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Biomedical subjects

M Sarter

Publications and source records attributed to M Sarter.

At least 73 records · Page 4Linked to original sources
PubMed1997

Lack of effects of lesions of the dorsal noradrenergic bundle on behavioral vigilance.

The effects of 6-hydroxydopamine (6-OHDA)-induced lesions of the dorsal noradrenergic bundle (DNB) were assessed in animals trained in a task designed to measure sustained attention, or vigilance. Infusions of 6-OHDA reduced frontal cortical noradrenaline contents but did not significantly affect striatal and hypothalamic noradrenaline contents. The performance of lesioned animals did not differ significantly from sham-lesioned controls. The performance of both the lesioned and sham-lesioned animals was impaired by the presentation of a visual distractor and by a decrease in the probability for a signal. The results from this study largely coincide with the results from previous studies on the effects of noradrenergic lesions on various aspects of attention. In contrast to the attentional functions assessed in this experiment, the ability to detect and select stimuli that are associated with activation of sympathetic functions is hypothesized to be sensitive to the effects of DNB lesions.

Afferent Pathways↗
PubMed1997

The cardiovascular startle response: anxiety and the benzodiazepine receptor complex.

Benzodiazepine receptor (BZR) agonists are prototypic anxiolytic agents, whereas BZR inverse agonists exert anxiogenic effects. The effects of these compounds offer a potentially important pharmacological model system to examine the central mechanisms of anxiety. In accord with its putative anxiogenic properties, we previously found that the BZR partial inverse agonist, FG 7142, enhances the cardiovascular defensive response to a nonsignal acoustic stimulus in rats. In contrast, we found in the present study that this agent attenuates both the somatic and cardiovascular components of the acoustic startle response. BZR agonists and inverse agonists are known to modulate the basal forebrain cortical cholinergic system, and we consider the potential involvement of this system in the disparate psychophysiological actions of FG 7142 and in anxiety states in general.

Animals↗
PubMed1997

Effects of ibotenic acid-induced loss of neurons in the medial prefrontal cortex of rats on behavioral vigilance: evidence for executive dysfunction.

Rats were trained in a previously validated task for the assessment of sustained attention, or vigilance. This task required the animals to discriminate between signals of variable lengths and non-signal events by making an appropriate lever press. The performance of sham-lesioned animals in this task was characterized by a signal-length dependent number of hits. Also, approximately 70 percent of the non-signals were correctly rejected. Ibotenic acid-induced lesions of the medial prefrontal cortex decreased the relative number of hits and correct rejections and, in essence, resulted in random lever selection. The lesion did not affect the number of omissions or side bias. Furthermore, the performance of lesioned animals was insensitive to the detrimental effects of distractors. The effects of the lesions do not support an interpretation in terms of sustained attention. Rather, the pattern of the lesioned animals' performance is speculated to reveal a fundamental disruption of decisional processes, reminiscent of the executive dysfunctions observed in patients with damage to ventromedial prefrontal areas or with schizophrenia.

Animals↗
PubMed1996

Interactions between D1 and muscarinic receptors in the induction of striatal c-fos in rats depleted of dopamine as neonates.

The contributions of striatal D1 receptors to the expression of sensorimotor behavior are qualitatively different in rats depleted of dopamine (DA) as neonates vs. as adults. In an effort to reveal neuronal mechanisms underlying these behavioral difference we determined the effects of the partial D1 agonist SKF 38393, the muscarinic antagonist scopolamine, and the combination of the two drugs on the induction of c-fos in the striatum and its projection sites, the globus pallidus and substantia nigra. Adult rats, given intracerebroventricular injections of 6-hydroxydopamine (6-OHDA, 50 micrograms/5 microliters/hemisphere) or its vehicle on postnatal day 3, were treated with SKF 38393 (1.5 mg/kg, i.p.), scopolamine (5.0 mg/kg, i.p.) or the combination of the two drugs. There was no significant induction of c-fos in vehicle-treated controls, regardless of drug administration. In DA-depleted rats, scopolamine also did not induce c-fos whereas SKF 38393 produced a significant increases in the number of FOS-positive cells in the dorsal, but not ventral, striatum. The combined administration of scopolamine and SKF 38393 resulted in a potent synergism in the number of FOS-positive cells in DA-depleted rats. These interactions between lesion condition and drugs on c-fos induction were not secondary to differences in drug-induced behavioral activity. Activity levels were no different in vehicle vs. DA-depleted rats following the combined administration of scopolamine + SKF 38393, yet the two groups of rats exhibited marked differences in the density of FOS-positive striatal neurons. The effects of scopolamine and SKF 38393 on c-fos induction in striatum are qualitatively similar to those reported in rats DA-depleted as adults and suggest that, at this single-label level of analysis, the ability of D1 and muscarinic receptors to influence striatal activity does not contribute to the marked age-related differences in the behavioral effects of DA depletions.

Animals↗
PubMed1996

Trans-synaptic stimulation of cortical acetylcholine release after partial 192 IgG-saporin-induced loss of cortical cholinergic afferents.

Environmental and pharmacological stimulation of cortical acetylcholine (ACh) efflux was determined in rats sustaining partial deafferentation of cortical cholinergic inputs. Rats were bilaterally infused with the selective cholinotoxin 192 IgG-saporin (0.005 microgram/0.5 microliter/site) into the frontoparietal cortex. In the first experiment, animals were pretrained to associate the onset of darkness with presentation of a palatable fruit cereal reward. The ability of this stimulus to enhance frontoparietal ACh efflux alone, and with the benzodiazepine receptor (BZR) weak inverse agonist ZK 93,426 (1.0 or 5.0 mg/kg, i.p.), was determined in lesioned and sham-lesioned rats. Intracortical infusions of 192 IgG-saporin reduced basal cortical ACh efflux by 47% of sham-lesioned values, consistent with reductions in the density of AChE-positive fibers. In spite of this deafferentation, ZK 93,426 produced a transient potentiation of the cortical ACh efflux induced by the darkness/cereal stimulus similar to that observed in control animals. In the second experiment, the ability of the more efficacious BZR partial inverse agonist FG 7142 (8.0 mg/kg, i.p.) to enhance basal cortical ACh efflux was compared in lesioned and sham-lesioned rats. Again, lesioned rats exhibited an increase comparable to control animals after FG 7142. This drug-induced stimulation of cortical ACh efflux was comparably and completely blocked in both groups by co-perfusion with tetrodotoxin (1.0 microM). These results suggest similarities in the modulation of cortical ACh efflux in intact and partially deafferented rats and indicate the potential of BZR inverse agonists for restoring transmission in animals with partial loss of cortical cholinergic inputs.

Acetylcholine↗
PubMed1996

A central cholinergic link in the cardiovascular effects of the benzodiazepine receptor partial inverse agonist FG 7142.

Previous work demonstrated that systemic administration of the benzodiazepine receptor (BZR) partial inverse agonist beta-carboline FG 7142 (FG) augments the cardiovascular response to non-signal stimuli, similar to the effects of an aversive context. Analysis of the parasympathetic and sympathetic contributions to the effects of FG prompted the hypothesis that increases in central cholinergic activity mediates the potentiation of the cardioacceleratory response by FG. Consistent with this hypothesis, the present experiments demonstrate: (a) intracerebroventricular (ICV) infusion of the cholinergic receptor agonist carbachol mimics the response-potentiating effects of FG; (b) this effect of carbachol was blocked by ICV co-administration of the muscarinic antagonist atropine; (c) ICV infusions of atropine blocked the potentiation of the cardioacceleratory response by systemically administered FG, but did not alter the basal response to the stimulus; and (d) 192 IgG-saporin-induced lesions of basal forebrain cholinergic neurons prevented the FG-induced potentiation of the cardioacceleratory response, again without altering the basal cardiac response. These data strongly support the hypothesis that the effects of FG on cardiac reactivity are mediated via an activation of central muscarinic cholinergic mechanisms.

Animals↗
PubMed1996

Neuronal mechanisms mediating drug-induced cognition enhancement: cognitive activity as a necessary intervening variable.

The conceptual foundations of a research aimed at the determination of potential neuronal, neuropharmacological, and behavioral/cognitive mechanisms mediating drug-induced cognition enhancement are discussed. The available evidence justifies a focus on attentional processes as a target for drug-induced cognition enhancement. Neuropharmacological mechanisms that may mediate drug-induced enhancement of attentional functions are proposed to interact necessarily with attention-associated neuronal activity. The elements of a transsynaptic approach to increase the excitability of basal forebrain cholinergic neurons and hence, attentional functions are discussed. Experimental tests of this hypothesis require the demonstration of interactions between cognition-induced increases in the activity of cortical cholinergic afferents and the effects of putative cognition enhancers. The available data illustrate that the effects of benzodiazepine receptor (BZR) agonists and inverse agonists on cortical acetylcholine (ACh) efflux interact with the state of activity in this system. The feasibility, potential heuristic power, and the experimental and conceptual problems of studies attempting to simultaneously assess drug effects on behavioral/cognitive abilities, ACh efflux, and neuronal activity have been revealed by an experiment intended to correlate performance in a task measuring sustained attention with medial prefrontal ACh efflux and medial prefrontal single-unit activity. The rational development of a psychopharmacology of cognition enhancers requires a union among behavioral/cognitive pharmacology, neuropharmacological and electrophysiological approaches.

Acetylcholine↗
PubMed1996

Brain imaging and cognitive neuroscience. Toward strong inference in attributing function to structure.

Cognitive neuroscience has emerged from the neurosciences and cognitive psychology as a scientific discipline that aims at the determination of "how brain function gives rise to mental activity" (S. M. Kosslyn & L. M. Shin, 1992, p. 146). While research in cognitive neuroscience combines many levels of neuroscientific and psychological analyses, modern imaging techniques that monitor brain activity during behavioral or cognitive operations have significantly contributed to the emergence of this discipline. The conclusions deduced from these studies are inherently localizationistic in nature; in other words, they describe cognitive functions as being localized in focal brain regions (brain activity in a defined brain region, phi, is involved in specific cognitive function, psi). A broad discussion about the virtues and limitations of such conclusions may help avoid the emergence of a mentalistic localizationism (i.e., the attribution of mentalistic concepts such as happiness, morality, or consciousness to brain structure) and illustrates the importance of a convergence with information generated by different research strategies (such as, for example, evidence generated by studies in which the effects of experimental manipulations of local neuronal processes on cognitive functions are assessed). Progress in capitalizing on brain-imaging studies to investigate questions of the form "brain structure or event phi is associated with cognitive function psi" may be impeded because of the way in which inferences are typically formulated in the brain imaging literature. A conceptual framework to advance the interpretation of data describing the relationships between cognitive phenomena and brain structure activity is provided.

Animals↗
PubMed1996

Behavioral vigilance following infusions of 192 IgG-saporin into the basal forebrain: selectivity of the behavioral impairment and relation to cortical AChE-positive fiber density.

Rats were trained in a previously validated behavioral vigilance task that required them to detect visual signals of variable length and to discriminate signal from nonsignal events. Baseline performance was characterized by a signal length-dependent ability to score hits, a decline in hits over time, and a correct rejection rate of approximately 70%. After the rats reached criterion performance in this task, the immunotoxin 192 IgG-saporin or its vehicle was infused into the area of the nucleus basalis/substantia innominata of the basal forebrain. Postoperative performance in lesioned rats was characterized by a decrease in their ability to detect signals while their ability to correctly reject nonsignals remained unaffected. The effect of the lesion did not recover in the course of over 180 sessions of postlesion testing. The overall performance of the rats correlated with acetylcholinesterase (AChE)-positive fiber density in all cortical areas measured except the cingulate and pyriform cortex. These findings help to elucidate the nature of the attentional impairments resulting from the loss of cortical cholinergic inputs.

Acetylcholinesterase↗
PubMed1996

Effects of benzodiazepine receptor inverse agonists and nicotine on behavioral vigilance in senescent rats.

Previous experiments demonstrated that, compared with 6-month-old rats, the performance of 20-month-old rats in a behavioral vigilance task was characterized by an impairment in their ability to detect visual signals, whereas their ability to discriminate between longer signals and nonsignal events was unaffected. The benzodiazepine receptor (BZR) agonist chlordiazepoxide potently and selectively interacted with the effects of age on the relative number of hits. However, negative modulators of GABAergic transmission (Zk 93 426, beta-CCtB, RU 33965) failed to attenuate the effects of age on behavioral vigilance. the present experiment tested the hypothesis that the performance of senescent animals (28 months) is further impaired and thus would allow the demonstration of beneficial effects of BZR inverse agonists or nicotine. However, administration of ZK 93 426 (0.39, 1.56, 6.25 mg/kg), Ru 33965 (0.1, 0.5 mg/kg), or nicotine (0.09, 0.287, 0.689 mg/kg) did not beneficially affect the performance of senescent animals; rather, detrimental effects were found. Considering the beneficial behavioral effects of these compounds in animals with experimentally induced impairments in cholinergic function, the present finding point to limitations of normal aging as a variable in animal experiments on BZR inverse agonist or nicotine-induced attenuation of cognitive impairments that result from cholinergic hypofunction.

Aging↗
PubMed1996

Behavioural vigilance in schizophrenia. Evidence for hyperattentional processing.

BACKGROUND: Despite 30 years of research, some surprisingly fundamental gaps remain in our understanding of schizophrenic input dysfunctions. METHOD: In a provisional test of a 'hyperattention' hypothesis, schizophrenic patients and control subjects performed a behavioural test that was adapted from a paradigm originally developed for characterising vigilance or sustained attention in animals. On this computerised operant testing procedure, subjects discriminated between signals of various salience and non-signal presentations. Hits and correct rejections resulted in monetary rewards while misses and false alarms entailed monetary costs. RESULTS: Data from in-patients with schizophrenia and age, education and gender-matched controls support hypotheses not only about hyperattentional dysfunctions in schizophrenia with respect to overall signal detectability but also in terms of resistance to the vigilance decrement that normally occurs over trials. CONCLUSIONS: The theoretical importance of impairments of this sort are discussed with respect to the cognitive and perceptual consequences of hypervigilance and 'input dysfunction'.

Adult↗
PubMed1995

Bidirectional modulation of cortical acetylcholine efflux by infusion of benzodiazepine receptor ligands into the basal forebrain.

In a previous in vivo microdialysis study in rats, it was found that cortical acetylcholine (ACh) efflux was reliably increased by a multimodal appetitive stimulus (onset of darkness with presentation of palatable food). Furthermore, this stimulated ACh efflux was significantly enhanced by systemic administration of a benzodiazepine receptor (BZR) weak inverse agonist and significantly reduced by a BZR full agonist. These effects contrasted with the minimal effects of BZR ligands on basal cortical ACh efflux in resting animals. The aim of the present study was to determine whether this modulation of stimulated cortical ACh efflux by BZR ligands was mediated within the basal forebrain. ACh efflux, measured with in vivo microdialysis, was stimulated by onset of darkness, an event which predicted delivery of palatable food. The BZR full inverse agonist, beta -CCM (3.0 micrograms/hemisphere) or the full agonist chlordiazepoxide (40.0 micrograms/hemisphere) was infused into the basal forebrain just prior to the darkness/food stimulus. Similar to previous results with systemic administration, the BZR full inverse agonist enhanced, while the full agonist reduced, stimulated cortical ACh efflux. These results demonstrate that the action of BZR ligands in the basal forebrain is sufficient for their modulation of cortical ACh release.

Acetylcholine↗
PubMed1995

Stimulation of cortical acetylcholine efflux by FG 7142 measured with repeated microdialysis sampling.

The effects of the benzodiazepine receptor partial inverse agonist beta-carboline FG 7142 on cortical ACh efflux were determined using in vivo microdialysis in freely-moving rats. Additionally, a within-subjects, repeated-dialysis experimental design (four microdialysis sessions; removable dialysis probe) was evaluated as a method for measuring changes in basal and FG 7142-stimulated ACh efflux in the frontoparietal cortex. FG 7142 (4.0, 8.0, and 16.0 mg/kg) produced a 150-470% increase in cortical ACh efflux, with a dose-dependent effect on the duration of the increase in efflux. Basal cortical ACh efflux was lower in session 4 than in session 1. However, the ability of FG 7142 to stimulate efflux was unchanged by repeated dialysis testing. The ability of tetrodotoxin (1.0 microM) to suppress both basal and FG 7142-stimulated ACh efflux was also unaffected by repeated dialysis testing. These results demonstrate that systemically administered benzodiazepine receptor inverse agonists stimulate cortical ACh efflux, and that repeated-measures experimental designs can be valid for determining certain changes in cortical ACh efflux with in vivo microdialysis.

Acetylcholine↗
PubMed1995

Effects of nicotinic acetylcholine receptor ligands on behavioral vigilance in rats.

The effects of nicotinic receptor ligands on performance in a task measuring sustained attention, or vigilance, were tested. This task required the animals to discriminate between signal and non-signal events. The sequence of signal (central panel light illumination for 500, 50 or 25 ms) and non-signal presentations was randomized over three blocks of 54 trials each (27 signal trials, 9 per length, and 27 non-signal trials). A left lever press following a signal was counted as a hit, and a right lever press following a non-signal event was counted as a correct rejection. Hits and correct rejections were rewarded, whereas misses and false alarms (defined as incorrect right and left lever presses, respectively) were not. Baseline performance was characterized by a signal length dependent ability of the animals to discriminate between signal and non-signal events. Administration of nicotine (0.19, 0.62, 1.9 mumol) or of two novel nicotinic receptor agonists, ABT-418 and A-82695, did not produce main effects on vigilance performance. Lobeline (1.9, 6.2, 19 mumol), a nicotinic receptor ligand with mixed agonist/antagonist activities, impaired the animals' ability to discriminate between signal and non-signal events. The antagonist mecamylamine (5, 15, 50 mumol) potently impaired performance while increasing the number of errors of omission. The lack of effect of nicotine largely corresponds with the findings from previous studies on the acute effects of nicotine in intact subjects and non-smoking humans. While the detrimental effects of lobeline may have been related to the antagonist effects of this compound, the reasons for the differences between the effects of nicotine and lobeline still remain unsettled. These data support the hypothesis that nicotine receptor mechanisms are maximally activated in intact animals performing this task, and suggest that effects of acute nicotinic agonist treatment would not produce further cognitive benefit for these animals.

Animals↗
PubMed1995

Behavioral vigilance in rats: task validation and effects of age, amphetamine, and benzodiazepine receptor ligands.

An operant task for the measurement of sustained attention or vigilance in rats was characterized. The task requires the animals to respond to the presentation of visual signals (presented for 25, 50, or 500 ms) by operating one lever ("hits") and to the absence of a signal by operating the opposite lever ("correct rejection"). Incorrect responses ("misses" and "false alarms", respectively) were not rewarded. Performance in this task is a function of signal length, i.e., the shorter the signals the higher the number of misses. An increase in "background noise" by flashing the chamber houselight (at 0.5 Hz) impaired the animals' ability to discriminate between signal and non-signal events. Also flashing the houselight augmented the vigilance decrement observed for shortest signals. An increase in the event-rate also resulted in a vigilance decrement. Finally, the inability of the animals to time signals was examined by testing the effects of an increase in event asynchrony. In a second experiment, the performance of differently aged rats (6- and 20 month-old male BNNia/F344 rats) was studied. Compared to young animals, 20-month-old rats showed a decrease in their ability to discriminate between shortest signals (25 ms) and non-signal events but did not differ in their ability to correctly reject non-signal trials. Administration of the benzodiazepine receptor (BZR) agonist chlordiazepoxide (CDP; 3, 5, 8 mg/kg) resulted in an impairment of the animals' ability to discriminate between signal and non-signal events and, similar to the effects of age, this effect was exclusively due to an increase in the number of misses. CDP generally produced potent effects while affecting the aged animals to a greater degree. BZR-ligands with weak or "selective" inverse agonist properties (ZK 93426; beta-CCtB) did not affect vigilance performance. The BZR partial inverse agonist RU 33965 (0.1, 0.5 mg/kg) dose-dependently impaired vigilance performance. The administration of amphetamine (0.4, 0.8 mg/kg) also impaired performance, but these impairments were possibly based on effects unrelated to attentional mechanisms. The finding that performance in this task revealed the interactions between the effects of age and BZR agonists on attentional abilities further supports the validity of measures of performance generated by this task.

Aging↗
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↗