Intellectual, adaptive and behavioural characteristics in four patients with 18p deletion syndrome.

BACKGROUND: The association of behavioural phenotype assessment with cytogenomic characterisation may provide a better comprehension of genotype-phenotype correlations in syndromes caused by chromosomal abnormalities, such as 18p deletion syndrome. METHOD: We report on four Brazilian patients with 18p deletion syndrome characterised by cytogenomic techniques and detailed neuropsychological evaluation. Intellectual, adaptive and behavioural characteristics were assessed through the Wechsler's Scales, the Vineland-II Scale and the Child Behaviour Checklist, respectively. Socio-economic measures including main caretaker educational level and family income as defined by Brazilian criteria for social class classification were also collected to evaluate a possible contribution of environmental factors in neurocognitive variability. RESULTS: Two out of four patients showed intellectual disability (IQ < 70). Wechsler's scale results suggest that in our sample, interpretation of social situations based on observation of non-verbal behaviour constitute a cognitive strength while judgement of social rules and language skills associated with word knowledge and verbal fluency may be a cognitive weakness. Concerning adaptive behaviour, motor and socialisation domains showed to better develop than communication and daily living skills on the Vineland-II Scale. Only one patient presented internalising behavioural problems based on the Child Behaviour Checklist. Our results also suggested that socio-economic status may contribute to overall patient development. CONCLUSION: Our results suggest that some 18p deletion syndrome patients may present average intellectual performance and that the segment deletion size and some families' socio-economic conditions may influence cognitive development.

The Prospective and Retrospective Memory Questionnaire: a population-based random sampling study.

The Prospective and Retrospective Memory Questionnaire (PRMQ) has been shown to have acceptable reliability and factorial, predictive, and concurrent validity. However, the PRMQ has never been administered to a probability sample survey representative of all ages in adulthood, nor have previous studies controlled for factors that are known to influence metamemory, such as affective status. Here, the PRMQ was applied in a survey adopting a probabilistic three-stage cluster sample representative of the population of Sao Paulo, Brazil, according to gender, age (20-80 years), and economic status (n=1042). After excluding participants who had conditions that impair memory (depression, anxiety, used psychotropics, and/or had neurological/psychiatric disorders), in the remaining 664 individuals we (a) used confirmatory factor analyses to test competing models of the latent structure of the PRMQ, and (b) studied effects of gender, age, schooling, and economic status on prospective and retrospective memory complaints. The model with the best fit confirmed the same tripartite structure (general memory factor and two orthogonal prospective and retrospective memory factors) previously reported. Women complained more of general memory slips, especially those in the first 5 years after menopause, and there were more complaints of prospective than retrospective memory, except in participants with lower family income.

Calcineurin deficiency decreases inflammatory lesions in transforming growth factor beta1-deficient mice.

Transforming growth factor (TGF) beta1) is an immunoregulatory cytokine involved in self-tolerance and lymphocyte homeostasis. Tgfb1 knock-out (KO) mice develop severe multi-focal autoimmune inflammatory lesions due to [Ca(2+)]i deregulation in T cells, and die within 3 weeks after birth. Because the calcineurin inhibitor FK506 inhibits the hyperresponsiveness of Tgfb1(-/-) thymocytes, and because calcineurin Abeta (CNAbeta)-deficient mice do not reject allogenic tumours, we have generated Tgfb1(-/-) Cnab(-/-) mice to address whether CNAbeta deficiency prevents T cell activation and inflammation in Tgfb1(-/-) mice. Here we show that in Tgfb1(-/-) Cnab(-/-) mice inflammation is reduced significantly relative to that in Tgfb1(-/-) mice. However, both CD4(+) and CD8(+) T cells in double knock-out (DKO) mice are activated, as revealed by up-regulation of CD11a lymphocyte function-associated antigen-1 (LFA-1), CD44 and CD69 and down-regulation of CD62L. These data suggest that deficiency of CNAbeta decreases inflammatory lesions but does not prevent activation of autoreactive T cells. Also Tgfb1(-/-) T cells can undergo activation in the absence of CNAbeta, probably by using the other isoform of calcineurin (CNAalpha) in a compensatory manner. CNAbeta-deficient T cells undergo spontaneous activation in vivo and are activated upon anti-T cell receptor stimulation in vitro. Understanding the role of calcineurin in T cell regulation should open up new therapeutic opportunities for inflammation and cancer.

The indirect amygdala-dorsal striatum pathway mediates conditioned freezing: insights on emotional memory networks.

The dorsal striatum (DS) is involved in various forms of learning and memory such as procedural learning, habit learning, reward-association and emotional learning. We have previously reported that bilateral DS lesions disrupt tone fear conditioning (TFC), but not contextual fear conditioning (CFC) [Ferreira TL, Moreira KM, Ikeda DC, Bueno OFA, Oliveira MGM (2003) Effects of dorsal striatum lesions in tone fear conditioning and contextual fear conditioning. Brain Res 987:17-24]. To further elucidate the participation of DS in emotional learning, in the present study, we investigated the effects of bilateral pretest (postraining) electrolytic DS lesions on TFC. Given the well-acknowledged role of the amygdala in emotional learning, we also examined a possible cooperation between DS and the amygdala in TFC, by using asymmetrical electrolytic lesions, consisting of a unilateral lesion of the central amygdaloid nucleus (CeA) combined to a contralateral DS lesion. The results show that pre-test bilateral DS lesions disrupt TFC responses, suggesting that DS plays a role in the expression of TFC. More importantly, rats with asymmetrical pre-training lesions were impaired in TFC, but not in CFC tasks. This result was confirmed with muscimol asymmetrical microinjections in DS and CeA, which reversibly inactivate these structures. On the other hand, similar pretest lesions as well as unilateral electrolytic lesions of CeA and DS in the same hemisphere did not affect TFC. Possible anatomical substrates underlying the observed effects are proposed. Overall, the present results underscore that other routes, aside from the well-established CeA projections to the periaqueductal gray, may contribute to the acquisition/consolidation of the freezing response associated to a TFC task. It is suggested that CeA may presumably influence DS processing via a synaptic relay on dopaminergic neurons of the substantia nigra compacta and retrorubral nucleus. The present observations are also in line with other studies showing that TFC and CFC responses are mediated by different anatomical networks.

Effects of lorazepam on visual perceptual abilities.

OBJECTIVE: 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. METHODS: 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. RESULTS: 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. CONCLUSION: 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.

Latent class analysis of attention and white matter correlation in children with attention-deficit/hyperactivity disorder.

This study aimed to explore attentional patterns among children with inattentive attention-deficit/hyperactivity disorder (ADHD-I) and children with typical development (TD), using a latent class analysis (LCA). Patterns of brain connectivity were also explored. The sample comprised 29 ADHD-I and 29 TD matched children. An LCA was conducted to reclassify subjects according to their attentional performance, considering cognitive measures of attention and behavioral symptoms, regardless of group of origin. The new clusters were then compared in respect to brain white matter measurements (extracted from diffusion tensor imaging). Participants were rearranged in 2 new latent classes, according to their performance in an attention task and the results of behavioral scales, resulting in groups with more homogeneous attentional profiles. A comparison of the 2 new classes using the white matter measurements revealed increased fractional anisotropy in the left inferior fronto-occipital fasciculus and left inferior longitudinal fasciculus for the class composed by participants with a higher risk of attentional problems. The findings indicated that it was possible to observe variability regarding neuropsychological profile, accompanied by underpinning neurobiological differences, even among individuals with the same disorder subtype - inattentive ADHD. This specific data-driven clustering analysis may help to enhance understanding of the pathophysiology of the disorder's phenotypes.

Effects of lorazepam on deductive reasoning.

RATIONALE: 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. OBJECTIVES: 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. METHODS: 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. RESULTS: 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. CONCLUSION: 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 transcription factor GATA4 is activated by extracellular signal-regulated kinase 1- and 2-mediated phosphorylation of serine 105 in cardiomyocytes.

The zinc finger-containing transcription factor GATA4 has been implicated as a critical regulator of multiple cardiac-expressed genes as well as a regulator of inducible gene expression in response to hypertrophic stimulation. Here we demonstrate that GATA4 is itself regulated by the mitogen-activated protein kinase signaling cascade through direct phosphorylation. Site-directed mutagenesis and phospho-specific GATA4 antiserum revealed serine 105 as the primary site involved in agonist-induced phosphorylation of GATA4. Infection of cultured cardiomyocytes with an activated MEK1-expressing adenovirus induced robust phosphorylation of serine 105 in GATA4, while a dominant-negative MEK1-expressing adenovirus blocked agonist-induced phosphorylation of serine 105, implicating extracellular signal-regulated kinase (ERK) as a GATA4 kinase. Indeed, bacterially purified ERK2 protein directly phosphorylated purified GATA4 at serine 105 in vitro. Phosphorylation of serine 105 enhanced the transcriptional potency of GATA4, which was sensitive to U0126 (MEK1 inhibitor) but not SB202190 (p38 inhibitor). Phosphorylation of serine 105 also modestly enhanced the DNA binding activity of bacterially purified GATA4. Finally, induction of cardiomyocyte hypertrophy with an activated MEK1-expressing adenovirus was blocked with a dominant-negative GATA4-engrailed-expressing adenovirus. These results suggest a molecular pathway whereby MEK1-ERK1/2 signaling regulates cardiomyocyte hypertrophic growth through the transcription factor GATA4 by direct phosphorylation of serine 105, which enhances DNA binding and transcriptional activation.

The dual-specificity phosphatase MKP-1 limits the cardiac hypertrophic response in vitro and in vivo.

Mitogen-activated protein kinase (MAPK) signaling pathways are important regulators of cell growth, proliferation, and stress responsiveness. A family of dual-specificity MAP kinase phosphatases (MKPs) act as critical counteracting factors that directly regulate the magnitude and duration of p38, c-Jun N-terminal kinase (JNK), and extracellular signal-regulated kinase (ERK) activation. Here we show that constitutive expression of MKP-1 in cultured primary cardiomyocytes using adenovirus-mediated gene transfer blocked the activation of p38, JNK1/2, and ERK1/2 and prevented agonist-induced hypertrophy. Transgenic mice expressing physiological levels of MKP-1 in the heart showed (1) no activation of p38, JNK1/2, or ERK1/2; (2) diminished developmental myocardial growth; and (3) attenuated hypertrophy in response to aortic banding and catecholamine infusion. These results provide further evidence implicating MAPK signaling factors as obligate regulators of cardiac growth and hypertrophy and demonstrate the importance of dual-specificity phosphatases as counterbalancing regulatory factors in the heart.

Errors in nonword repetition: bridging short- and long-term memory.

According to the working memory model, the phonological loop is the component of working memory specialized in processing and manipulating limited amounts of speech-based information. The Children's Test of Nonword Repetition (CNRep) is a suitable measure of phonological short-term memory for English-speaking children, which was validated by the Brazilian Children's Test of Pseudoword Repetition (BCPR) as a Portuguese-language version. The objectives of the present study were: i) to investigate developmental aspects of the phonological memory processing by error analysis in the nonword repetition task, and ii) to examine phoneme (substitution, omission and addition) and order (migration) errors made in the BCPR by 180 normal Brazilian children of both sexes aged 4-10, from preschool to 4th grade. The dominant error was substitution [F(3,525) = 180.47; P < 0.0001]. The performance was age-related [F(4,175) = 14.53; P < 0.0001]. The length effect, i.e., more errors in long than in short items, was observed [F(3,519) = 108.36; P < 0.0001]. In 5-syllable pseudowords, errors occurred mainly in the middle of the stimuli, before the syllabic stress [F(4,16) = 6.03; P = 0.003]; substitutions appeared more at the end of the stimuli, after the stress [F(12,48) = 2.27; P = 0.02]. In conclusion, the BCPR error analysis supports the idea that phonological loop capacity is relatively constant during development, although school learning increases the efficiency of this system. Moreover, there are indications that long-term memory contributes to holding memory trace. The findings were discussed in terms of distinctiveness, clustering and redintegration hypotheses.

Cross-cultural differences for three visual memory tasks in Brazilian children.

Norms for three visual memory tasks, including Corsi's block tapping test and the BEM 144 complex figures and visual recognition, were developed for neuropsychological assessment in Brazilian children. The tasks were measured in 127 children ages 7 to 10 years from rural and urban areas of the States of São Paulo and Minas Gerais. Analysis indicated age-related but not sex-related differences. A cross-cultural effect was observed in relation to copying and recall of Complex pictures. Different performances between rural and urban children were noted.

Effects of a physical fitness program on memory and blood viscosity in sedentary elderly men.

The aim of this study was to investigate the effects of a 6-month exercise program on cognitive function and blood viscosity in sedentary elderly men. Forty-six healthy inactive men, aged 60-75 years were randomly distributed into a control group (n=23) and an experimental group (n=23). Participants underwent blood analysis and physical and memory evaluation, before and after the 6-month program of physical exercise. The control group was instructed not to alter its everyday activities; the experimental group took part in the fitness program. The program was conducted using a cycle ergometer, 3 times per week on alternate days, with intensity and volume individualized at ventilatory threshold 1. Sessions were continuous and maximum duration was 60 min each. There was significant improvement in memory (21%; P<0.05), decreased blood viscosity (-19%; P<0.05), and higher aerobic capacity (48%; P<0.05) among participants in the experimental group compared with the control group. These data suggest that taking part in an aerobic physical fitness program at an intensity corresponding to ventilatory threshold-1 may be considered a nonmedication alternative to improve physical and cognitive function.

Colchicine inhibits GABA(A) receptors independently of microtubule depolymerization.

Colchicine is a microtubule depolymerizing agent used extensively in the study of cytoskeleton-dependent cell functions. In studying the possible functional interaction between the GABA(A) receptor and the cytoskeleton, we found that colchicine inhibits GABA(A) receptor function by mechanisms independent of microtubule depolymerization. Human GABA(A) receptor alpha1beta2gamma2L subunits were co-expressed in Xenopus oocytes and the effects of colchicine on GABA(A) receptor function was assessed using the two-electrode voltage-clamp technique. Co-application of GABA (10 microM) with colchicine (100 microM) resulted in a 59.9% inhibition of GABA-gated chloride currents. This effect was instantaneous in onset with no pre-incubation required and reversed within seconds. Other depolymerizing agents, such as nocodazole (20 microM) and vinblastine (200 microM), did not affect GABA(A) receptor function using the same co-application protocol used with colchicine. The polymerizing agent taxol (10-50 microM) did not affect colchicine inhibition of the GABA responses and did not itself alter GABA-gated chloride currents. The inhibitory effect of colchicine was present under conditions in which the oocyte microtubules had been depolymerized by cold temperature. These results indicate that colchicine inhibits the GABA(A) receptor via mechanisms unrelated to microtubule depolymerization. To further examine the inhibitory effect of colchicine on the GABA response, GABA (10-3000 microM) concentration-response curves were performed in the absence or presence of various concentrations of colchicine (30-300 microM). In the presence of colchicine, the GABA concentration-response curve was shifted to the right in a parallel fashion. A Schild plot of this data yielded a linear slope indicating that colchicine acts as a competitive antagonist at the GABA binding site. We conclude that colchicine is a competitive antagonist at the GABA(A) receptor and that studies using colchicine to examine the functional interaction between GABA(A) receptors and microtubules should be interpreted with caution.

Functional characterization and visualization of a GABAA receptor-GFP chimera expressed in Xenopus oocytes.

The GABAA receptor is a ligand-gated chloride channel belonging to the superfamily of ligand-gated ion channels of which the nicotinic acetylcholine (nACh) receptor is prototypic. In the central nervous system the GABAA receptor mediates fast neuronal inhibition. To facilitate the study of this receptor, a GABAA receptor-green fluorescent protein (GABAAR-GFP) chimera was constructed by fusing green fluorescent protein (GFP) to the C-terminus region of the GABAA receptor alpha1 subunit. When expressed in Xenopus oocytes, this chimera responded in a manner indistinguishable from the wild-type GABAA receptor with respect to agonist potency, receptor desensitization, allosteric modulation, rectification, and ion selectivity of the channel. The addition of GFP to the GABAA receptor alpha1 subunit did not appear to alter the assembly or efficiency of expression of the GABAA receptor complex. The GABAAR-GFP chimera generated a strong fluorescent signal that was restricted to the animal pole of the oocyte plasma membrane. This signal was readily detectable using either epifluorescence or laser confocal microscopy. To confirm the extracellular location of the GFP portion of the chimera, non-permeabilized oocytes were immunolabeled with an anti-GFP antibody. Fluorescence microscopy showed that GFP was located extracellularly since it was accessible to the GFP antibody. These results confirm the predicted extracellular location of the C-terminus of the GABAA receptor alpha1 subunit and also demonstrate that GFP retains its fluorescent property when expressed extracellularly. The usefulness of the GABAAR-GFP chimera in receptor trafficking was investigated using non-hydrolyzable GTP analogues since GTP binding proteins participate in protein transport in oocytes. Microinjections of GTP-gamma-S but not GDP-beta-S reduced both GABA-gated chloride currents and cell surface GFP fluorescence in oocytes expressing the GABAAR-GFP chimera indicating that the chimera undergoes internalization upon stimulation of oocyte GTP-binding proteins. The results of the present study show that the GABAAR-GFP chimera is functionally similar to the wild-type GABAA receptor and can be used to study receptor trafficking in living cells. This is the first demonstration of a ligand-gated ion channel-GFP chimera for an ion channel belonging to this superfamily and also is the first example of the fusion of GFP to an extracellular domain of an integral membrane protein.

Zolpidem and memory: a study using the process-dissociation procedure.

RATIONALE: There is a dearth of studies which have employed sophisticated paradigms to investigate the effects of zolpidem on memory. OBJECTIVES: To explore anterograde cognitive deficits induced by acute oral doses of zolpidem by means of the process-dissociation procedure (PDP). METHODS: The present study followed a placebo-controlled, double-blind, parallel-group design. Young, healthy females were randomly allocated to one of three treatments with 12 subjects each: placebo, 5 mg and 10 mg zolpidem. Two word-stem completion tasks were carried out close to theoretical peak-plasma concentration: a) direct inclusion task with cued recall, in which participants had to try to use words seen at study to complete stems; and b) direct exclusion task, in which words seen at study were to be avoided as completions. The PDP was applied to the results in these tasks to yield indices of explicit/controlled (C) and implicit/automatic (A) memory. Classical psychometric tests were also carried out. RESULTS: Zolpidem 10 mg led to cognitive effects similar to benzodiazepines (except for the atypical lorazepam), including impairment of exclusion, but not inclusion-task performance. Results of the application of the PDP were inconclusive but concurred with the pattern established in previously published work on benzodiazepine effects, i.e. that zolpidem (10 mg) impaired C. CONCLUSIONS: Zolpidem leads to cognitive effects similar to most benzodiazepines. Although the application of PDP in drug studies may be counterproductive in view of methodological difficulties that are discussed, the pattern of effects on the stem-completion tasks involved in this paradigm is potentially useful in the investigation of cognitive effects of psychoactive drugs.

Cholinergic modulation of inhibitory avoidance impairment induced by paradoxical sleep deprivation.

1. Male Wistar rats were submitted to paradoxical sleep deprivation for 96 hr by a modified multiple platform technique. 2. Training of step-through inhibitory avoidance was performed immediately after the last day of paradoxical sleep deprivation. Twenty-four hr after training the animals were submitted to the retention test. 3. In Experiment 1, pilocarpine (4 mg/kg, i.p.) or atropine (4 mg/kg, i.p.) were administered daily during the paradoxical sleep deprivation period. Pilocarpine, but not atropine, reversed the impairment induced by PS deprivation. 4. In Experiment 2, pilocarpine (4, 8 and 12 mg/kg, i.p.) was injected 1 hr before training in order to verify if the reversal of memory impairment was an effect secondary to residual enhanced blood levels of pilocarpine during training. Acute treatment with pilocarpine, in any dose, did not reverse the impairment produced by paradoxical sleep deprivation 5. Activation of the cholinergic system during the period of deprivation is able to prevent memory deficits induced by paradoxical sleep deprivation.

Dissociated paradoxical sleep deprivation effects on inhibitory avoidance and conditioned fear.

Rats were submitted to paradoxical sleep deprivation (PSD) for 24, 72, or 96 h and were trained on a double aversively motivated task, encompassing a step-through inhibitory avoidance and a classical conditioning of fear to a brief tone serving as conditional stimulus. Retention test of the inhibitory avoidance was performed at the same apparatus of training (without tone presentation). Retention of conditioned fear was assessed in an open field apparatus, where the freezing reaction to the tone was measured. PSD for 24 and 72 h preceding the training session had no effect on either task. However, PSD during the 96 h preceding the training session impaired acquisition of inhibitory avoidance, but had no effect on classically conditioned fear. It is concluded that PSD had differential effects on the two tasks, both aversively motivated and trained at the same time and conditions.

Lorazepam induces an atypical dissociation of visual and auditory event-related potentials.

Lorazepam has been reported to atypically disrupt visual processing compared to other benzodiazepines (BZs), but it is not known to what extent this effect extends to impairment in other modalities. Our objective was to compare the effects of lorazepam with those of flunitrazepam, a BZ with standard effects, on visual and auditory event-related potentials (ERPs) using the same paradigm. The study followed a placebo-controlled, double-blind, parallel group-design and involved single oral doses of lorazepam (2.0 mg), flunitrazepam (1.2 mg) and placebo. Thirty-six young, healthy subjects completed a test battery before and after treatment including classic behavioural tests, visual and auditory ERPs. Both drugs led to comparable alterations on behavioural tests and double-dissociations were found, indicating that the doses used were equipotent: lorazepam was more deleterious than flunitrazepam and placebo in fragmented shape identification, while simple reaction times were prolonged for flunitrazepam in comparison to lorazepam and placebo. Effects on P3 latencies were also distinct: alterations in both modalities for flunitrazepam were equivalent and greater than placebo's. In contrast, lorazepam at the frontal and central electrode sites led to greater changes in visual than in auditory latency, and also to longer visual latencies than flunitrazepam and placebo, but lorazepam's auditory latency effects were only different to placebo's at the parietal electrode site. Peripheral visual changes were not responsible for these effects. Differences in the impairment profile between equipotent doses of lorazepam and flunitrazepam suggests that lorazepam induces atypical central visual processing changes.

A double-dissociation of behavioural and event-related potential effects of two benzodiazepines with similar potencies.

This study was designed to explore the role of benzodiazepine affinity to benzodiazepine binding site on acute psychomotor, subjective and memory effects, as well as auditory Event Related Potential (ERP) latencies, in healthy volunteers. Two benzodiazepines with similar affinity to benzodiazepine binding sites, or potency, were compared: the atypical compound lorazepam (2.0 mg), which has been reported to impair priming, and a standard benzodiazepine, flunitrazepam (0.6 mg, 0.8 mg, 1.0 mg). The study followed a placebo-controlled, double-blind, parallel-group design. Sixty subjects completed a test battery before treatment and at theoretical peak plasma concentration of drugs. Lorazepam and 1.0 mg of flunitrazepam led to comparable alterations on psychomotor, subjective and auditory episodic memory measures. A double-dissociation was found for lorazepam and the equipotent dose of flunitrazepam (1.0 mg): lorazepam was more deleterious than flunitrazepam in time taken to identify fragmented shapes. Lorazepam also impaired direct and indirect stem-completion in comparison to placebo, but this effect was abolished when time to identify shapes was used as a covariate. By contrast, 1.0 mg of flunitrazepam prolonged auditory ERP latencies to a greater extent than lorazepam. High affinity to the benzodiazepine binding sites does not seem to explain the consistent lorazepam-induced impairment of indirect stem-completion. Differences in impairment profile between the benzodiazepines employed may relate to the modality (visual or not) of the tasks used.

On delay-of-punishment and preexposure time: effects on passive avoidance behavior in rats.

Some procedures commonly employed in testing hypotheses of instrumental learning and classical conditioning as applied to the step-through passive avoidance task in rats are examined. In Experiment I, a 'delay-of-punishment gradient', i.e., decreased passive avoidance performance, was obtained by increasing response-shock time intervals (from 0 to 600 s) in training sessions. In Experiment II, decreased passive avoidance behavior was also obtained by submitting animals to nonreinforced preexposure (0 to 600 s) in the shock compartment prior to their receiving shock contingent on the response in training sessions. Experiment III repeated the 'delay-of-punishment gradient' and showed that adequate nonreinforced preexposure time before training decreases passive avoidance performance in animals trained through a noncontingent procedure. The results clearly show that environment training preexposure has a decreasing effect on passive avoidance performance. Increasing response-shock interval also has a decremental effect on this task. With large time intervals the latter effect can be explained as the result of preexposure to the training environment; the possibility of interaction between both processes was not discarded. For smaller time ranges (up to 30 s), the usual interpretation of 'delay-of-punishment gradient', namely decreased response-shock association, seems to be adequate to account for the results.