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M Sarter

Publications and source records attributed to M Sarter.

At least 91 records · Page 5Linked to original sources
PubMed1995

Effects of chlordiazepoxide and scopolamine, but not aging, on the detection and identification of conditional visual stimuli.

Our previous studies revealed impairments in the ability of aged rats to detect brief, rarely and unpredictably occurring stimuli. The failure of these impairments to interact with the effects of benzodiazepine receptor (BZR) ligands was attributed to low demands on stimulus-related information processing. Thus, in the present experiment, rats of different ages were trained to detect visual stimuli that were flashing at 20 Hz, or were constantly illuminated, for 8, 3, or 5 sec. Additionally, selection of the correct lever to report detection required the processing of propositional rules (e.g., flashing-go left; constant-go right), i.e., the identification of the stimulus. All measures of performance varied with stimulus duration. Subsedative doses of the BZR agonist chlordiazepoxide (CDP; 3.13, 4.69 mg/kg), similar to the effects of the muscarinic antagonist scopolamine (.025, 0.1 mg/kg), impaired response accuracy, increased the number of errors of omission and decreased response latencies. Animals aged 28 months omitted more trials following the administration of CDP than 12-month-old rats. Age did not produce main effects and did not interact with the effects of the drugs on response accuracy. It is speculated that, as stimuli had to be presented for relatively long periods of time (to maintain above chance-level discrimination performance), demands on detection remained too low to replicate previously documented effects of age. The demonstration of interactions between the effects of age and of BZR-ligands appears to depend on combined demands for stimulus detection and identification.

Aging↗
PubMed1994

Cortical cholinergic deafferentation following the intracortical infusion of 192 IgG-saporin: a quantitative histochemical study.

The immunotoxin 192 IgG-saporin has been hypothesized to selectively lesion cholinergic neurons that bear the low-affinity p75 nerve growth factor (NGF) receptor. To evaluate the usefulness of this toxin in studies intended to determine the functions of cholinergic afferents of cortical areas, relatively small concentrations and volumes of the immunotoxin (0.01-0.05 micrograms/0.5-1.0 microliters) were infused into cortical areas of one hemisphere of rats, while the vehicle was infused into homologous areas of the contralateral hemisphere. The effects of these infusions on the density of cortical acetylcholinesterase (AChE)-positive fibers and of normal fibers (as revealed by a reduced silver stain) were quantified. The infusion of the immunotoxin did not produce local gliosis in excess of the gliosis resulting from the infusion of vehicle. When compared with the frontoparietal cortex of the intact hemisphere, the number of cortical AChE-positive fibers was reduced by 36-39% and the density of the silver-stained fibers was decreased by 20-25%. While the loss of AChE-positive fibers and silver-stained fibers correlated significantly in layers V/VI, a linear regression analysis suggested that the magnitude of the loss of AChE-positive fibers was greater than would be predicted on the basis of the residual density of normal fibers. Thus, the data suggest that infusions of 192 IgG-saporin into the cortex did not result in the loss of non-cholinergic afferents. Intracortical infusions of relatively small concentrations and volumes of 192 IgG-saporin appear to provide a useful approach for the examination of the functions of cholinergic inputs to specific cortical regions.

Acetylcholinesterase↗
PubMed1994

Crossmodal divided attention in rats: effects of chlordiazepoxide and scopolamine.

"Divided attention" is a psychological construct that hinges on assumptions about a fixed finite capacity of subjects to simultaneously process multiple sets of information. A model of a crossmodal divided attention task was developed in rats. Initially, rats were trained consecutively in operant auditory and visual conditional discrimination tasks. The final task consisted of two successive blocks of 20 trials per modality (modality certainty), followed by 60 trials comprising a semi-randomized sequence of stimuli of both modalities (auditory or visual) and qualities (flashing/pulsing or constantly turned on; modality uncertainty). In comparison to unimodal blocks of trials, performance in the mixed condition was assumed to reflect the demands on the parallel processing of two sets of stimulus-response rules. While response accuracy remained unchanged, response latencies were generally longer in the bimodal condition. Administration of scopolamine (0.03, 0.06, 0.1 mg/kg) or chlordiazepoxide (1, 3, 5, 8 mg/kg) dose-dependently increased response latencies. The scopolamine-induced increase in response latencies was greater in the mixed condition. Cost-benefit analyses demonstrated that the absolute divided attention costs (in ms) were generally higher for visual than for auditory stimuli. Both drugs produced qualitatively similar effects; however, scopolamine was more potent in increasing the absolute divided attention costs than chlordiazepoxide. These data are discussed in terms of the validity of this animal paradigm, and of hypotheses about the effects of benzodiazepine receptor agonists and muscarinic antagonists on brain information processing capacity.

Acoustic Stimulation↗
PubMed1994

Neuronal mechanisms of the attentional dysfunctions in senile dementia and schizophrenia: two sides of the same coin?

Deficits in early stages of information processing, specifically the inability to "disattend" irrelevant stimuli and to selectively allocate processing resources (i.e., hyperattention), have been associated with the development of psychotic symptoms. Opposite deficits, i.e., the failure to attend and select stimuli, and to divide attention (i.e., hypoattention), represent a major variable in the development of dementia. The hypothesis that hyperattention and hypoattention are mediated via cortical cholinergic hyperactivity and hypoactivity, respectively, is discussed. Several lines of evidence support the role of cholinergic hyperactivity in the development of psychotic symptoms, including the therapeutic effects of anticholinergic drugs in schizophrenic patients, the psychotic effects of chronic exposure to irreversible cholinesterase inhibitors, and the worsening of psychotic symptoms as a result of the treatment with cholinomimetic compounds. The potent impairments of attentional abilities as a result of the administration of muscarinic antagonists in intact subjects, and the attentional effects of cholinomimetic compounds in demented patients are two examples of the evidence that supports the role of cholinergic hypofunction in the cognitive impairments of dementia. A neuronal model of dopamine-GABAergic modulation of cortical acetylcholine is proposed on the basis of evidence indicating that nucleus accumbens dopamine, via a GABAergic pathway to the substantia innominata of the basal forebrain, modulates cortical acetylcholine release. The available evidence confirms several predictions derived from this model, including the dopaminergic regulation of cortical acetylcholine (ACh) release, the bidirectional modulation of this release by benzodiazepine receptor (BZR) agonists and inverse agonists, and the antipsychotic effects of BZR agonists. Bidirectional deviations in the activity of cortical cholinergic inputs are hypothesized to represent a major neuronal substrate of the attentional dysfunctions associated with, or even underlying, the development of psychotic symptoms and dementia.

Attention↗
PubMed1993

Bidirectional modulation of stimulated cortical acetylcholine release by benzodiazepine receptor ligands.

In vivo microdialysis was used to determine the ability of benzodiazepine receptor (BZR) ligands to modulate stimulated cortical acetylcholine (ACh) efflux in awake, freely-moving Fischer-344/BNNia rats. Cortical ACh efflux was reliably enhanced during presentation of a complex stimulus (exposure to darkness coupled with presentation of a small amount of palatable food) in animals entrained with that stimulus. Administration of the BZR selective inverse agonist ZK 93,426 (5.0 mg/kg, i.p.) potentiated the ability of the darkness/food stimulus to enhance efflux, whereas administration of the BZR full agonist, chlordiazepoxide (5.0 mg/kg, i.p.) blocked the enhancement. The interaction of the BZR ligands with the entrained stimulus in affecting cortical ACh efflux was not secondary to effects on motor activity. These results, combined with results from a previous study, suggest that modulation of cortical ACh efflux by BZR ligands is bidirectional and dependent on the level of activity within cortical cholinergic neurons. This relationship enables the trans-synaptic stimulation of cortical ACh transmission by BZR inverse agonists to be most effective during behavioral activities which recruit the basal forebrain cholinergic system.

Acetylcholine↗
PubMed1993

Interactions between the effects of basal forebrain lesions and chronic treatment with MDL 26,479 on learning and markers of cholinergic transmission.

The effects of ibotenic acid-induced basal forebrain lesions and treatment with the triazole MDL 26,479 on the acquisition of an operant visual conditional discrimination task and on [3H]hemicholinium-3 and [3H]vesamicol binding were examined. Lesioned animals required more training sessions to acquire the stimulus-response rules of this task. They also showed longer response latencies throughout the experiment. The effects of the treatment with MDL 26,479 (5 mg/kg; i.p. 60 min before each training session) interacted with the effects of the lesion, producing a decrease in the number of sessions required to perform above chance-level in lesioned but not in control animals. MDL 26,479 did not seem to produce immediate performance effects but interacted with the learning process. The lesions destroyed the cell bodies in the area of the substantia innominata, basal nucleus of Meynert, and the globus pallidus. The number of frontocortical cholinergic terminals as primarily indicated by hemicholinium-3 binding was reduced in lesioned animals; however, another measure of cholinergic terminals, vesamicol binding, was unchanged. Behavioral performance of animals correlated significantly with hemicholinium binding in the frontal cortex of the right hemisphere. The fact that the lesion delayed but did not block the acquisition of the task may have been a result of compensatory mechanisms in remaining cholinergic terminals as indicated by stable vesamicol binding. These data allow assumptions about the conditions for the demonstration of beneficial behavioral effects of MDL 26,479. They also suggest that the long-term effects of basal forebrain lesions on cortical cholinergic transmission remain unsettled.

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↗