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J P Bruno

Publications and source records attributed to J P Bruno.

At least 19 recordsLinked to original sources
PubMed2001

Dissociations between the effects of intra-accumbens administration of amphetamine and exposure to a novel environment on accumbens dopamine and cortical acetylcholine release.

Previous research has demonstrated an interaction between the effects of amphetamine and exposure to a novel environment on the activity of neurons in the nucleus accumbens. Given a model in which these accumbens efferents gate the excitability of basal forebrain cholinergic corticopetal neurons, the administration of intra-accumbens amphetamine was hypothesized to potentiate the increase in cortical acetylcholine produced by introduction to a novel environment. Dual probe microdialysis revealed no synergistic interactions between exposure to a novel environment and amphetamine on nucleus accumbens dopamine or cortical acetylcholine efflux. This finding indicates that exposure to a novel environment failed to recruit the telencephalic activation of the nucleus accumbens presumably necessary to reveal modulatory effects of accumbens dopaminergic transmission on cortical acetylcholine release.

Acetylcholine↗
PubMed2001

Amphetamine-stimulated cortical acetylcholine release: role of the basal forebrain.

Systemic administration of amphetamine results in increases in the release of acetylcholine in the cortex. Basal forebrain mediation of this effect was examined in three experiments using microdialysis in freely-moving rats. Experiment 1 examined whether dopamine receptor activity within the basal forebrain was necessary for amphetamine-induced increase in cortical acetylcholine by examining whether intra-basalis perfusion of dopamine antagonists attenuates this increase. Systemic administration of 2.0 mg/kg amphetamine increased dopamine efflux within the basal forebrain nearly 700% above basal levels. However, the increase in cortical acetylcholine efflux following amphetamine administration was unaffected by intra-basalis perfusions of high concentrations of D1- (100 microM SCH 23390) or D2-like (100 microM sulpiride) dopamine receptor antagonists. Experiments 2 and 3 determined whether glutamatergic or GABAergic local modulation of the excitability of the basal forebrain cholinergic neurons influences the ability of systemic amphetamine to increase cortical acetylcholine efflux. In Experiment 2, perfusion of kynurenate (1.0 mM), a non-selective glutamate receptor antagonist, into the basal forebrain attenuated the increase in cortical acetylcholine produced by amphetamine. Experiment 3 revealed that positive modulation of GABAergic transmission by bilateral intra-basalis infusion of the benzodiazepine receptor agonist chlordiazepoxide (40 microg/hemisphere) also attenuated the amphetamine-stimulated increase in cortical acetylcholine efflux. These data suggest that amphetamine increases cortical acetylcholine release via a complex neuronal network rather than simply increasing basal forebrain D1 or D2 receptor activity.

Acetylcholine↗
PubMed2001

Basal forebrain glutamatergic modulation of cortical acetylcholine release.

The mediation of cortical ACh release by basal forebrain glutamate receptors was studied in awake rats fitted with microdialysis probes in medial prefrontal cortex and ipsilateral basal forebrain. Repeated presentation of a stimulus consisting of exposure to darkness with the opportunity to consume a sweetened cereal resulted in a transient increase in cortical ACh efflux. This stimulated release was dependent on basal forebrain glutamate receptor activity as intrabasalis perfusion with the ionotropic glutamate receptor antagonist kynurenate (1.0 mM) markedly attenuated darkness/cereal-induced ACh release. Activation of AMPA/kainate receptors by intrabasalis perfusion of kainate (100 microM) was sufficient to increase cortical ACh efflux even under basal (nonstimulated) conditions. This effect of kainate was blocked by coperfusion with the antagonist DNQX (0.1-5.0 mM). Stimulation of NMDA receptors with intrabasalis perfusion of NMDA (50 or 200 microM) did not increase basal cortical ACh efflux. However, perfusion of NMDA in rats following exposure to the darkness/cereal stimulus resulted in a potentiation of both the magnitude and duration of stimulated cortical ACh efflux. Moreover, intrabasalis perfusion of the higher dose of NMDA resulted in a rapid increase in cortical ACh efflux even before presentation of the darkness/cereal stimulus, suggesting an anticipatory change in the excitability of basal forebrain cholinergic neurons. These data demonstrate that basal forebrain glutamate receptors contribute to the stimulation of cortical ACh efflux in response to behavioral stimuli. The specific roles of basal forebrain glutamate receptor subtypes in mediating cortical ACh release differ and depend on the level of activity of basal forebrain cholinergic neurons.

Acetylcholine↗
PubMed2001

Psychotogenic properties of benzodiazepine receptor inverse agonists.

The neurochemical, behavioral, and cognitive effects of the benzodiazepine receptor partial inverse agonist beta-carboline FG 7142 (FG), a drug traditionally described as exhibiting 'anxiogenic' effects, are proposed to model core components of present theories of the neuronal mechanisms of schizophrenia. FG activates the mesolimbic dopaminergic system and, via increases in dopaminergic activity in the nucleus accumbens, disinhibits corticopetal cholinergic projections. The latter effect of FG is hypothesized to mediate the hyperattentional impairments that contribute to the development of psychotic cognition. Furthermore, the FG-induced abnormal overprocessing of conditioned stimuli and contexts provides an explanation of the 'anxiogenic' effects of FG. The FG-induced increases in the activity of cortical cholinergic inputs and the FG-induced cognitive impairments in rats and monkeys were demonstrated to be attenuated by the administration of typical and atypical antipsychotic drugs. Compared to the classic psychotogenic drugs amphetamine and phencyclidine, the effects of FG serve as an alternative psychotogenic manipulation in research focusing on the cortical and cognitive aspects of current theories of schizophrenia.

Acetylcholine↗
PubMed2001

The cognitive neuroscience of sustained attention: where top-down meets bottom-up.

The psychological construct 'sustained attention' describes a fundamental component of attention characterized by the subject's readiness to detect rarely and unpredictably occurring signals over prolonged periods of time. Human imaging studies have demonstrated that activation of frontal and parietal cortical areas, mostly in the right hemisphere, are associated with sustained attention performance. Animal neuroscientific research has focused on cortical afferent systems, particularly on the cholinergic inputs originating in the basal forebrain, as crucial components of the neuronal network mediating sustained attentional performance. Sustained attention performance-associated activation of the basal forebrain corticopetal cholinergic system is conceptualized as a component of the 'top-down' processes initiated by activation of the 'anterior attention system' and designed to mediate knowledge-driven detection and selection of target stimuli. Activated cortical cholinergic inputs facilitate these processes, particularly under taxing attentional conditions, by enhancing cortical sensory and sensory-associational information processing, including the filtering of noise and distractors. Collectively, the findings from human and animal studies provide the basis for a relatively precise description of the neuronal circuits mediating sustained attention, and the dissociation between these circuits and those mediating the 'arousal' components of attention.

Animals↗
PubMed2001

The effects of manipulations of attentional demand on cortical acetylcholine release.

In vivo microdialysis was used to measure acetylcholine (ACh) efflux in the frontoparietal cortex while rats performed in one of two operant tasks. One task was designed and validated to generate measures of sustained attention, while the other task was designed to minimize explicit demands on sustained attentional resources (low-demand task). Transferring animals from the baseline environment into the operant chambers robustly increased cortical ACh efflux regardless of subsequent task demands. Performance in the sustained attention task further increased frontoparietal ACh efflux, and these increases were not observed when animals were simply exposed to the operant chamber without task performance. Manipulations of the task parameters within a session, to either increase or decrease explicit demands on sustained attention, were not associated with fluctuations in ACh efflux. Unexpectedly, performance in the low-demand task was also associated with significant increases in ACh efflux that were similar to those observed during the sustained attention task. However, widespread depletions of cortical cholinergic inputs produced by intra-basalis infusions of 192 IgG-saporin failed to impair performance in the low-demand task, suggesting that cholinergic transmission is not necessary for performance in this task. The present results indicate that although a wider range of instrumental processes than previously hypothesized are associated with increases in cortical ACh release, the dependence of performance on the integrity of cortical cholinergic inputs may be limited to tasks with explicit attentional demands.

Acetylcholine↗
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

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

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

The Comprehensive Osteopathic Medical Licensing Examination, COMLEX-USA: a new paradigm in testing and evaluation.

Medical licensure in the United States demands a dynamic and current means to evaluate the competency of physicians seeking to practice medicine. A systematic measuring tool is required--one that is based on actual patient encounters and how physicians should apply their knowledge and skills to the clinical setting according to their level of training and professional development. Osteopathic physicians have a distinctive approach to healthcare, applying the biopsychosocial model with emphasis on the neuromusculoskeletal system. A component of this distinctive approach is a high level of knowledge and skill in the application of osteopathic manipulative treatment. Developed by the National Board of Osteopathic Medical Examiners, COMPLEX-USA is the new sequential three-level examination process for osteopathic medical licensure in the United States. The examination process is interdisciplinary and highly clinical, with even basic science components tested within a clinical context. Examination content is based on wide expert consensus and data consistent with osteopathic medical education, training, and practice. Its design is a novel multidimensional structure that emphasizes clinical problem-solving skills and osteopathic principles and practice within the context of life cycle, gender, ethnicity, and points of service. Design schemata and blueprints are included along with descriptions of strategic research and development. COMPLEX-USA represents the most appropriate pathway for initial licensure for a distinctive and unique professional: the osteopathic physician in the United States.

Educational Measurement↗
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

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↗
PubMed1999

In vivo neurochemical correlates of cognitive processes: methodological and conceptual challenges.

The advent of the use of in vivo microdialysis and voltammetry techniques in behaving animals has ushered in a great deal of research on the neurochemistry of cognition. While studies exploring the relationship between neurotransmitter release and cognitive processing are quite feasible, a number of methodological and conceptual issues pose challenges to the interpretation of experimental results. These challenges include: 1) a demonstration that the behavioral task highlights the particular cognitive construct under study; 2) a determination of the role of non-cognitive variables (i.e. transfer effects, sensory stimulation, motivational variables, and motor activity) in affecting transmitter release, and 3) a recognition of the value of a distributed systems approach to studying the neurochemistry of cognition. This review summarizes the data on the validity of microdialysis and voltammetry as correlates of neurotransmitter release and then illustrates the impact that the above challenges can have on the conclusions drawn from various studies.

Acetylcholine↗