuetiapineA Case of Myopathy Associated With Valproic AcidNew Approvals: Saphris (Asenapine) for Schizophrenia, Bipolar DisorderNew Approval: Intuniv (Guanfacine) for ADHD

Differential effects of lorazepam on sleep and activity in C57BL/6J and BALB/cJ strain mice

Compared to C57BL/6 mice, BALB/c mice exhibit greater 'anxiousness' on behavioural tests of anxiety, and can show significantly longer sleep disruptions after exposure to anxiogenic situations. Relative to C57BL/6 mice, BALB/c mice also have reduced benzodiazepine (BZ) receptor densities in the brain and fivefold less BZ receptor density in the amygdala, a region important in anxiety and in the control of arousal. Lorazepam is a BZ receptor full agonist and has been used to treat both anxiety and insomnia. Differences between C57BL/6 and BALB/c mice raise the question of whether BZ agonists would impact sleep and activity differentially in the two strains. We examined the effects of two doses of lorazepam (0.5 and 1.5 mg kg(-1)) or saline alone (0.2 mL) on sleep and activity in C57BL/6 (n = 8) and BALB/c (n = 7) mice. Compared to saline, both doses of lorazepam significantly increased non-rapid eye movement (NREM) and reduced activity in both strains. In C57BL/6 mice, rapid eye movement (REM) was increased at both doses. In BALB/c mice, the 0.5 mg kg(-1) dose had no significant influence on REM, whereas REM was reduced significantly after the 1.5 mg kg(-1) dose. The results demonstrate significant differences between C57BL/6 and BALB/c mice in the effects of lorazepam on REM, whereas the effects on NREM and activity were similar. Strain differences in the number of BZ receptors in the amygdala, but not other brain regions, suggests possible site specificity in the effects of lorazepam on REM. These differences in BZ-binding sites in the amygdala could be a significant factor in differences in the sleep response between C57 and BALB/c mice.

Neonatal allopregnanolone increases novelty-directed locomotion and disrupts behavioural responses to GABAA receptor modulators in adulthood

Recent findings indicate that neurosteroids could act as important modulators during brain development. The aim of the present work is to screen whether developmentally altered AlloP levels may have long-lasting effects on behaviour and influence the emotional response to several GABAA receptor modulating drugs in adulthood. Acute allopregnanolone administration (10mg/kg) in the fifth postnatal day: (1) provoked long-term effects, as an increase of the novelty-directed locomotor activity and a decrease of its habituation in the open field in adult rats; (2) altered GABAA receptor response in adulthood, as reflected by the disruption of the effects of midazolam (1mg/kg) and flumazenil (10mg/kg) on the locomotor habituation in adulthood. Whereas the behavioural responses to 0.75mg/kg of lorazepam or 3mg/kg of 4,5,6,7-tetrahydroisoxazolo[5,4-c]pyridin-3-ol (THIP) were not affected, although lorazepam decreased locomotor activity in both neonatal AlloP and control rats, probably related to the sedative properties of the dose tested. Also, in the elevated plus-maze, the anxiolytic effects of lorazepam were observed in controls, but not in neonatal allopregnanolone-treated rats. This suggests that neonatal allopregnanolone decreases sensitivity to the anxiolytic effects of lorazepam at a dose of 0.75mg/kg. Results suggest that alterations in neonatal allopregnanolone could result in an altered GABAA receptor response in adulthood that is evident behaviourally. These results point out the importance of the maturation of the endogenous neurosteroid mechanisms in the brain related to locomotor response to novelty and the responses to GABAA modulators in adulthood. This work opens future directions focused on the effects of acute and long-lasting neonatal alterations of AlloP levels on vulnerability to psychopathology in adulthood.

Effects of lorazepam on brain activity pattern during an anxiety symptom provocation challenge

Human models of anxiety are useful to develop new effective anxiolytics. The objective of this study was to use functional magnetic resonance imaging (fMRI) to test the hypothesis that a single dose of lorazepam modifies brain activation during an anxiety challenge. Eighteen healthy male subjects underwent fMRI associated with a challenge based on the anticipation of aversive electrical stimulations after pretreatment, either with placebo or with 1.0 mg of oral lorazepam. Anxiety was rated before fMRI and after, referring to the threat condition periods, using State Trait Anxiety Inventory (STAI) and Hamilton scales. The conditioning procedure induced anxiety, as indicated by clinical rating score changes. Lorazepam did not modify anxiety rating as compared to placebo. Lorazepam reduced cerebral activity in superior frontal gyrus, anterior insula/inferior frontal gyrus and cingulate gyrus. The current finding provides the first evidence of the modulatory effects of an established anxiolytic agent on brain activation related to anticipatory anxiety.

Effects of lorazepam on visual perceptual abilities

To evaluate the effects of an acute dose of the benzodiazepine (BZ) lorazepam in young healthy volunteers on five distinguishable visual perception abilities determined by previous factor-analytic studies. This was a double-blind, cross-over design study of acute oral doses of lorazepam (2 mg) and placebo in young healthy volunteers. We focused on a set of paper-and-pencil tests of visual perceptual abilities that load on five correlated but distinguishable factors (Spatial Visualization, Spatial Relations, Perceptual Speed, Closure Speed, and Closure Flexibility). Some other tests (DSST, immediate and delayed recall of prose; measures of subjective mood alterations) were used to control for the classic BZ-induced effects. Lorazepam impaired performance in the DSST and delayed recall of prose, increased subjective sedation and impaired tasks of all abilities except Spatial Visualization and Closure Speed. Only impairment in Perceptual Speed (Identical Pictures task) and delayed recall of prose were not explained by sedation. Acute administration of lorazepam, in a dose that impaired episodic memory, selectively affected different visual perceptual abilities before and after controlling for sedation. Central executive demands and sedation did not account for results, so impairment in the Identical Pictures task may be attributed to lorazepam's visual processing alterations.

Systemic vs. Central Administration of Common Hypnotics Reveals Opposing Effects on Genioglossus Muscle Activity in Rats

To determine if systemic administration of selected sedative-hypnotics that modulate the function of the y-amino-butyric acid-A (GABAA) receptor can: (i) delay arousal thereby allowing genioglossus (GG) activity to increase more in response to respiratory stimulation during sleep, (ii) also cause the robust increase in GG activity during undisturbed sleep recently observed with barbiturates. We also determined effects on GG activity with local application to the hypoglossal motor nucleus (HMN). Sleep-wake states, GG and diaphragm activities were recorded in freely-behaving rats after systemic administration of lorazepam (0.5 mg/kg and 1 mg/kg, n = 9 and 5 mg/kg, n = 7), zolpidem (5 mg/kg and 10 mg/kg, n = 6) and the antihistamine diphenhydramine (20 mg/kg, n = 9). Rats were also exposed to ramp increases in inspired CO2 in NREM sleep. The effects of lorazepam and zolpidem applied directly to the HMN were also determined in 37 anesthetized rats. Lorazepam, zolpidem and diphenhydramine all increased arousal threshold, consistent with their sedative action. GG activity before arousal in response to hypercapnia was increased with lorazepam and zolpidem only, an effect mainly due to increased baseline activity before CO2 stimulation. Lorazepam and zolpidem applied directly to the HMN, however, decreased GG activity. Lorazepam and zolpidem have an inhibitory effect on GG activity via local effects at the HMN. Following systemic administration, however, this inhibitory effect can be outweighed both by a delay in arousal (allowing greater CO2-mediated respiratory stimulation in sleep) and excitatory influences on baseline GG activity via mechanisms operating outside the HMN.

Acute and rebound effects of lorazepam on orolingual motor function in young versus aged Fischer 344/Brown Norway rats

The purpose of this study was to measure the acute effects of lorazepam [a short-acting benzodiazepine (BZ) with no active metabolites] on orolingual motor function in young (6 months) versus aged (24 months) Fischer 344/Brown Norway hybrid (F344/BN) rats. Rats licked water from an isometric force-sensing operandum so that the number of licks per session, licking rhythm (licks/second), and lick force could be measured during daily sessions. Acute doses (1.0 and 2.0 mg/kg) of lorazepam were administered 30 min before the testing sessions, 4 days apart. Whereas aged rats produced more licks per session, lorazepam increased this measure primarily in the young group. On the days after each lorazepam dose, rats licked less than they did before receiving the drug. This effect was shown by both groups. Aged rats showed significantly slower licking rhythm than young rats. Lorazepam slowed this measure in both groups. Peak tongue forces were significantly increased by lorazepam. These findings suggest that BZs such as lorazepam can affect tongue force output and exacerbate age-related tongue motility deficits. They also suggest that although BZs can directly influence motivation to engage in water-reinforced tasks, opposite 'rebound' effects may occur, even after acute dosing.

Pilot Study of Lorazepam and Tiagabine Effects on Sleep, Motor Learning, and Impulsivity in Cocaine Abstinence

Objectives: To test the effects of mechanistically different GABA modulating agents on the disrupted sleep and cognitive function associated with abstinence from cocaine. Methods: We examined the effects of lorazepam and tiagabine on polysomnographically measured sleep and cognition in six cocaine dependent persons. Participants were studied during the first and second week of controlled abstinence following intravenous, laboratory cocaine administration. Results: Lorazepam and tiagabine decreased sleep latency, but whereas lorazepam markedly increased light sleep, tiagabine caused a dramatic shift toward slow-wave sleep. Despite increasing total sleep time, lorazepam impaired sleep dependent learning and increased next day impulsivity. Conclusions: These results introduce the possibility of different, sleep-related cognitive effects of mechanistically distinct GABAergic sedative hypnotics.

Pharmacological manipulations of arousal and memory for emotional material: effects of a single dose of methylphenidate or lorazepam

Benzodiazepines produce robust impairments of memory alongside global decreases in physiological and subjective arousal. Recently one benzodiazepine (triazolam) has been found to disproportionately impair memory for emotionally arousing material (Buchanan et al., 2003). The extent to which this effect may be mediated by the drug's sedative action is unclear. The present study aimed to assess how pharmacologically decreasing physiological arousal with a benzodiazepine and increasing arousal with a stimulant impact on memory for emotional material. A double-blind placebo controlled trial with 48 volunteers was used to investigate the effects of methylphenidate (40 mg) and Lorazepam (1.5 mg) on incidental memory for emotional material in Cahill and McGaugh's (1995) slide-story task. The slide-story was presented to participants administered either active drug or placebo and retrieval was assessed one week later. Methylphenidate produced stimulant effects and Lorazepam produced sedative effects. Significantly enhanced memory for emotional material was observed in participants given placebo, but not in those given either methylphenidate or Lorazepam. Despite producing opposite effects upon arousal, both methylphenidate and Lorazepam lessen the impact of emotionally arousing material on memory. The effects of Lorazepam add to a growing literature that benzodiazepines may exert their clinical, anxiolytic effects in part via altering emotionaL cognitive function.

Lorazepam induces multiple disturbances in selective attention: attentional overload, decrement in target processing efficiency, and shifts in perceptual discrimination and response bias

There is a general consensus that benzodiazepines affect attentional processes, yet only few studies have tried to investigate these impairments in detail. The purpose of the present study was to investigate the effects of a single dose of Lorazepam on performance in a target cancellation task with important time constraints. We measured correct target detections and correct distractor rejections, misses and false positives. The results show that Lorazepam produces multiple kinds of shifts in performance, which suggests that it impairs multipLe processes: (a) the evolution of performance over time was not the same between the placebo and the Lorazepam groups, with the Lorazepam affecting performance quite early after the beginning of the test. This is suggestive of a depletion of attentional resources during sequential attentional processing; (b) Lorazepam affected differently target and distractor processing, with target detection being the most impaired; (c) misses were more frequent under Lorazepam than under placebo, but no such difference was observed as far as false positives were concerned. Signal detection analyses showed that Lorazepam (d) decreased perceptual discrimination, and (e) reliably increased response bias. Our results bring new insights on the multiple effects of Lorazepam on selective attention which, when combined, may have deleterious effects on human performance.

Effects of lorazepam on deductive reasoning

Benzodiazepines slow reasoning performance, but it is still unknown which phase of reasoning is affected and whether this effect is present for different types of relations between entities in reasoning problems. We investigated which phases of deductive reasoning are affected by lorazepam and whether this effect varies according to the type of relations in deductive reasoning problems. This was a double-blind, crossover design study of acute oral doses of lorazepam (2 mg) and placebo, using young healthy volunteers. We focused on response delay of three separable phases of deductive reasoning and matched working memory tasks (that involved only maintenance of information) the premise processing phase, the premise integration phase, and the validation phase, in which reasoners decide whether a conclusion logically follows from the premises (reasoning task) or is identical to one of the premises (maintenance task). Type of relations in the premises was also manipulated. We employed material that was difficult to envisage visually and visuospatially ("subiconic") and material easy to envisage visually or visuospatially. Lorazepam slowed response as memory load increased, irrespective of type of relations. It also specifically slowed validation in reasoning problems with visual relations, an effect that disappeared after subtraction of maintenance scores, and increased validation time in problems with subiconic relations, which remained after this subtraction. Acute lorazepam administration affected reasoning in two ways: it slowed processing nonspecifically when working memory demands increased and augmented validation time depending on the difficulty in generating and/or manipulating mental representations by the central executive.

The effects of lorazepam on skin conductance responses to aversive stimuli in healthy subjects

Autonomic responses to aversive stimuli are widely used to model anxiolytic drug effects in healthy humans. Benzodiazepine anxiolytics dose dependently attenuate autonomic responses to aversive stimuli by their anxiolytic as well as sedative action. The present study aimed to examine the effects of non-sedative doses of lorazepam on skin cutaneous responses to aversive stimuli and subjective mood. A randomized, double blind, cross over study of 12 healthy male volunteers aged 24 years (23-32; median; range) was carried out. Subjects received single oral doses of 0.5 and 1.0 mg lorazepam as well as placebo on three different occasions with at least 5 days in-between. Skin conductance responses (SCRs) to unpleasant pictures and noises, pupillary unrest index as well as subjective levels of anxiety were measured repeatedly before and after drug administration. SCRs were found significantly lower 2 hours following ingestion of 0.5 mg lorazepam as well as 1, 2 and 3 hours after 1.0 mg lorazepam were given as compared to baseline conditions. By contrast, administration of placebo did not influence SCRs to a significant extent. Both doses of lorazepam did not change pupillary unrest index nor subjective mood. Lorazepam may attenuate SCRs to aversive stimuli without affecting vigilance nor subjective mood. Attenuation of autonomic responses to aversive stimuli may not be specific for an anxiolytic effect.

The effect of chronic lorazepam administration in aging mice

To assess benzodiazepine tolerance in aged animals, lorazepam or vehicle was administered chronically to male Crl: CD-1(ICR)BR mice. Pharmacodynamic and neurochemical endpoints were examined on days 1 and 14 of drug administration. There was no age-related significant difference in plasma lorazepam levels. Young and middle-aged animals demonstrated behavioral tolerance to lorazepam, while the aged animals showed a similar trend which failed to reach significance. In addition, aged animals also showed a trend toward tolerance to the anticonvulsant effects of lorazepam. There were no changes in α1 mRNA levels in cortex or hippocampus following administration of lorazepam when compared to vehicle-treated animals in any age group. Aged animals, however, had an initial increase in α1 mRNA expression in cortex and hippocampus on day 1 of vehicle treatment followed by decreased expression on day 14. These age-related changes were abolished by lorazepam administration. In summary, age-related sensitivity to the effects of lorazepam was not demonstrated in the present study. However, comparison of these data to other studies indicates that the effect of chronic benzodiazepine treatment may be specific to the benzodiazepine administered, the technique used to quantify mRNA expression changes, the subunits of the GABA A receptor investigated and the brain region analyzed. The phenomenon of benzodiazepine sensitivity in the elderly is an area of research which remains controversial and may well be compound specific. Determining benzodiazepines that do not produce pharmacodynamic sensitivity, such as lorazepam, may allow more careful prescribing and dosing of these drugs, and perhaps even the development of specific agents which could avoid this sensitivity.

Pharmacodynamic and pharmacokinetic effects of TPA023, a GABAA α2,3 subtype-selective agonist, compared to lorazepam and placebo in healthy volunteers

TPA023, a GABA(A) alpha2,3 alphasubtype-selective partial agonist, is expected to have comparable anxiolytic efficacy as benzodiazepines with reduced sedating effects. The compound lacks efficacy at the alpha1 subtype, which is believed to mediate these effects. This study investigated the effects of 0.5 and 1.5 mg TPA023 and compared them with placebo and lorazepam 2 mg (therapeutic anxiolytic dose). Twelve healthy male volunteers participated in this placebo-controlled, double-blind, double-dummy, four-way, cross-over study. Saccadic eye movements and visual analogue scales (VAS) were used to assess the sedative properties of TPA023. The effects on posturaL stability and cognition were assessed using body sway and a standardized battery of neurophysiological memory tests. Lorazepam caused a significant reduction in saccadic peak velocity, the VAS alertness score and impairment of memory and body sway. TPA023 had significant dose dependent effects on saccadic peak velocity (85 deg/sec maximum reduction at the higher dose) that approximated the effects of lorazepam. In contrast to lorazepam, TPA023 had no detectabLe effects on saccadic latency or inaccuracy. Also unlike lorazepam, TPA023 did not affect VAS alertness, memory or body sway. These results show that the effect profile of TPA023 differs markedly from that of lorazepam, at doses that were equipotent with regard to effects on saccadic peak veLocity. Contrary to lorazepam, TPA023 caused no detectable memory impairment or postural imbalance. These differences reflect the selectivity of TPA023 for different GABA(A) receptor subtypes.

Dissociation between the cognitive process and the phenomenological experience of TOT: Effect of the anxiolytic drug lorazepam on TOT states

TOT states may be viewed as a temporary and reversible microamnesia. We investigated the effects of lorazepam on TOT states in response to general knowledge questions. The lorazepam participants produced more commission errors and more TOTs following commission errors than the placebo participants (although the rates did not change). The resolution of the TOTs was unimpaired by the drug. Neither feeling-of-knowing accuracy nor recognition were affected by lorazepam. The higher level of incorrect recalls produced by lorazepam participants may be due to the fact that they were more frequently temporarily unable to access a known item. For some of these items, the awareness of the retrieval failure resulted in a commission TOT (phenonemological TOT after a commission error). The resolution of the TOT conflict is discussed in the light of the anxiolytic and anticonflict effects of lorazepam. The data are discussed in terms of contemporary theories of TOTs and the effects that benzodiazepines have on semantic memory.