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M Sarter

Publications and source records attributed to M Sarter.

At least 19 recordsLinked to original sources
PubMed1995

Dissociation between the attentional effects of infusions of a benzodiazepine receptor agonist and an inverse agonist into the basal forebrain.

The effects of infusions of the benzodiazepine receptor (BZR) full agonist chlordiazepoxide (CDP) or the full inverse agonist beta-CCM into the basal forebrain on behavioral vigilance were tested. Vigilance was measured by using a previously characterized task that requires the animals to discriminate between visual signals of variable length and non-signal events. Measures of performance included hits, misses, correct rejections, false alarms, side bias, and errors of omission. Following the infusion of saline (0.5 microliters/hemisphere), the relative number of hits varied with signal length. In response to shorter signals, the number of hits decreased over time, indicating a vigilance decrement. Infusions of CDP (20, 40 micrograms/hemisphere) initially decreased the relative number of hits in response to shorter signals and, later in the course of the test sessions, to longer signals as well. CDP did not affect the relative number of correct rejections. In contrast, infusions of the inverse agonist beta-CCM (1.5, 3.0 micrograms/hemisphere) did not affect the relative number of hits but decreased the relative number of correct rejections (i.e., increased the number of false alarms). These data suggest that the basal forebrain mediates the attentional effects of BZR ligands. As systemic or intrabasalis administration of BZR agonists and inverse agonists was previously demonstrated to decrease and augment, respectively, activated cortical acetylcholine (ACh) efflux, their effects on behavioral vigilance are hypothesized to be mediated via their effects on cortical ACh.

Animals↗
PubMed1992

Age-dependent modulation of in vivo cortical acetylcholine release by benzodiazepine receptor ligands.

In vivo microdialysis was utilized to determine the effects of benzodiazepine receptor (BZR) ligands on cortical acetylcholine (ACh) release in awake young and aged rats. There were no significant differences in baseline cortical ACh release as a function of age. While administration of the BZR selective inverse agonist ZK 93 426 increased ACh release in both groups of animals, the aged rats exhibited a greater stimulation. Unexpectedly, under the present testing conditions, the BZR agonist chlordiazepoxide (CDP) had no systematic effect on ACh release in either group. The presence or absence of these drug effects or drug-age interactions was not secondary to the impact of these compounds on behavioral activity. Cortical ACh release could also be stimulated by turning off the lights in the observation room or by the systemic administration of scopolamine. Aged rats were at least as able as their younger counterparts to respond to these manipulations with increased release. These results suggest that basal and stimulated release of cortical ACh is not impaired at the ages studied. Moreover, selective inverse BZR agonists may be a potent way of trans-synaptically stimulating cortical cholinergic transmission.

Acetylcholine↗
PubMed1992

Failure of a chlordiazepoxide to reproduce the behavioral effects of muscimol administered into the basal forebrain.

Bilateral infusion of the GABAA-receptor agonist muscimol into the basal forebrain was previously found to impair visual conditional discrimination performance in rats. In order to examine whether the GABAergic input into the basal forebrain is active during performance of this task, the benzodiazepine receptor agonist chlordiazepoxide (15, 25, 40 micrograms/0.5 microliters/hemisphere) was bilaterally infused. Surprisingly, chlordiazepoxide did not affect performance. The impact of this result for the understanding of basal forebrain GABAergic functions is discussed.

Animals↗
PubMed1992

Behavioral screening for cognition enhancers: from indiscriminate to valid testing: Part I.

Preclinical efforts to detect and characterize potential cognition enhancers appear to have been dominated by a strategy of demonstrating a wide variety of apparently beneficial behavioral effects with little attention given to the specific psychological mechanisms underlying behavioral enhancement. In particular, the question of whether or not behavioral facilitation is based on relevant mnemonic mechanisms and is independent of the stimulus properties and/or the motivational and attentional components of a task is not often considered. As a result, an overwhelming number of compounds have failed to produce the clinical effects predicted for them on the basis of preclinical research. The available data suggest that a more successful approach requires deductive research strategies rather than the indiscriminate accumulation of apparently beneficial effects in a variety of behavioral tasks and animal models. The first step towards such an approach is a systematic and rigorous evaluation of the different aspects of validity for the models most frequently used in preclinical research. It is concluded that a combination of good construct validity and good face validity represents a necessary condition for screening tests with predictive validity, and that the most popular paradigms fail to fulfil these criteria. Future screening programs for cognition enhancers will probably be characterized by a depreciation of "fast and dirty tests" in favor of approaches focussing on the validity of the effects of potential cognition enhancers.

Animals↗
PubMed1992

Behavioral microanalysis of spatial delayed alternation performance: rehearsal through overt behavior, and effects of scopolamine and chlordiazepoxide.

Rats were trained in an operant spatial delayed alternation task utilizing retention intervals from 2 to 32 s. In addition to response accuracy, operations of the levers during the retention intervals were recorded and analyzed. Animals were tested following the administration of the muscarinic antagonists scopolamine hydrobromide and methylbromide, and the benzodiazepine receptor agonist chlordiazepoxide. In vehicle-treated animals, the relative number of correct responses and correct rehearsal operations (operation of the forthcoming correct lever during retention intervals) varied with the length of the retention intervals, and these measures were correlated. The response rate for rehearsal operations increased with the length of the retention intervals. It is speculated that the delay-dependent increase in response rate reflects an effect of delayed reward that was also associated with a delay-dependent increase in the tendency to alternate between levers. The effects of delay on the accuracy of rehearsal operations may have contributed to the delay-dependent correct responding. Scopolamine hydrobromide (0.01, 0.03, 0.1, 0.3 mg/kg) and methylbromide (0.1, 0.3 mg/kg) impaired correct responding, but did not seem to interfere with the relative number of correct rehearsal operations. As only the presentation of the panel light indicated trial onset, it is speculated that the cholinergic receptor blockade resulted in an increase in the probability of a repositioning response that was triggered by light onset. Chlordiazepoxide (1, 3, 5, 10 mg/kg) did not affect behavioral performance. These results suggest that in tasks that allow the development of rehearsal operations, delay-dependent response accuracy does not represent a sufficient condition for conclusions on task demands on memory.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1992

Dissociation between the effects of benzodiazepine receptor agonists on behavioral vigilance and responsitivity.

The effects of benzodiazepine receptor (BZR) full agonists chlordiazepoxide and midazolam, and the partial agonist beta-carboline ZK 91,296 on the rat's performance in a simple reaction time paradigm were examined. This task required the animals to respond to a rarely and unpredictably occurring brief (50 ms) visual stimulus. Non-parametric measures of signal sensitivity and response bias derived from signal-detection theory were used as a basis for the dissociation between the effects of these drugs on attentional abilities and general responsivity. The dose-dependent effects of midazolam (0.1-3.13 mg/kg) on signal sensitivity and general responsivity occurred in parallel. In contrast, the effects of chlordiazepoxide (1.56-12.5 mg/kg) on signal sensitivity were largely independent from effects on response bias. The partial agonist ZK 91,296 (0.39-25 mg/kg) in general had little effect on performance. The effects of the highest doses of chlordiazepoxide and midazolam were reversed by the co-administration of the BZR antagonist Ro15-1788 (15 mg/kg). Additionally, extension of the stimulus presentation time to 500 ms decreased the magnitude of the effect of chlordiazepoxide on signal sensitivity. These results support the hypothesis that BZR agonist-induced disruption of attentional abilities is not necessarily confounded by effects on general responsivity or sedation, and thus may represent a discrete pharmacological property of BZR-agonists.

Animals↗
PubMed1992

Attenuation of muscarinic receptor blockade-induced impairment of spatial delayed alternation performance by the triazole MDL 26,479.

The interactions between the effects of MDL 26,479 (0.1, 0.39, 1.56, 6.25 mg/kg; IP) and the muscarinic antagonist scopolamine (0.03, 0.1 mg/kg; IP) on the performance of rats in a delayed alternation task (retention intervals: 2, 4, 8, 16, 32 s) were examined. Scopolamine dose-dependently reduced the relative number of correct responses and interacted with the effects of the length of retention intervals. MDL 26,479 did not affect correct responding but attenuated the behavioral impairments produced by scopolamine. Although this task did not explicitly exclude the possibility that the animals acquired mediational response strategies, and although the effects of scopolamine appeared to interfere with the execution of these strategies, to a major extent, the attenuative effects of MDL 26,479 were not related to its effects on mediational strategies. Thus, it is concluded that administration of MDL 26,479 mainly resulted in a re-establishment of the animals' ability to memorize and/or to recall the information required to exert correct responses.

Animals↗
PubMed1991

GABAergic control of basal forebrain cholinergic neurons and memory.

The involvement of the GABAergic innervation of basal forebrain neurons in the rats' conditional visual discrimination performance was examined. Performance in such a task is based on the subjects's ability to retrieve information about response rules, and previous experiments have demonstrated that basal forebrain lesions interfere with this ability. Following the acquisition of the task, chronic guide cannulae were stereotaxically implanted into the substantia innominata of both hemispheres, and the animals were retrained. Administration of the GABAA-agonist muscimol into the substantia innominata (0, 25, 50 ng/0.5 microliters/hemisphere) dose-dependently decreased the number of correct responses, increased the number of errors of omission, increased response latency, but did not affect side bias. Systemic co-administration of the cholinesterase inhibitor physostigmine (0, 0.1, 0.2 mg/kg; i.p.) exclusively interacted with the effects of muscimol on correct responding. Specifically, physostigmine dose-dependently intensified and attenuated the muscimol-induced reduction in correct responding. Although it cannot be excluded that alternative neuronal mechanisms were involved in the mediation of the effects of muscimol and their interaction with physostigmine, these findings support previous evidence indicating that the activity of basal forebrain cholinergic neurons is controlled by a GABAergic input, and that this neuronal link is involved in mnemonic processing.

Animals↗
PubMed1991

Taking stock of cognition enhancers.

An increasing number of structurally heterogeneous compounds, which may act via very different categories of neuronal mechanisms, have been proposed to facilitate attentional abilities and acquisition, storage and retrieval of information, and/or to attenuate the impairments of such cognitive functions associated with age or dementia. In this article, Martin Sarter briefly reviews the data on putative cognition enhancers and examines the possible bases for the discrepancy between preclinical predictions of efficacy and the fact that unequivocal demonstration of drug-induced cognition enhancement in humans has only rarely been reported. Previous preclinical research strategies appear to have focused on the demonstration of drug effects in a wide variety of tests of uncertain validity, rather than on determination of the specific psychological and neurobiological processes affected by putative cognition enhancers. Some criteria are proposed for evaluating the validity of preclinical tests for cognition enhancers.

Animals↗
PubMed1991

Dissociative effects of ibotenic and quisqualic acid-induced basal forebrain lesions on cortical acetylcholinesterase-positive fiber density and cytochrome oxidase activity.

The behavioral effects of excitatory amino acid-induced basal forebrain lesions have been conventionally attributed to the loss of cholinergic neurons innervating cortical areas. However, comparative examinations of quisqualic acid- and ibotenic acid-induced lesions to this region have suggested that the behavioral consequences of ibotenate-induced lesions may not be exclusively related to the loss of cholinergic neurons [Etherington R. et al. (1987) Neurosci. Res. Commun. 1, 135-143; Robbins T. W. et al. (1989) Neuroscience 28, 337-352]. These findings prompted the present investigation of the effects of quisqualic acid- and ibotenic acid-induced basal forebrain lesions on cortical cholinergic fiber density and cytochrome oxidase activity. Parallel brain sections from rats with unilateral lesions produced by each toxin were examined for cytochrome oxidase activity and acetylcholinesterase-positive fiber density, at a period of four, eight and 20 days postlesion. Quisqualic acid-induced lesions resulted in a greater loss of cortical acetylcholinesterase-positive fibers than did ibotenic acid-induced lesions, but the latter lesions produced a greater reduction in cytochrome oxidase activity. These results suggest that the loss of cortical cholinergic afferents does not contribute to the cortical metabolic decrease induced by infusions of ibotenic acid into the basal forebrain. Thus, the behavioral and metabolic consequences of ibotenic acid-induced lesions may be due to the destruction of an additional, noncholinergic pathway.

Acetylcholinesterase↗
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↗