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Biomedical subjects

M Sarter

Publications and source records attributed to M Sarter.

At least 109 records · Page 6Linked to original sources
PubMed1990

Elevations of local cerebral glucose utilization by the beta-carboline ZK 93426.

The effects of the benzodiazepine receptor antagonist ZR 93,426, a beta-carboline, on local cerebral glucose utilization (LCGU) was examined by using quantitative in-vivo autoradiography with [3H]2-deoxyglucose. ZK 93,426 was found to increase local cerebral glucose utilization primarily in prefrontal, cingulate, olfactory and visual cortical regions, as well as the claustrum, nucleus accumbens, anteroventral thalamus, substantia nigra, and dorsal raphe nucleus. This pattern of changes of LCGU produced by ZK 93,426 seems to represent neither a mirror image of the metabolic effects of benzodiazepine receptor agonists nor the pattern of effects on LCGU induced by the partial inverse agonist beta-carboline FG 7142. The unique pattern of regional changes of glucose utilization induced by ZK 93,426 are discussed with respect to recent findings on its promnestic and antiamnestic properties in animals and humans. It is concluded that ZK 93,426 does not seem to fit into the conventional classification scheme of benzodiazepine receptor ligands; thus, the term 'selective inverse agonist' is proposed.

Animals↗
PubMed1990

Activating the damaged basal forebrain cholinergic system: tonic stimulation versus signal amplification.

The hypothesis that the cognitive decline in senile dementia is related to the loss of cortical cholinergic afferent projections predicts that pharmacological manipulations of the remaining cholinergic neurons will have therapeutic effects. However, treatment with cholinesterase inhibitors or muscarinic agonists has been, for the most part, largely unproductive. These drugs seem to disrupt the normal patterning of cholinergic transmission and thus may block proper signal processing. An alternative pharmacological strategy which focuses on the amplification of presynaptic activity without disrupting the normal patterning of cholinergic transmission appears to be more promising. Such a strategy may make use of the normal GABAergic innervation of basal forebrain cholinergic neurons in general, and in particular of the inhibitory hyperinnervation of remaining cholinergic neurons which may develop under pathological conditions. Disinhibition of the GABAergic control of cholinergic activity is assumed to intensify presynaptic cortical cholinergic activity and to enhance cognitive processing. Although the extent to which compounds such as the benzodiazepine receptor antagonist beta-carboline ZK 93,426 act via the basal forebrain GABA-cholinergic link is not yet clear, the available data suggest that the beneficial behavioral effects of this compound established in animals and humans are based on indirect cholinomimetic mechanisms. It is proposed that an activation of residual basal forebrain cholinergic neurons can be achieved most physiologically via inhibitory modulation of afferent GABAergic transmission. This modulation may have a therapeutic value in treating behavioral syndromes associated with cortical cholinergic denervation.

Animals↗
PubMed1989

Autoradiographic mapping of a selective cyclic adenosine monophosphate phosphodiesterase in rat brain with the antidepressant [3H]rolipram.

Rolipram is a clinically effective antidepressant with selective cAMP phosphodiesterase (PDE) inhibiting properties. (+/-)-[3H]Rolipram binds with high affinity (Kd = 2.52 +/- 0.47 nM) to sections of rat brain (Hill number = 0.90 +/- 0.05). Binding is stereospecific. Association of (+/-) [3H]rolipram to sections is rapid (47% of specific binding in the first minute, kobs = 0.52 min-1). Dissociation of (+/-)-[3H]rolipram exhibits non first order kinetics (3 component model; t1/2 = 2.5 min, 50 min and 6 h, respectively). A number of PDE inhibitors reduce (+/-)-[3H]rolipram binding to the level of nonspecific binding ((-)-rolipram, IC50 = 0.9 nM; (+/-)-rolipram, IC50 = 1.5 nM; Ro 20-1724, IC50 = 11 nM; ICI 63.197, IC50 = 35 nM; medazepam, IC50 = 240 nM; diazepam, IC50 = 1200 nM; IBMX, IC50 = 3800 nM). In vitro autoradiography reveals high binding site densities in the cerebellum, olfactory bulb, lateral septal nucleus, frontal cortex, subiculum and CA1 of hippocampus. Most of the labeled structures are part of the limbic system. In vivo autoradiography of (+/-)-[3H]rolipram binding shows much more nonspecific binding than in vitro, nevertheless the distribution pattern of (+/-)-[3H]rolipram binding sites is similar. A comparison of the distribution pattern of (+/-)-[3H]rolipram binding sites with that of an antidepressant (monoamine oxidase inhibitor, monoamine uptake inhibitor) reveals no overlap. Limited, though significant correlations exist with the distribution of beta 1-adrenergic, adenosine1 and glutamate/quisqualate receptors as well as protein kinase C, but not with beta 2-adrenergic receptors and forskolin binding sites.

3',5'-Cyclic-AMP Phosphodiesterases↗
PubMed1989

Spontaneous exploration of a 6-arm radial tunnel maze by basal forebrain lesioned rats: effects of the benzodiazepine receptor antagonist beta-carboline ZK 93 426.

Nine days following ibotenic acid induced basal forebrain lesions or a sham-operation, rats were allowed to explore an automated six-arm radial tunnel maze. From each session, several measures of locomotor and exploratory activity were registered. Lesioned and sham-operated animals were treated with either the benzodiazepine receptor antagonist beta-carboline ZK 93 426 (5 mg/kg; IP) or vehicle (Cremofor EL 10% in saline; IP; n = 10 for each group). Treatment was carried out 30 min before each session during acquisition (seven sessions) and reversals of the maze configuration (seven sessions). Eight days following the 14th session, the animals were retested without any further drug treatment. The main results suggest that the lesion resulted in locomotor hyperactivity, an increase in the number of blind arm entries, and of choice stereotypy. Treatment with ZK 93 426 attenuated the lesion-induced alterations of locomotor and exploratory activities. During the retest, the lesioned, previously vehicle-treated rats revisited arms which they had already explored during this session more frequently than the lesioned, previously ZK-treated rats; the latter group did not differ from the sham-lesioned controls. It is concluded that basal forebrain lesioned animals explored the tunnel maze less efficiently than sham-lesioned controls and that the lesioned animals benefited from the treatment with ZK 93 426. Although the specificity of the lesion in terms of destruction of cholinergic neurons remains unsettled, and although the psychological significances of the behavioral measures obtained from the tunnel maze are not yet fully understood, these results suggest that antagonists or partial inverse agonists at the benzodiazepine receptor may be able to normalize basal forebrain lesion-induced behavioral alterations.

Animals↗
PubMed1989

2-[3H]deoxyglucose uptake patterns in rats exploring a six-arm radial tunnel maze: differences between experienced and nonexperienced rats.

In an automated tunnel maze, rats were allowed to explore either a 6-arm radial configuration ("experienced") or an alley maze configuration ("nonexperienced"). The activity of control rats was restricted to the center of the maze. After 8 daily sessions and a 5-day break, catheters were implanted into the jugular vein. Two days later, 2-deoxyglucose was administered before both experimental groups were exposed to the 6-arm radial configuration. Nonexperienced rats differed from experienced rats in terms of efficiency of exploration, but not in locomotor activity. Compared with experienced animals, nonexperienced rats showed an increase in 2-deoxyglucose uptake in prefrontal and cingulate cortices and in mediodorsal and laterodorsal thalamic nuclei. Exposure of rats to familiar and unfamiliar maze patterns resulted in different patterns of brain metabolic activity.

Animals↗
PubMed1988

Bidirectional nature of benzodiazepine receptor ligands extends to effects on vigilance.

The classification of benzodiazepine receptor ligands into agonists, antagonists and inverse agonists is based on biochemical, electrophysiological and behavioural evidence. Agonists potentiate the effects of gamma-aminobutyric acid (GABA) and exhibit anxiolytic, anticonvulsant, hypnotic, amnesic and muscle-relaxant properties; inverse agonists show mirror-image effects in that they may be convulsant and anxiogenic and may increase muscle tone. Antagonists antagonise the effects of both agonists and inverse agonists. Some of the most interesting ligands, however, are those substances with actions intermediate between either those of the agonists and the antagonists, or between those of the antagonists and the inverse agonists. These partial agonists and partial inverse agonists possess only some of the properties of the agonists and inverse agonists, respectively. The present experiments show that the agonist and inverse agonist properties of benzodiazepine receptor ligands can also be revealed in an animal continuous attention task in which rats were required to detect a brief signal during which operation of a lever was rewarded by food. Benzodiazepines and a beta-carboline benzodiazepine receptor agonist, ZK 93423, disrupted performance of this task, as did the antimuscarinic substance, scopolamine. Another beta-carboline, ZK 91296, which has anxiolytic and anticonvulsant properties like benzodiazepines, did not affect performance of the continuous attention task, demonstrating a separation of anxiolytic and sedative properties of such substances. A partial inverse agonist beta-carboline, FG 7142, was able to antagonise the disruptive effects of scopolamine on this task, as was, to a smaller extent, the antagonist ZK 93426. These results are discussed in terms of vigilance-enhancing properties of the inverse agonist beta-carbolines, and the possibility that such vigilance-enhancing effects might contribute to improvement of performance in learning tasks.

Animals↗
PubMed1988

Beta-carbolines as tools in memory research: animal data and speculations.

Benzodiazepines induce in animals, as in humans, almost exclusively anterograde amnesia. The mechanism of this effect is still unsettled; however, explanations like state dependency which may be based on sedative or emotional properties of benzodiazepines are usually favoured in contrast to an interpretation in terms of true amnesia. It is proposed that by the use of beta-carbolines with agonist, partial agonist, antagonist and partial inverse agonist properties, the nature of the amnesia induced by benzodiazepine receptor agonists may be characterised. From a series of experiments it is concluded that the major reason for benzodiazepine-induced amnesia might be an impaired ability to filter interfering stimuli; that is, an attentional deficit. Since the antagonist beta-carbolines may play a key role in providing evidence as to the GABAergic involvement in cognitive processes, the pharmacological profile of ZK 93426 is presented. The results of the interaction of beta-carbolines with scopolamine will provide a basis on which to speculate on the GABAergic control of cholinergic neurotransmission and its therapeutic implications.

Animals↗
PubMed1988

Attenuation of scopolamine-induced impairment of spontaneous alteration behaviour by antagonist but not inverse agonist and agonist beta-carbolines.

Mice were tested in a simple automated Y-maze. Total number of arm entries and alternation behaviour were measured. The latter is thought to reflect working memory capacity at a rudimentary level. During an 8 min session, vehicle-treated mice performed 32.4 +/- 7.4 arm entries, 51.0 +/- 12.4% of which were organized in alternations (triplets). The two variables showed a negative correlation. Scopolamine (1.0 mg/kg) significantly enhanced activity, reduced alternation behaviour and diminished the correlation between the two variables. The effects of benzodiazepine receptor inverse agonist, antagonist and agonist beta-carbolines on this spontaneous behaviour and on the effects of scopolamine were examined. The effects of inverse agonists and agonists on locomotor activity were complex in interaction with both vehicle and scopolamine. The scopolamine-induced reduction of alternation behaviour was significantly reversed by the antagonist ZK 93426 but not by inverse agonists; furthermore, partial agonists and agonists showed no effects. It is hypothesized that the interaction of antagonist beta-carbolines with scopolamine is based on a direct GABA-ergic control of cholinergic neurotransmission, and suggests an ability of antagonist beta-carbolines to antagonize amnestic properties of scopolamine.

Animals↗
PubMed1988

High density of benzodiazepine binding sites in the substantia innominata of the rat.

In order to study the neuronal basis of the pharmacological interactions between benzodiazepine receptor ligands and cortical cholinergic turnover, we examined the regional distribution of specific benzodiazepine binding sites using in vitro autoradiography. In the basal forebrain, the substantia innominata contained a high density of [3H]lormetazepam (LMZ) binding sites (Bmax = 277 fmol/mg tissue; Kd = 0.55 nM). The label could be displaced by diazepam (IC50 = 100 nM), the benzodiazepine receptor antagonist beta-carboline ZK 93426 (45 nM) and the partial inverse agonist beta-carboline FG 7142 (540 nM). It is hypothesized that the amnesic effects of benzodiazepine receptor agonists are exerted through benzodiazepine receptors which are situated on cholinergic neurons in the substantia innominata and are involved in a tonic inhibition of cortical acetylcholine release. The benzodiazepine receptor antagonist ZK 93426 may exert its nootropic effects via benzodiazepine receptors in the substantia innominata and, consequently, by disinhibiting cortical acetylcholine release.

Animals↗
PubMed1987

Bidirectional effects of beta-carbolines and benzodiazepines on cognitive processes.

Experiments with benzodiazepine receptor ligands in two paradigms involving cognitive processing were performed in order to test whether the concept of bidirectional effects of benzodiazepine receptor ligands could also be applied to cognitive functions. Benzodiazepine receptor agonists like chlordiazepoxide, lorazepam, ZK 93423 and ZK 91296 induced amnesia in a passive avoidance paradigm. Mice treated with the benzodiazepine receptor antagonist, ZK 93426, reached a learning criterion after fewer foot-shocks than saline treated mice both in naive animals and in scopolamine pre-treated animals. Furthermore, ZK 93246, attenuated the amnesic effect of corneal electroshock. The inverse agonists FG 7142 and DMCM decreased the detrimental effect of scopolamine on retrieval. In a signal detection paradigm, chlordiazepoxide impaired signal detection. In aged rats ZK 93426, ZK 90886 and FG 7142 had no effect on signal detection but ZK 93426 and FG 7142 attenuated the impairment of signal detection induced by scopolamine. These effects of benzodiazepine receptor ligands may reflect changes in arousal/vigilance, suggesting that BZ inverse agonists may have useful properties in enhancing vigilance.

Animals↗
PubMed1987

Measurement of cognitive abilities in senescent animals.

The behavioral paradigms used in investigating for differences in the cognitive abilities of young and aged animals are critically reviewed with regard to their power to discriminate between young and aged animals' mental capacity. Irrespective of the kind of task, geronto-behavioral research especially is afflicted with difficulties in controlling motivational and emotional influences on cognitive processes. It is hypothesized-somewhat provocatively-that most of the findings indicating an age-related decline are better attributed to the altered motivational status and/or emotional reactiveness than to impaired cognitive processes of senescent animals. Of the common tasks used in this field, it is concluded that complex mazes and different delayed response tasks seem to represent appropriate paradigms in order to study changed capacities in short- and long-term memory (working- and reference-memory, respectively).

Aging↗
PubMed1987

Animal models of brain ageing and dementia.

Six animal models of human brain ageing or of age-related diseases, especially Alzheimer's disease, are evaluated. Special emphasis is laid on comparing the neuropathological symptoms found in aged human brains or in Alzheimer patients, with the neuronal symptoms induced experimentally by the different treatments described here. For each model, the experimental methods for induction of the neuropathological symptoms (lipofuscin accumulation, senile plaques, neurofibrillary degeneration, etc.) and for their identification are discussed. In addition, the behavioral significance of each animal model is evaluated in the content of its meaning for cognitive alterations in senescence or in dementia.

Aging↗
PubMed1986

Some considerations of different modes of action of nootropic drugs.

Four possible types of nootropic drugs are classified theoretically according to their possible effects on cognitive functions. Among the factors usually varied in psychopharmacological designs, the significance of the time of application of the drug is stressed. Considering the relations between the time of application of nootropic drugs within standardized experimental plans and their effects on cognitive processes, ideal time of application-response curves for each of these types of nootropic compounds are proposed. These curves may represent experimental tools in investigating the mode of action of nootropic drugs. Finally, some experimental results are presented which are relevant to this approach. Overall, however, the rationale of these theoretical considerations remains largely unproven because of the lack of studies to date designed to evaluate the mechanisms of drug action by varying the time of application of a nootropic compound.

Adrenal Cortex Hormones↗
PubMed1986

Denervation-induced collateral sprouting: no case for tracing methods.

Sprouting of axonal collaterals is assumed to represent a major feature of the regenerative capacity of the CNS. Following the denervation of a brain region, synaptic contact sites become free and are replaced by sprouted collaterals of intact afferents of this area. During the last three years, numerous studies have been published which have used anatomical tracing methods to demonstrate this morphological consequence of lesions. This paper criticizes the use of tracing methods in this research field because of the striking problems in quantifying the altered connectivity of a denervated structure. This critique is illustrated by summarizing the studies on the lesion-induced morphological effects within the nigro-striatal system which has become a paradigmatic neuronal circuit for the study of neuronal and functional reorganization. It is concluded that anatomical tracing methods seem to be inappropriate in studying denervation-induced collateral sprouting.

Animals↗
PubMed1985

Convergence of intra- and interhemispheric cortical afferents: lack of collateralization and evidence for a subrhinal cell group projecting heterotopically.

The distribution of corticocortical projecting neurons in the rat's brain was investigated with fluorescent dyes and the retrograde transport of horseradish peroxidase. Although the fluorescent techniques especially revealed the existence of a considerable number of neurons interconnecting the limbic areas (sub- and perirhinal cortex, prefrontal, cingulate, and retrosplenial cortex) both intra- and interhemispherically, only a negligibly small number of neurons with collateralized axons could be detected. In the rat's anterior dorsolateral cortex an area is described whose neurons are organized in a columnlike fashion and project intra- and interhemispherically to the limbic areas examined. The density of efferent connections differed between areas, with an especially high density found in a small region of the subrhinal cortex. Injections of horseradish peroxidase into different regions of the cingulate and retrosplenial cortex confirmed the existence of widespread heterotopic interhemispheric connections originating from this defined subrhinal area, though the number of retrogradely labeled cells remained consistently smaller than that obtained following the injection of fluorescent dyes. Among the regions studied with horseradish peroxidase injections, those into the retrosplenial cortex showed the highest density of labeled cells within this subrhinal area. A more detailed examination of the subrhinal region containing the densely labeled neurons (projecting to the contralateral hemisphere) made use of Nissl stains and revealed a morphologically separable area which was characterized by medium-sized, dark-staining neurons whose long axons were oriented mediolaterally. The region includes portions of the insular-perirhinal, entorhinal, and piriform cortex. It is suggested that the corticocortical projections are basically noncollateralized in the rat. However, there apparently is a dense interhemispheric interconnectivity between the limbic areas. Functional evidence for the defined subrhinal area suggests a prominent role of its neurons in cognitive information processing. The present evidence for considerable interhemispheric cortical projections may provide a new impetus for studying the intercommunication of the two sides of the brain with both anatomical and behavioral methods.

Animals↗