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Biomedical subjects

I Izquierdo

Publications and source records attributed to I Izquierdo.

At least 19 recordsLinked to original sources
PubMed1992

Benzodiazepines in the brain. Their origin and possible biological roles.

Great progress has been made in the last 5 yr in demonstrating the presence of benzodiazepines (BDZs) in mammalian tissues, in beginning studies on the origin of these natural compounds, and in elucidating their possible biological roles. Many unanswered questions remain regarding the sources and biosynthetic pathways responsible for the presence of BDZs in brain and their different physiological and/or biochemical actions. This essay will focus on recent findings supporting that: (1) BDZs are of natural origin; (2) mammalian brain contains BDZs in concentrations ranging between 5 x 10(-10)-10(-8) M; (3) dietary source of BDZs might be a plausible explanation for their occurrence in animal tissues, including man; (4) the formation of BDZ-like molecules in brain is a possibility, experimentally supported; (5) BDZ-like molecules including diazepam and N-desmethyldiazepam are elevated in hepatic encephalopathy; and (6) natural BDZs in the brain are involved in the modulation of memory processes. Future studies using the full range of biochemical, physiological, behavioral, and molecular biological techniques available to the neuroscientist will hopefully continue to yield exciting and new information concerning the biological roles that BDZs might play in the normal and pathological functioning of the brain.

Animals↗
PubMed1992

Late posttraining memory processing by entorhinal cortex: involvement of NMDA and GABAergic receptors.

The NMDA receptor antagonist, D-2-amino-5-phosphonopentanoic acid (AP5) (5 micrograms) and the GABAA receptor agonist, muscimol (0.03 microgram) were infused bilaterally into the entorhinal cortex of rats 0, 90, 180, or 360 min after training in habituation to a novel environment or in step-down inhibitory avoidance. Animals were tested for retention 22 h after training in each task. AP5 and muscimol were amnestic for both tasks when given 90 or 180 min after training, but had no effect when given 0 or 360 min after training. In contrast, intraamygdala injections or AP5 or muscimol were amnestic when given 0 but not 90 min after inhibitory avoidance training. The results indicate that the entorhinal cortex plays a late but important role in posttraining memory processing; this role involves glutamatergic NMDA receptors and is inhibited by GABAA receptors. The intervention of the entorhinal cortex in posttraining memory processing is subsequent, and could be secondary, to that of the amygdala and other limbic structures.

2-Amino-5-phosphonovalerate↗
PubMed1992

Effect of various training procedures on performance in an elevated plus-maze: possible relation with brain regional levels of benzodiazepine-like molecules.

Rats submitted to one, two, or seven sessions of exploration to a new environment (habituation) or exposed to an inhibitory avoidance training showed different degrees of anxiety, evaluated by the elevated plus-maze test. Also, the brain regional levels of benzodiazepine (BDZ)-like molecules in rats submitted to one, two, or seven sessions of habituation were differentially decreased with respect to nontrained rats. The percentage of time spent in the open arms of the elevated plus-maze for each group correlates with the data of decrease in the BDZ-like immunoreactivity in amygdala (r = 0.77, p < 0.0005), hippocampus (r = 0.68, p < 0.0005), and septum (r = 0.57, p < 0.005). These results suggest that the limbic system responds to anxiogenic experiences by changing the BDZ-like molecule levels in relation to the degree of anxiety and/or stress that accompany these experiences.

Animals↗
PubMed1992

Neurotransmitter receptors involved in post-training memory processing by the amygdala, medial septum, and hippocampus of the rat.

Rats were trained and tested in habituation to a novel environment and step-down inhibitory avoidance. Immediately after training in each task the animals received intra-amygdala, intraseptal, or intrahippocampal micro-injections of agonists and antagonists of various neurotransmitter receptors. In the habitation task, intrahippocampal, but not intra-amygdala or intraseptal administration of the NMDA receptor antagonist aminophosphornopentanoic acid (AP5, 5.0 micrograms) or of the muscarinic receptor antagonist, scopolamine (2.0 micrograms) caused amnesia and the indirect antagonist of GABA-A receptors, picrotoxin (0.08 microgram), caused retrograde facilitation. Intrahippocampal administration of the respective agonists, glutamate, oxotremorine, and muscimol, had effects of their own opposite to those of the blockers, and norepinephrine (0.3 microgram) caused memory facilitation. In the avoidance task, results obtained with drug infusions given into the three structures were very similar: in all cases, AP5, scopolamine, and muscimol were amnestic, and glutamate, oxotremorine, norepinephrine, and picrotoxin caused memory facilitation. In addition, also in the three structures, picrotoxin counteracted the amnestic effect of AP5 and/or scopolamine and the beta-adrenoceptor blocker, timolol (0.3 microgram), while ineffective on its own, attenuated all the effects of picrotoxin. The results suggest that similar synaptic mechanisms in the amygdala, medial septum, and hippocampus are involved in memory consolidation: NMDA, muscarinic, and beta-noradrenergic receptors stimulate and GABA-A receptors inhibit this process, and beta-noradrenergic receptors modulate the GABAergic synapses. In the avoidance task these mechanisms operate in the three structures: in habituation only those in the hippocampus are operative. Possibly in each structure these mechanisms regulate, if not actually consolidate, a different aspect, component, or form of memory.

Amygdala↗
PubMed1992

Amnesia by post-training infusion of glutamate receptor antagonists into the amygdala, hippocampus, and entorhinal cortex.

The blockers of glutamate receptors, aminophosphonovaleric acid (AP5) (5.0 micrograms) and cyano-nitroquinoxaline-dione (CNQX) (0.5 microgram), were infused bilaterally into the amygdala, dorsal hippocampus, or entorhinal cortex of rats through indwelling cannulae 0, 90, 180, or 360 min after step-down inhibitory avoidance training. Animals were tested for retention 24 h after training. In the amygdala or hippocampus, AP5 was amnestic when given 0 min after training and CNQX was amnestic when given 0, 90, or 180 min after training. In the entorhinal cortex, AP5 was amnestic when given 90 or 180 min after training and CNQX had no effect. The results suggest that a phenomenon sensitive first to AP5 and then to CNQX in the amygdala and hippocampus, probably long-term potentiation (LTP), is crucial to post-training memory processing. LTP in these two structures could underlie their role in memory consolidation and could explain the late involvement of the entorhinal cortex in post-training memory processing.

Amnesia, Retrograde↗
PubMed1992

Differential diagnosis between dementia and depression: a study of efficiency increment.

A battery of neuropsychological tests was examined to establish its value in differentiating mild dementia from depression. The battery was applied to 84 subjects: 31 dementia patients of several etiologies, 31 patients with major depression and 22 volunteers whose age and educational level was similar to that of the patients. The battery consisted of tests for immediate, recent and remote memory, the Mini Mental State examination, a screening test for language disorders, and tests measuring abstraction, calculation, judgement, praxic and gnosic functions. The results showed significant differences among the three groups in all memory tests. Deficits of abstraction, calculation, praxis and language functions were strongly associated with dementia. The epidemiological analysis of efficiency increment, with determination of sensitivity and specificity, showed a highly significant enhancement of efficiency for diagnostic purposes when the results of the tests were combined. These findings suggest that the entire battery of neuropsychological tests should be applied, and their results compared using the efficiency increment procedure, in order to establish a firm differential diagnosis between dementia and depression, and/or to detect the former when it is at a mild early stage.

Adult↗
PubMed1992

Memory consolidation of a habituation task: role of N-methyl-D-aspartate, cholinergic muscarinic and GABA-A receptors in different brain regions.

1. The immediate post-training microinjection of the N-methyl-D-aspartate receptor antagonist amino-5-phosphonopentanoic acid (5 micrograms) or of scopolamine, the cholinergic muscarinic antagonist (2 micrograms), into the dorsal hippocampus of rats caused retrograde amnesia for habituation to a novel environment, as measured by the number of rearings and crossings performed in a test session. In contrast, picrotoxin (0.08 microgram), the indirect GABA-A antagonist, caused retrograde memory facilitation. 2. Receptor agonists administered into the hippocampus had effects opposite to those of the respective antagonists: glutamate (5 micrograms) and oxotremorine (2 micrograms) enhanced memory and muscimol (0.03 microgram) was amnestic. 3. Aminophosphonopentanoic acid, scopolamine and picrotoxin had no effect when injected into the amygdala or medial septum. Our result contrasted with the recent report of an inhibitory avoidance task in which these drugs, at the doses used here, were effective when injected post-training into any of the three structures. 4. These findings suggest that similar neurotransmitter mechanisms operate in different brain regions in order to regulate memory consolidation processes; however, there is a specialization of these brain regions in relation to different types or components of memory.

2-Amino-5-phosphonovalerate↗
PubMed1992

Local and systemic tolerance of flutrimazole skin creams following single and repeated topical application in healthy volunteers.

A double-blind, randomized phase I study was performed in 21 healthy volunteers to evaluate the dermal tolerance of skin creams containing 1% and 2% 1-[(2-fluorophenyl)(4-fluorophenyl)phenylmethyl]-1H-imidazole (flutrimazole, UR-4056, CAS 119006-77-8) or only the excipient, versus a commercial skin cream containing 1% clotrimazole. The study was carried out using the patch-test procedure performed in three stages: 1. single application in the back skin; 2. induction period (usage test) using three skin areas on the volar side of the forearm of each subject, where skin cream samples were applied once a day for a period of three weeks; and 3. after a wash-out period of two weeks, challenge applications in the back and forearm skin. The systemic tolerance of the formulations was also tested. There was no evidence of allergic sensitization after the application of flutrimazole creams, or their excipients, with signs of mild and doubtful skin reactions being observed in few subjects with all formulations. Furthermore, no systemic side effects after topical administration were detected throughout the study.

Administration, Topical↗
PubMed1992

Pharmacokinetic profile of [14C]flutrimazole following single topical application in normal and scarified skin of healthy volunteers.

14C-labelled 1-[(2-fluorophenyl)(4-fluorophenyl)phenylmethyl]-1H- imidazole (flutrimazole, UR-4056, CAS 119006-77-8) was administered topically (dermally) in three male volunteers to normal skin and scarified skin, respectively. Blood, urine and faeces were collected and radioassayed by liquid scintillation counting techniques. After topical application to healthy skin area, less than 1% of flutrimazole was absorbed percutaneously from a 1% cream and the amount absorbed was excreted with the urine. Following administration of the drug to scarified skin, the proportions absorbed were very similar to those measured after application to normal skin. About 0.5% of the administered dose is recovered in urine. The absorbed amount of drug leads to very low concentrations in the circulation, lower than a few ng/ml.

Administration, Topical↗
PubMed1991

Habituation and inhibitory avoidance training alter brain regional levels of benzodiazepine-like molecules and are affected by intracerebral flumazenil microinjection.

The effects of habituation and inhibitory avoidance training on the rat brain regional levels of benzodiazepine (BZD)-like molecules and on central type BZD binding sites were examined. BZD-like immunoreactivity was decreased by 26-50% in the amygdala, cerebral cortex and septum of rats sacrificed immediately after stepping-down from the platform of an inhibitory avoidance apparatus (non-trained group) as compared to naive controls. Rats submitted to a second step-down session 20 h later (habituated group) have significantly lower BZD-like immunoreactivity in the septum (-60%) as compared to non-trained animals. Rats exposed to an inhibitory avoidance training, i.e. stepping-down and receiving a footshock (trained group), showed a significant reduction in the content of BZD-like molecules in cerebral cortex (-44%), amygdala (-68%), septum (-80%) and hippocampus (-82%) as compared to non-trained rats. In addition, the density of central type BZD binding sites was slightly increased in the hippocampus and septum of trained rats. No changes were observed in the apparent dissociation constant. No changes were observed in parallel measurements of [3H]-L-quinuclidinyl benzylate binding constants at cholinergic muscarinic binding sites. The immediate posttraining intrahippocampal bilateral injection of the central type BZD receptor antagonist flumazenil (10 nmol/hippocampus), enhanced the retention of habituation but not when injected in the amygdala or septum. In contrast, retention of the inhibitory avoidance task was significantly increased by flumazenil administered bilaterally into any of the 3 brain structures.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1991

Memory facilitation by post-training intraperitoneal, intracerebroventricular and intra-amygdala injection of Ro 5-4864.

Post-training i.p. (2.0 or 5.0 mg/kg), i.c.v. (2.5 micrograms/rat), or intra-amygdala (1.6-40 ng/amygdala) administration of Ro 5-4864 causes memory facilitation of step-down inhibitory avoidance in rats. The effect is expressed as an increased latency to step down in a retention test carried out 24 h after training. Ro 5-4864 is a blocker of the Cl(-)-channel associated with GABAA receptors, at a site sensitive to the antagonist, PK11195, and different from that sensitive to picrotoxin. PK11195, given i.c.v. (2.5 micrograms/rat) or into the amygdala (8 ng/amygdala), antagonized the effect of Ro 5-4864. Intra-amygdala picrotoxin administration (80 ng/amygdala) also caused retrograde memory facilitation, but its effect was not antagonized by PK11195. At a higher dose (40 ng/amygdala), PK11195 had an amnestic effect of its own, which suggests that it might be acting against an endogenous ligand of receptor to Ro 5-4864 in the Cl(-)-channel. These findings support the hypothesis that there is a GABAA mechanism in the amygdala normally involved in the modulation of the post-training memory processing of aversive learnings.

Amygdala↗
PubMed1991

Changes in gentamicin pharmacokinetic profiles induced by mechanical ventilation.

The influence of controlled mechanical ventilation (CMV) on the pharmacokinetic profile of gentamicin has been examined in 23 patients after elective open heart surgery. A parallel design was adopted in two groups of patients; 13 patients requiring CMV for at least 32 h after surgery, all of whom were able to breath spontaneously (SB) after 72 h (study group), and 10 patients who required CMV for only a brief period and who showed SB at 32 h postsurgery. Haemodynamic parameters remained stable throughout the study. Apparent volume of distribution (VZ), half-life (t1/2), total clearance (CL), peak (Cmax") and trough (Cmin") plasma levels at steady-state for target levels (6-8 microgram/ml), were measured. In the study group significant differences between CMV and SB conditions were found in VZ (mean 0.36 and 0.25 l/kg). t1/2 (mean 3.63 and 2.90 h) and Cmax" (mean 4.30 and 5.53 microgram/ml) while Cmin" (mean 1.06 microgram.ml-1 and 0.92 microgram.ml-1) did not change significantly. In contrast, the pharmacokinetics in the control group showed no differences. It appears that CMV leads to an increase in gentamicin Vz which accounts for the fall in Cmax" below the therapeutic dose range (less than 5 microgram/ml) recommended for gentamicin. It seems advisable to use a large dose of gentamicin in patients receiving CMV, even before the level is assessed.

Adult↗
PubMed1991

The effect of flumazenil on acquisition, retention, and retrieval of spatial information.

The effect of flumazenil, a benzodiazepine-receptor antagonist, was evaluated in a spatial-reference memory procedure in a water maze. Flumazenil (1.0, 3.0, and 10.0 mg/kg, ip) did not modify acquisition of spatial information. Retention was similar between control and experimental rats 24 h after the training phase, as all groups showed bias to the target quadrant in a free swim trial. However, 10 days later, only flumazenil-injected rats (3.0 mg/kg) showed bias to the target quadrant. Flumazenil did not affect retrieval of spatial information in a group of well-trained rats. These results suggest that a benzodiazepine-receptor mediated endogenous mechanism is activated during learning of spatial tasks and that its blockade facilitates retention of spatial information.

Animals↗
PubMed1991

GABAA receptor modulation of memory: the role of endogenous benzodiazepines.

GABAA receptors are known to downregulate memory consolidation processes: picrotoxin and bicuculline enhance memory, and benzodiazepines and muscimol depress it. The discovery of naturally occurring benzodiazepines in the brain prompted a recent investigation of whether these compounds could act as physiological regulators of the GABAA receptors involved in memory modulation. Different forms of learning cause a rapid reduction of benzodiazepine-like immunoreactivity in septum, amygdala and hippocampus; microinjection of the benzodiazepine antagonist flumazenil into these regions, at the time that consolidation is taking place, enhances memory. Ivan Izquierdo and Jorge Medina suggest that these and other findings indicate that benzodiazepines released in the septum, amygdala and hippocampus do indeed physiologically downregulate memory storage processes; moreover, benzodiazepine release could be modulated by the anxiety and/or stress associated with each type of learning.

Animals↗
PubMed1991

Benzodiazepine receptor ligand influences on learning: an endogenous modulatory mechanism mediated by benzodiazepines possibly of alimentary origin.

In rats, pre- but not post-training ip administration of either flumazenil, a central benzodiazepine (BZD) receptor antagonist, or of n-butyl-B-carboline-carboxylate (BCCB), an inverse agonist, enhanced retention of inhibitory avoidance learning. Flumazenil blocked the enhancing effect of BCCB, and the inhibitory effect of the BZD agonists clonazepam and diazepam also given pre-training. Post-training administration of these drugs had no effect. The peripheral BZD receptor agonist/chloride channel blocker Ro5-4864 had no effect on the inhibitory avoidance task when given ip prior to training, but it caused enhancement when given immediately post-training either ip or icv. This effect was blocked by PK11195, a competitive antagonist of Ro5-4864. These results suggest that there is an endogenous mechanism mediated by BZD agonists, which is sensitive to inverse agonists and that normally down-regulates the formation of memories through a mechanism involving GABA-A receptors and the corresponding chloride channels. The most likely agonists for the endogenous mechanism suggested are the diazepam-like BZDs found in brain whose origin is possibly alimentary. Levels of these BZDs in the cortex were found to sharply decrease after inhibitory avoidance training or mere exposure to the training apparatus.

Animals↗