Search PubMed⌕ Search

Biomedical subjects

M Sarter

Publications and source records attributed to M Sarter.

At least 37 records · Page 2Linked to original sources
PubMed2000

Effects of intra-accumbens infusions of amphetamine or cis-flupenthixol on sustained attention performance in rats.

Attentional abilities, as reflected by performance in sustained, selective, or divided attention tasks, have been extensively demonstrated to depend on the integrity of cortical cholinergic inputs and their basal forebrain afferent circuits. As nucleus accumbens (NAC) efferent projections have been hypothesized to modulate the excitability of basal forebrain corticopetal projections, the effects of drug-induced modulation of NAC dopaminergic transmission on sustained attention performance in rats were assessed. Unexpectedly, bilateral infusions of amphetamine (AMPH; 0, 3.0, 10.0, 30.0 microg/microl/hemisphere) into the shell region of the NAC did not affect sustained attention performance. In contrast, microinjections of the non-selective dopamine (DA) receptor antagonist cis-flupenthixol (FLU; 0, 3.0, 10.0, 25.0 microg/microl/hemisphere) into the NAC of a separate group of animals impaired the detection of both signals and non-signals, as reflected by decreases in the relative numbers of hits and correct rejections. As the effects of neither AMPH nor FLU followed the predictions made on the basis of current hypotheses about the modulation of basal forebrain neuronal activity by NAC DA, the present results challenge such hypotheses and indicate that the conditions which implicate NAC DA in attentional performance remain unsettled.

Amphetamine↗
PubMed2000

Sustained visual attention performance-associated prefrontal neuronal activity: evidence for cholinergic modulation.

Cortical cholinergic inputs are hypothesized to mediate attentional functions. The present experiment was designed to determine the single unit activity of neurons within the medial prefrontal cortex (mPFC) of rats performing a sustained visual attention task. Demands on attentional performance were varied by the presentation of a visual distractor. The contribution of cholinergic afferents of the mPFC to performance-associated unit activity within this area was determined by recording neuronal activity before and after unilateral cholinergic deafferentation using intracortical infusion of the immunotoxin 192 IgG-saporin. Presentation of the visual distractor resulted in a decrease in the detection of brief, unpredictable visual signals. As predicted, the unilateral loss of cholinergic inputs within the recording area of the mPFC did not affect sustained attentional performance. Cholinergic deafferentation, however, resulted in a decrease in the overall firing rate of medial prefrontal neurons and a substantial reduction in the proportion of neurons whose firing patterns correlated with specific aspects of behavioral performance. Furthermore, cholinergic deafferentation attenuated the frequency and amplitude of increased mPFC neuronal firing rates that were associated with the presentation of the visual distractor. The main findings from this experiment suggest that cholinergic inputs to the mPFC strongly influence spontaneous and behaviorally correlated single unit activity and mediate increases in neuronal activity associated with enhanced demands for attentional processing, all of which may be fundamental aspects in the maintenance of attentional performance.

Afferent Pathways↗
PubMed2000

Attenuation of the bidirectional effects of chlordiazepoxide and FG 7142 on conditioned response suppression and associated cardiovascular reactivity by loss of cortical cholinergic inputs.

RATIONALE: Basal forebrain cortical cholinergic projections have been hypothesized to mediate the enhanced cardiovascular defensive response initiated by the putative anxiogenic benzodiazepine receptor (BZR) partial inverse agonist FG 7142 (FG). The present study was designed to test the broader hypothesis that the integrity of this cholinergic projection is required for the mediation of the bidirectional modulatory effects of BZR agonists and inverse agonists on anxiety and associated cardiovascular reactivity. OBJECTIVES: The interactions between the effects of 192 IgG-saporin-induced lesions of basal forebrain corticopetal cholinergic neurons and of the BZR agonist chlordiazepoxide (CDP) and FG on the performance of rats tested in a conditioned suppression paradigm and on associated cardiovascular reactivity were assessed. METHODS: Lesioned and control animals were equipped with a telemetric device to record heart rate, trained in an operant lever task, and then tested for suppression of responding during presentation of a conditioned stimulus (CS) and a general contextual cue that was previously associated with shock. FG, CDP (8 mg/kg) and vehicle were administered IP in separate extinction sessions. RESULTS: In control animals, operant responding was suppressed during presentation of the CS and contextual cue. Administration of FG enhanced this suppression, while CDP attenuated it. Lesions attenuated overall response suppression as well as the modulatory effects of BZR ligands on responding during presentation of the contextual stimulus. Likewise, lesions attenuated the cardioacceleratory response to the contextual stimulus and the ability of the BZR ligands to modulate this response. CONCLUSIONS: The behavioral and autonomic responses to anxiety-related stimuli, as well as the modulatory effects of BZR ligands, are mediated in part via cortical cholinergic inputs.

Animals↗
PubMed2000

Repeated pretreatment with amphetamine sensitizes increases in cortical acetylcholine release.

RATIONALE: Previous studies on the attentional effects of repeated psychostimulant administration in rats suggested the possibility that these effects are mediated via increases in the efficacy of psychostimulants to stimulate cortical acetylcholine (ACh) release. Furthermore, neurochemical data have raised the possibility that increases in nucleus accumbens (NAC) dopamine (DA) release trans-synaptically increase the excitability of basal forebrain corticopetal cholinergic projections, thereby supporting speculations about relationships between the effects of repeated psychostimulant administration on NAC DA and cortical ACh release. OBJECTIVES: To determine whether repeated exposure to amphetamine would potentiate the stimulating effects of the drug on cortical ACh and NAC DA efflux. METHODS: Rats were implanted with microdialysis guide cannula in the medial prefrontal cortex and the shell region of the ipsilateral NAC. Amphetamine (2.0 mg/kg i.p.) or saline (0.9%) was administered every other day for 10 days, for a total of five injections. ACh and DA efflux and locomotor activity were measured on the day of the first and last injections of this pretreatment regimen. All animals were retested following a challenge dose of amphetamine (2.0 mg/kg i.p.) given 10 and 19 days after the last pretreatment injection. RESULTS: The initial injections of amphetamine stimulated ACh and DA efflux and locomotor behavior in both groups. The pretreatment with amphetamine potentiated the ability of the drug to stimulate cortical ACh efflux on day 19 of the withdrawal period. The pretreatment with amphetamine also increased the effects of the challenge dose on motoric activity on day 10. Pretreatment with amphetamine did not result in a significant augmentation of the amphetamine-induced increase in DA efflux in the NAC. CONCLUSIONS: Pretreatment with amphetamine sensitizes the ability of amphetamine to stimulate cortical ACh efflux. These results support the hypothesis that sensitized release of cortical ACh mediated the previously observed hyperattentional impairments in amphetamine pretreated rats. Sensitized cortical ACh release following repeated exposure to psychostimulants may mediate the overprocessing of addictive drug-related stimuli, thus contributing to repeated compulsive addictive drug use.

Acetylcholine↗
PubMed2000

The role of cortical cholinergic afferent projections in cognition: impact of new selective immunotoxins.

Previous investigations aimed at determining the role of corticopetal cholinergic afferents in cognition have relied upon human psychopharmacological studies, neuropsychological analyses of Alzheimer's patients, or psychopharmacological manipulations and excitotoxic lesions in animals. Unfortunately, each approach has its limitations. The interpretation of neuropsychological data relies upon correlations of post-mortem assessments of cholinergic degeneration that may be quite temporally distant from the time of cognitive assessment. In contrast, the use of animals allows direct manipulations of the cholinergic system and the establishment of causal relationships between acetylcholine and cognitive function but is limited by the selectivity of the toxins and drugs available to manipulate the system. The recent introduction of immunotoxins to lesion cortical cholinergic pathways with greater selectivity has allowed the effective testing of these hypotheses of cholinergic functions in cognition. Previous neuropsychological, psychopharmacological and excitotoxic lesion data are reviewed and compared to results produced using the more selective immunotoxins to provide an update to the current hypotheses of the role of corticopetal cholinergic afferents in cognitive function. Additionally, the conceptual and methodological cost and benefits of the methods of infusion used to produce lesions with these immunotoxins is assessed.

Alzheimer Disease↗
PubMed2000

Cortical cholinergic inputs mediating arousal, attentional processing and dreaming: differential afferent regulation of the basal forebrain by telencephalic and brainstem afferents.

Basal forebrain corticopetal neurons participate in the mediation of arousal, specific attentional functions and rapid eye movement sleep-associated dreaming. Recent studies on the afferent regulation of basal forebrain neurons by telencephalic and brainstem inputs have provided the basis for hypotheses which, collectively, propose that the involvement of basal forebrain corticopetal projections in arousal, attention and dreaming can be dissociated on the basis of their regulation via major afferent projections. While the processing underlying sustained, selective and divided attention performance depends on the integrity of the telencephalic afferent regulation of basal forebrain corticopetal neurons, arousal-induced attentional processing (i.e. stimulus detection, selection and processing as a result of a novel, highly salient, aversive or incentive stimuli) is mediated via the ability of brainstem ascending noradrenergic projections to the basal forebrain to activate or "recruit" these telencephalic afferent circuits of the basal forebrain. In rapid eye movement sleep, both the basal forebrain and thalamic cortiocopetal projections are stimulated by cholinergic afferents originating mainly from the pedunculopontine and laterodorsal tegmenta in the brainstem. Rapid eye movement sleep-associated dreaming is described as a form of hyperattentional processing, mediated by increased activity of cortical cholinergic inputs and their cortical interactions with activated thalamic efferents. In this context, long-standing speculations about the similarities between dreaming and psychotic cognition are substantiated by describing the role of an over(re)active cortical cholinergic input system in either condition. Finally, while determination of the afferent regulation of basal forebrain corticopetal neurons in different behavioral/cognitive states assists in defining the general cognitive functions of cortical acetylcholine, this research requires a specification of the precise anatomical organization of basal forebrain afferents and their interactions in the basal forebrain. Furthermore, the present hypotheses remain incomplete because of the paucity of data concerning the regulation and role of basal forebrain non-cholinergic, particularly GABAergic, efferents.

Afferent Pathways↗
PubMed2000

Systemic and intra-accumbens administration of amphetamine differentially affects cortical acetylcholine release.

The present experiments tested the hypothesis that the amphetamine-induced increase in dopamine release in the nucleus accumbens represents a necessary and sufficient component of the ability of systemically administered amphetamine to stimulate cortical acetylcholine release. The effects of systemic or intra-accumbens administration of amphetamine on accumbens dopamine release and cortical acetylcholine release were assessed simultaneously in awake animals equipped with dialysis probes inserted into the shell of the nucleus accumbens and the medial prefrontal cortex. Additionally, the ability of intra-accumbens administration of dopamine D(1) and D(2) receptor antagonists to attenuate the effects of systemic amphetamine on cortical acetylcholine was tested. The effects of all treatments were assessed in interaction with a stimulus-induced activation of cortical acetylcholine release to account for the possibility that the demonstration of the trans-synaptic effects of accumbens dopamine requires pre-activation of basal forebrain circuits. Systemic amphetamine resulted in increases in basal cortical acetylcholine and accumbens dopamine efflux. Intra-accumbens administration of amphetamine substantially increased accumbens dopamine efflux, but did not significantly affect cortical acetylcholine efflux. Furthermore, intra-accumbens administration of sulpiride or SCH 23390 did not attenuate the systemic amphetamine-induced increase in cortical acetylcholine efflux. Collectively, the present data suggest that increases in accumbens dopamine release are neither sufficient nor necessary for the effects of systemically administered amphetamine on cortical acetylcholine release. The systemic amphetamine-induced increase in cortical acetylcholine may be mediated via multiple, parallel pathways and may not be attributable to a single afferent pathway of the basal forebrain.

Acetylcholine↗
PubMed2000

Increases in cortical acetylcholine release during sustained attention performance in rats.

Acetylcholine (ACh) efflux in the frontoparietal cortex was studied with in vivo microdialysis while rats performed in an operant task designed to assess sustained attention. Transferring animals from the baseline environment into the operant chambers elicited a robust increase in cortical ACh efflux that persisted throughout the 18-min pre-task period. Subsequent performance in the 36-min sustained attention task was associated with further significant increases in frontoparietal ACh efflux, while the termination of the task resulted in a delayed decline in ACh levels. Upon the 12-min presentation of a visual distracter (flashing houselight, 0.5 Hz) during task performance, animals initially developed a significant response bias to the left lever in the first 6-min distracter block, reflecting a reduction of attentional effort. Under continued conditions of increased attentional demand, performance recovered during the second 6-min distracter block. This return to attentional processing was accompanied by an increase in cortical ACh efflux, suggesting that the augmentation of attentional demand produced by the distracter elicited further increases in ACh release. The enhancement of cortical ACh efflux observed prior to task performance implies the presence of complex relationships between cortical ACh release and anticipatory and/or contextual factors related to operant performance and attentional processing. This finding, along with the further increases in cortical ACh efflux associated with task performance, extends hypotheses regarding the crucial role of cortical cholinergic transmission for attentional functions. Furthermore, the effects of the distracter stimulus provide evidence for a direct relationship between attentional effort and cortical ACh release.

Acetylcholine↗
PubMed2000

Preclinical psychopharmacology of AIDS-associated dementia: lessons to be learned from the cognitive psychopharmacology of other dementias.

Following a brief discussion of the epidemiology, underlying neuropathological mechanisms, neuropsychological symptoms and present treatment strategies of AIDS-associated dementia (AAD), parallels are drawn between the longer standing research on drugs for the treatment of other cognitive disorders, particularly senile dementia, and ongoing efforts to develop psychopharmacological approaches for the treatment of the cognitive impairments in AAD. Important aspects of hypotheses designed to guide such a research are indicated with the help of a speculative, paradigmatic hypothesis concerning the role of cortical cholinergic inputs in AAD. Furthermore, aspects of validity of animal models, and cognition as a crucial intervening variable in the effects of potential treatments, are evaluated.

AIDS Dementia Complex↗
PubMed2000

Cortical cholinergic inputs mediate processing capacity: effects of 192 IgG-saporin-induced lesions on olfactory span performance.

An olfactory span task that required rats to discriminate an olfactory stimulus added to an increasing list of such stimuli (nonmatching-to-sample; NMTS) was employed to assess the role of the basal forebrain cholinergic system in the animals' olfactory working memory capacity. A separate group of animals was trained in a matching-to-sample (MTS) version of this task that did not tax span performance. NMTS animals required significantly more sessions to reach an olfactory span of 18 stimuli than MTS rats. Infusions of the cholino-immunotoxin 192 IgG-saporin into the basal forebrain resulted in decreases of cortical acetylcholinesterase (AChE)-positive fibre density ranging from 80% in frontodorsal and frontoparietal regions to 35% in the pyriform cortex and 24% in the olfactory bulb. Postsurgery span performance was significantly reduced in lesioned NMTS but not MTS animals. Span performance in lesioned NMTS animals recovered following 4 weeks of postoperative training; however, these animals' span remained vulnerable to the effects of increased intertrial intervals. The distribution of errors in lesioned animals indicated a recency effect. In NMTS animals, olfactory span performance during the initial two postoperative weeks correlated significantly with AChE-positive fibre density in neocortical but not olfactory areas. The privileged, automatic processing of olfactory stimuli in rats may have contributed to the transience of the lesion effect. The results support the crucial role of cortical cholinergic input in the mediation of aspects of processing capacity.

Acetylcholinesterase↗
PubMed1999

Basal forebrain afferent projections modulating cortical acetylcholine, attention, and implications for neuropsychiatric disorders.

Cortical acetylcholine (ACh) mediates the detection, selection, and processing of stimuli and associations, and the allocation of processing resources for these attentional functions. For example, loss of cortical cholinergic inputs impairs the performance of rats in tasks designed to assess sustained or divided attention. Intrabasalis infusions of benzodiazepine receptor (BZR) agonists block increases in cortical ACh efflux and impair attentional abilities. Studies on the regulation of cortical ACh efflux by nucleus accumbens (NAC) dopamine (DA) demonstrate that increases in cortical ACh efflux are attenuated by intra-accumbens administration of D1 and, more potently, D2 receptor antagonists. These and other data support the hypothesis that NAC DA, via GABAergic projections to the basal forebrain, controls the excitability of basal forebrain cholinergic neurons. As increases in NAC DA have been hypothesized to represent a major neuronal mediator of schizophrenia and the compulsive use of addictive drugs, the data predict that the abnormal regulation of cortical ACh release represents a crucial neuronal mechanism mediating the cognitive components of these psychopathological disorders.

Acetylcholine↗
PubMed1999

Effects of feline immunodeficiency virus on cognition and behavioral function in cats.

Experimental intravenous challenge of 8-week old cats with the Maryland isolate of feline immunodeficiency virus, Maryland isolate (FIV-MD) was investigated for its effects on cognitive and behavioral function at 12 months postinfection. Six cats infected with FIV-MD were compared with age-matched controls on several behavioral measures. These measures included an open field observation, locomotion tests, traversing planks of various widths for food reinforcement, and a spatial learning task. No group differences were observed on any measure of locomotion. Differences were present with exploratory and stationary activity in the open field observation, with infected cats exhibiting higher levels of exploratory activity and in less stationary activity compared with that of control cats. In the plank-walking experiment, infected cats were less able to successfully cross progressively narrower planks compared with control animals. A holeboard paradigm was constructed to test spatial learning and memory, in which cats were required to locate food reinforcement based on position in the holeboard array. As a group, FIV-infected cats committed more reference (exploring an unbaited cup) and working memory (returning to a previously visited baited cup) errors than control cats. The main difference demonstrated was a higher activity level and associated distractibility in FIV-infected cats that appears to be related to their overall deficient performance when learning new tasks. These results indicate that behavioral function is altered and cognition is quantitatively impaired in FIV-infected cats.

Animals↗
PubMed1999

Enhancement of sustained attention performance by the nicotinic acetylcholine receptor agonist ABT-418 in intact but not basal forebrain-lesioned rats.

RATIONALE: Loss of telencephalic cholinergic projections has been postulated to contribute significantly to the cognitive decline associated with aging and dementia. OBJECTIVE: The effects of the nicotinic acetylcholine receptor agonist ABT-418, a potential therapeutic drug for the treatment of the age- and dementia-associated cognitive disorders, were tested in an animal model of the cortical cholinergic deafferentation-induced impairments in sustained attention. METHODS: Animals were trained in an operant task designed to test sustained attention performance. A partial loss of cortical cholinergic inputs was produced by infusions of 192 IgG-saporin into the basal forebrain. The effects of the systemic administration of ABT-418 (0.04, 0.13, 0.39 mg/kg) and the psychostimulant methylphenidate (0.2, 0.4, 0.8 mg/kg) were assessed. RESULTS: Compared with sham-lesioned animals, this lesion resulted in a decrease in the relative number of hits while the relative number of correct rejections remained unaffected. Administration of ABT-418 significantly improved the relative number of hits. Furthermore, this effect of ABT-418 interacted with the effects of the lesion. Unexpectedly, this interaction was based on a significant enhancement of the performance of sham-lesioned animals while no effects were found in 192 IgG-saporin-lesioned animals. Administration of methylphenidate did not affect performance. CONCLUSIONS: While these data do not support the hypothesis that administration of ABT-418 attenuates the impairments in attentional performance that result from loss of cortical cholinergic inputs, they support previous notions about this drug's ability to enhance cognitive processes in intact subjects.

Animals↗
PubMed1999

Abnormal regulation of corticopetal cholinergic neurons and impaired information processing in neuropsychiatric disorders.

Cholinergic neurons originating in the basal forebrain innervate all cortical areas and participate in the gating of cortical information processing. Aberrations in the excitability of cortical cholinergic inputs fundamentally alter the processing of sensory stimuli and higher processes, thereby advancing the development of major neuropsychiatric disorders. Cortical cholinergic deafferentation has been considered to be a major neuropathological variable that contributes to the development of age- and dementia-associated impairments in cognition. Conversely, it has been suggested that increases in the excitability of cortical cholinergic inputs mediate the abnormal cognitive processes that escalate into psychotic symptoms and contribute to addictive-drug-seeking behavior, anxiety and phobia. Abnormal regulation of the excitability of cortical cholinergic afferents represents a 'final common pathway' that mediates the manifestation of major neuropsychiatric disorders.

Cerebral Cortex↗
PubMed1999

Role of accumbens and cortical dopamine receptors in the regulation of cortical acetylcholine release.

Cortical acetylcholine, under resting and stimulated conditions, was measured in frontoparietal and prefrontal cortex using in vivo microdialysis in freely-moving rats. Cortical acetylcholine efflux was stimulated by systemic administration of the benzodiazepine receptor partial inverse agonist FG 7142. Administration of FG 7142 (8.0 mg/kg; i.p.) significantly elevated acetylcholine efflux in both cortical regions (150-250% relative to baseline) for 30 min after drug administration. The ability of endogenous dopamine to regulate cortical acetylcholine efflux under resting or stimulated conditions and the relative contributions of D1- and D2-like dopamine receptor activation was also assessed. In a first series of experiments, systemic administration of the antipsychotic drug haloperidol (0.15, 0.9 mg/kg, i.p.) blocked FG 7142-stimulated acetylcholine efflux in frontoparietal, cortex while the D1-like antagonist, SCH 23390 (0.1, 0.3 mg/kg), was less effective in attenuating stimulated acetylcholine efflux. In a second series of experiments, the effects of infusions of these antagonists and of the D2-like antagonist sulpiride (10, 100 microM) into the nucleus accumbens were assessed. Infusions of haloperidol and sulpiride significantly blocked FG 7142-stimulated acetylcholine efflux while SCH 23390 did not. By contrast, a third series of experiments demonstrated that perfusion of these antagonists (100 microM) locally into the cortex (through the probe) did not affect FG 7142-stimulated acetylcholine efflux. Moreover, none of these dopamine receptor antagonists, whether administered systemically or perfused into the nucleus accumbens or cortex, affected basal cortical acetylcholine efflux. These results reveal similarities in stimulated cortical acetylcholine release across frontal cortical regions and suggest a prominent role for D2-mediated accumbens dopamine transmission in the regulation of cortical acetylcholine release. The findings provide evidence in support of a neural substrate that links dysregulation of mesolimbic dopaminergic transmission to changes in cortical cholinergic transmission. Dysregulation within this circuit is hypothesized to contribute to the etiology of disorders such as schizophrenia, dementia and drug abuse.

Acetylcholine↗
PubMed1999

Age-related attenuation of stimulated cortical acetylcholine release in basal forebrain-lesioned rats.

In vivo microdialysis was used to measure the effects of partial deafferentation of cortical cholinergic inputs on acetylcholine efflux in young (four to seven months) and aged (24-28 months) male F344/BNNIA rats. Partial deafferentation was produced by bilateral infusions of the immunotoxin 192 immunoglobulin G-saporin (0.56 microg/1.0 microl) or its vehicle solution into the ventral pallidum/substantia innominata region of the basal forebrain. The lesion produced comparable (65%) decreases in basal cortical acetylcholine efflux in young and aged rats. Presentation of a complex environmental stimulus (exposure to darkness/palatable food), in conjunction with the systemic administration of the benzodiazepine receptor weak inverse agonist ZK 93 426, increased cortical acetylcholine efflux in young shams, aged shams and young lesioned rats, but not in aged lesioned rats. Administration of the benzodiazepine receptor partial inverse agonist FG 7142, in the absence of the environmental stimulus, comparably stimulated cortical acetylcholine efflux in young and aged sham rats. FG 7142-induced increases in acetylcholine efflux were attenuated by approximately 50% following partial deafferentation in both young and aged rats. These results suggests that, under certain conditions, ageing potently interacts with the integrity of the cortical cholinergic afferent system. The effects of ageing on cortical cholinergic function may be most potently revealed by experiments assessing age-related limitations in the responsiveness of a partially deafferented cholinergic system to certain behavioral and/or pharmacological stimuli.

Acetylcholine↗