Sustained attention
From Biohack
Localization of a human system for sustained attention by positron emission tomography
José V. Pardo, Peter T. Fox & Marcus E. Raichle
Departments of * Psychiatry,‡Neurology and Neurological Surgery, § Mallinckrodt Institute of Radiology, †McDonnell Center for Studies of Higher Brain Function, Washington University Medical Center, St Louis, Missouri 63110, USA
POSITRON emission tomographic (PET) studies of human attention have begun to dissect isolable components of this complex higher brain function, including a midline attentional system in a region of the anterior cingulate cortex 1–3. The right hemisphere may play a special part in human attention 4; neglect, an important phenomenon associated with damage to attentional systems, is more severe, extensive and long-lasting after lesions to the right hemisphere. Here we use PET measurements of brain blood flow in healthy subjects to identify changes in regional brain activity during simple visual and somatosensory tasks of sustained attention or vigilance. We find localized increases in blood flow in the prefrontal parietal cortex and superior parietal cortex primarily in the right hemisphere, regardless of the modality or laterality of sensory input. The anterior cingulate was not activated during either task. These data localize the vigilance aspects of normal human attention to sensory stimuli, thereby clarifying the biology underlying asymmetries of attention to such stimuli that have been reported in clinical lesions.
References 1-3
1. Posner, M. I., Petersen, S. E., Fox, P. T. & Raichle, M. E. Science 240, 1627−1631 (1988). | PubMed | ISI | ChemPort |
2. Pardo, J. V., Pardo, P. J., Janer, K. W. & Raichle, M. E. Proc. natn. Acad. Sci. U.S.A. 87, 256−259 (1990). | ChemPort |
3. Corbetta, M., Miezin, F. M., Dobmeyer, S., Shulman, G. L. & Petersen, S. E. Science 248, 1556−1559 (1990). | PubMed | ISI | ChemPort |
Sustained attention performance in rats with intracortical infusions of 192 IgG-saporin-induced cortical cholinergic deafferentation: effects of physostigmine and FG 7142
Sustained attention performance in rats with intracortical infusions of 192 IgG-saporin-induced cortical cholinergic deafferentation: effects of physostigmine and FG 7142.
McGaughy J, Sarter M.
Department of Psychology, The Ohio State University, Columbus 43210, USA.
Rats with extensive lesions of cortical cholinergic afferents as a result of infusions of 192 IgG-saporin into the basal forebrain show persistent impairments in sustained attention performance (J. McGaughy, T. Kaiser, & M. Sarter, 1996). However, the administration of neither the cholinesterase inhibitor physostigmine nor the benzodiazepine receptor partial inverse agonist FG 7142 attenuated the lesion-induced impairments in performance. The present study demonstrated that less extensive cortical cholinergic deafferentation, produced by intracortical infusions of a relatively small concentration of 192 IgG-saporin, resulted in a significant impairment in sustained attention. However, the administration of neither physostigmine (0.01-0.1 mg/kg) nor FG 7142 (0.1-1.0 mg/kg) benefited the performance of the animals. Because neither compound selectively augments performance-associated increases in acetylcholine release from residual neurons, beneficial effects on cortical cholinergic deafferentation-based impairments in attention may remain limited.
http://heybryan.org/2008-05-13_hyperfocusing.html mentions cholinergic neurons in the neocortex.
Cited by 54 - http://scholar.google.com.ezproxy.lib.utexas.edu/scholar?num=100&hl=en&lr=&output=search&cites=7138094952444751640
- M Sarter, JP Bruno
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.
Unraveling the attentional functions of cortical cholinergic inputs: interactions between signal-driven and cognitive modulation of signal detection
Neurophysiological studies demonstrated that increases in cholinergic transmission in sensory areas enhance the cortical processing of thalamic inputs. Cholinergic activity also suppresses the retrieval of internal associations, thereby further promoting sensory input processing. Behavioral studies documented the role of cortical cholinergic inputs in attentional functions and capacities by demonstrating, for example, that the integrity of the cortical cholinergic input system is necessary for attentional performance, and that the activity of cortical cholinergic inputs is selectively enhanced during attentional performance. This review aims at integrating the neurophysiological and behavioral evidence on the functions of cortical cholinergic inputs and hypothesizes that the cortical cholinergic input system generally acts to optimize the processing of signals in attention-demanding contexts. Such signals ‘recruit’, via activation of basal forebrain corticopetal cholinergic projections, the cortical attention systems and thereby amplify the processing of attention-demanding signals (termed ‘signal-driven cholinergic modulation of detection’). The activity of corticopetal cholinergic projections is also modulated by direct prefrontal projections to the basal forebrain and, indirectly, to cholinergic terminals elsewhere in the cortex; thus, cortical cholinergic inputs are also involved in the mediation of top-down effects, such as the knowledge-based augmentation of detection (see Footnote 1) of signals and the filtering of irrelevant information (termed ‘cognitive cholinergic modulation of detection’). Thus, depending on the quality of signals and task characteristics, cortical cholinergic activity reflects the combined effects of signal-driven and cognitive modulation of detection. This hypothesis begins to explain signal intensity or duration-dependent performance in attention tasks, the distinct effects of cortex-wide versus prefrontal cholinergic deafferentation on attention performance, and it generates specific predictions concerning cortical acetylcholine (ACh) release in attention task-performing animals. Finally, the consequences of abnormalities in the regulation of cortical cholinergic inputs for the manifestation of the symptoms of major neuropsychiatric disorders are conceptualized in terms of dysregulation in the signal-driven and cognitive cholinergic modulation of detection processes.
Repeated pretreatment with amphetamine sensitizes increases in cortical acetylcholine release
http://www.psy.ohio-state.edu/bruno/PDF%20files/Repeated%20pretreatment%20with%20amphet.pdf
Abstract 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.
The neglected constituent of the basal forebrain corticopetal projection system: GABAergic projections
At least half of the basal forebrain neurons which project to the cortex are GABAergic. Whilst hypotheses about the attentional functions mediated by the cholinergic component of this corticopetal projection system have been substantiated in recent years, knowledge about the functional contributions of its GABAergic branch has remained extremely scarce. The possibility that basal forebrain GABAergic neurons that project to the cortex are selectively contacted by corticofugal projections suggests that the functions of the GABAergic branch can be conceptualized in terms of mediating executive aspects of cognitive performance, including the switching between multiple input sources and response rules. Such speculations gain preliminary support from the effects of excitotoxic lesions that preferentially, but not selectively, target the noncholinergic component of the basal forebrain corticopetal system, on performance in tasks involving demands on cognitive flexibility. Progress in understanding the cognitive functions of the basal forebrain system depends on evidence regarding its main noncholinergic components, and the generation of such evidence is contingent on the development of methods to manipulate and monitor selectively the activity of the GABAergic corticopetal projections.
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.
Address correspondence to Martin Sarter, The Ohio State University, Department of Psychology, 27 Townshend Hall, 1885 Neil Avenue, Columbus, OH 43210. Voice: 614-292-1751; fax: 614-688-4733; sarter.2@osu.edu.
More attention must be paid: The neurobiology of attentional effort
Increases in attentional effort are defined as the motivated activation of attentional systems in response to detrimental challenges on attentional performance, such as the presentation of distractors, prolonged time-on-task, changing target stimulus characteristics and stimulus presentation parameters, circadian phase shifts, stress or sickness. Increases in attentional effort are motivated by the expected performance outcome; in the absence of such motivation, attentional performance continues to decline or may cease altogether. The beneficial effects of increased attentional effort are due in part to the activation of top-down mechanisms that act to optimize input detection and processing, thereby stabilizing or recovering attentional performance in response to challenges. Following a description of the psychological construct “attentional effort”, evidence is reviewed indicating that increases in the activity of cortical cholinergic inputs represent a major component of the neuronal circuitry mediating increases in attentional effort. A neuronal model describes how error detection and reward loss, indicating declining performance, are integrated with motivational mechanisms on the basis of neuronal circuits between prefrontal/anterior cingulate and mesolimbic regions. The cortical cholinergic input system is activated by projections of mesolimbic structures to the basal forebrain cholinergic system. In prefrontal regions, increases in cholinergic activity are hypothesized to contribute to the activation of the anterior attention system and associated executive functions, particularly the top-down optimization of input processing in sensory regions. Moreover, and influenced in part by prefrontal projections to the basal forebrain, increases in cholinergic activity in sensory and other posterior cortical regions contribute directly to the modification of receptive field properties or the suppression of contextual information and, therefore, to the mediation of top-down effects. The definition of attentional effort as a cognitive incentive, and the description of a neuronal circuitry model that integrates brain systems involved in performance monitoring, the processing of incentives, activation of attention systems and modulation of input functions, suggest that ‘attentional effort’ represents a viable construct for cognitive neuroscience research.
Ageing: the cholinergic hypothesis of cognitive decline
The concept that memory loss in ageing might be attributable to deficiencies in cholinergic function was first proposed two decades ago. This proposal gained additional definition when pathology was found in the basal forebrain cholinergic system of patients with Alzheimer's disease, and substantial deterioration of these neurons was detected in several animal models of ageing. A recently developed method for selectively removing basal forebrain cholinergic neurons using an immunotoxin provides a powerful tool for examining the function of the basal forebrain cholinergic system. This review will address new information that has come from this approach, with an emphasis on understanding the contribution of basal forebrain cholinergic neurons to age-related cognitive impairment.
Experimentation in the arbitrary increase in cortical acetylcholine
- Does acetylcholine pass the blood-brain barrier?
- Using acetylcholine reuptake inhibition, perhaps there is a way to flood the blood with acetylcholine. Theoretically, this will cause increased sustained attention.
- Flooding methodology: something that can block the reuptake of acetylcholine in the peripheral nervous system, either a dietary supplement or a way of sending action potentials that trigger the release of acetylcholine that subsequently is not immediately re-absorbed into the post-synaptic membranes within the peripheral nervous system. Hopefully the acetylcholine will travel to the prefrontal cortex instead.
- Fast-twitch muscle movements ?
- "anticholinesterase drugs—by permitting the concentration of acetylcholine molecules to build up" ...
- anticholinesterase (like physostigmine)
- anticholinesterase inhibitors (tacrine, donepezil, galanthamine, huperzine, and heptylphysostigmine)
- Synthesis and acetylcholinesterase/butyrylcholinesterase inhibition activity of new tacrine-like analogues
- Flooding methodology: something that can block the reuptake of acetylcholine in the peripheral nervous system, either a dietary supplement or a way of sending action potentials that trigger the release of acetylcholine that subsequently is not immediately re-absorbed into the post-synaptic membranes within the peripheral nervous system. Hopefully the acetylcholine will travel to the prefrontal cortex instead.
- In one of the articles mentioned above, there's evidence that REM is hyperattentional in nature, no doubt due to cholinergic neurons in the prefrontal cortex; if this is true, what is it that causes the sustained hyperattention in REM? Is it the rapid eye movements themselves that release excess acetylcholine into the blood and thus to the brain, or are the muscular movements for a different reason?
- "Human Retinas Synthesize and Release Acetylcholine" (Hutchins & Hollyfield)
2008-07-02: Increases in cortical acetylcholine release during sustained attention performance in rats
Increases in cortical acetylcholine release during sustained attention performance in rats
Anne Marie Himmelheber, Martin Sarter and John P. Bruno
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.
Author Keywords: Acetylcholine; Sustained attention; Microdialysis; Cortex; Basal forebrain; Operant performance
Sleep Deprivation and Brain Acetylcholine
Rats deprived of D-state sleep (and, to some extent, of slow-wave sleep) for 96 hours show a significant fall in brain acetylcholine in the telencephalon; there were no significant changes in the diencephalon and brain stem. Restraint stress and activity wheel stress produced no significant change in acetylcholine levels in any of these regions; the telencephalic response to sleep deprivation, therefore, cannot be attributed to nonspecific stress. The effects of D-state deprivation and the psychoactive anticholinergic drugs on telencephalic acetylcholine levels are similar.
Cholinesterase inhibitor effects on extracellular acetylcholine in rat cortex.
Messamore E, Warpman U, Ogane N, Giacobini E. Department of Pharmacology, Southern Illinois University School of Medicine, Springfield 62794-9230.
A microdialysis technique was used to sample acetylcholine (ACh) from the cerebral cortex of conscious rats. We thus investigated the effects of systemically administered cholinesterase inhibitors (ChEI) such as physostigmine (300 micrograms/kg), heptylphysostigmine (5 mg/kg) and tetrahydroaminoacridine (tacrine, 5 mg/kg) on extracellular ACh levels. Baseline quantities of extracellular ACh could be detected, even in the absence of ChEI. Acetylcholine levels increased to 1100% over baseline within 30 min of physostigmine administration and returned to control levels after 1.25 hr. Heptylphysostigmine elicited a maximal increase of 1000% within 1.5 hr, and the effect persisted up to 9.5 hr. A 500% increase was observed 1.5 hr after tacrine administration, and ACh returned to control levels after 4 hr. Although the ACh effects observed in this study correlated with previously determined levels of acetylcholinesterase (AChE) inhibition, we conclude that measures of cortical AChE activity alone are not sufficient to predict extracellular ACh levels following systemic ChEI administration.
Three dimensional structure of erabutoxin b neurotoxic protein: inhibitor of acetylcholine receptor.
The three-dimensional structure of erabutoxin b, a neurotoxin in the venom of the sea snake Laticauda semifasciata, has been determined from a 2.75 A resolution electron density map. Erabutoxin b is one of a family of snake venom neurotoxins, all low-molecular-weight proteins, which block neuromuscular transmission at the postsynaptic membrane. They specifically inhibit the acetylcholine receptor. The molecular shape is that of a shallow elongated saucer with a footed stand formed by the six-membered ring at the COOH-terminal end. The central core of the molecule is an assembly of four disulfide bridges. Three long chain loops emerge as broad fronds from the core region. Approximately 40% of the main chain is organized into a twisted antiparallel beta-pleated sheet of five short strands. In 28 snake venom neurotoxins of established sequence which inhibit the acetylcholine receptor, the four disulfide bridges and seven other residues remain invariant. Three substitution positions conserve residue type. In one wing of the molecule, there is a broad shallow depression which may characterize the reactive site. It is populated by the sevent invariant residues and two of the three type conserved residues. This region is "anchored" on the undersurface of the molecule by the hydroxyl group of Ser-9, the remaining conservatively substituted residue.
Manganism
Information on changes in the central nervous system (CNS) cholinergic systems following exposure to manganese are considerably less extensive than that associated with other neurotransmitter systems. However, experimental and clinical evidence support the notion that cholinergic activity plays a key role in the pathophysiology of manganese-induced neurotoxicity. Manganese acts as a chemical stressor in cholinergic neurons in a region-specific manner causing breakdown of the cellular homeostatic mechanisms. In fact, a number of cholinergic synaptic mechanisms are putative targets for manganese activity: presynaptic choline uptake, quantal release of acetylcholine into the synaptic cleft, postsynaptic binding of acetylcholine to receptors and its synaptic degradation by acetylcholinesterase. Moreover, manganese significantly influences astrocytic choline transport systems and astrocytic acetylcholine-binding proteins. Thus, manganese exerts its effect on the highly dynamic reciprocal relationship between astrocytes and cholinergic neurons. Cholinergic afferents are crucial in the physiology of locomotion, cognition, emotion and behavioral response, and therefore, it is not surprising that the anatomical selectivity of most manganese-induced cholinergic effects is compatible with the clinical correlates of manganism, which involves impairment of emotional response, decline in higher cortical functions and movement disorder. Manganism, also referred to as Parkinson's-like disorder, is initially manifested by a neuropsychiatric syndrome (locura manganica), the most frequent symptoms and signs of which are compulsive behavior, emotional lability, visual hallucinations and flight of ideas, cognitive decline and memory loss. These signs and symptoms are followed by an extrapyramidal syndrome, which shares numerous clinical and pathophysiological characteristics with idiopathic Parkinson's disease (PD). This natural history of disease could be a clinical reflection of the preferential involvement of the cholinergic systems, initially in the septo-hippocampus and later in the basal ganglia. These observations highlight the importance of studying the role of the CNS cholinergic systems in manganese-mediated neurotoxicity.
- The effect of manganese on ACh release: Manganese acts at presynaptic levels within the striatum by blocking release of the neurotransmitter (Fig. 1, point 3) thus creating a localized, relative deficit in caudate function
- The effect of manganese on AChE activity: Significant inhibition AChE activity (Fig. 1, point 4) was observed following lengthy periods of exposure to manganese.
Sleep
http://en.wikipedia.org/wiki/Sleep_paralysis
Paralysis occurs during REM sleep. What relation does this have to the 'sustained attention' (of REM) (mentioned above in this document), the ability of the retina to produce acetylcholine, cholinergic neurons for that sustained attention, and the inability to move (paralysis) ?? Where is the acetylcholine? Is there a defecit in the rest of the body?
Stuff
- Repeated pretreatment with amphetamine sensitizes increases in cortical acetylcholine release
- Cortical acetylcholine and processing capacity: effects of cortical cholinergic deafferentation on …
- Dopaminergic regulation of cortical acetylcholine release: effects of dopamine receptor agonists.
- Changes in cortical acetylcholine output induced by modulation of the nucleus basalis. -
- Basal forebrain glutamatergic modulation of cortical acetylcholine release - (Enki-2)
- Glutamatergic Modulation of Cortical Acetylcholine Release in the Rat: A Combined In Vivo …
- Operant performance and cortical acetylcholine release: role of response rate, reward density, and …
Trans-synaptic stimulation of cortical acetylcholine and enhancement of attentional functions: a … - Get this article - all 4 versions »
M Sarter, JP Bruno - Behavioural Brain Research, 1997 - Elsevier
... The complex effects of acetylcholine (ACh) in the ... of the performance-associated
increases in cortical ... of BZR inverse agonists to increase cortical ACh release ...
Cited by 22 - Related Articles - Web Search
The effects of manipulations of attentional demand on cortical acetylcholine release - all 8 versions » AM Himmelheber, M Sarter, JP Bruno - Cognitive Brain Research, 2001 - Elsevier ... into the operant chambers robustly increased cortical ACh efflux ... ACh efflux, and these increases were not ... within a session, to either increase or decrease ... Cited by 29 - Related Articles - Web Search
Dopaminergic regulation of cortical acetylcholine release. - all 2 versions » J Day, HC Fibiger - Synapse, 1992 - ncbi.nlm.nih.gov ... vivo microdialysis of cortical acetylcholine (ACh ... agonist apomorphine significantly increased dialysate concentrations ... amphetamine-induced increase in cortical ... Cited by 59 - Related Articles - Web Search - Find it at UT - BL Direct
Stimulation of cortical acetylcholine efflux by FG 7142 measured with repeated microdialysis … - all 2 versions » H Moore, S Stuckman, M Sarter, JP Bruno - Synapse, 1995 - ncbi.nlm.nih.gov Stimulation of cortical acetylcholine efflux by FG 7142 measured ... beta-carboline FG 7142 on cortical ACh efflux ... mg/kg) produced a 150-470% increase in cortical ... Cited by 41 - Related Articles - Web Search - Find it at UT - BL Direct
Basal forebrain glutamatergic modulation of cortical acetylcholine release
email: John P. Bruno (bruno.1@osu.edu)
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 M) 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 M) 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. Synapse 39:201-212, 2001. © 2001 Wiley-Liss, Inc.
kainate is a ionotropic glutamate agonist ($154 for 10 mg at Sigma-Aldrich - with genes for humans, mice, etc.) and apparently kainate mimics the effects of glutamate.
aniracetam -- selectively modulates the AMPA ionotropic glutamate receptor
Types of ionotropic glutamate receptors:
query: acetylcholine efflux cholinergic afferents
- Role of accumbens and cortical dopamine receptors in the regulation of cortical acetylcholine …
Role of accumbens and cortical dopamine receptors in the regulation of cortical acetylcholine release
- benzodiazepine receptor partial inverse agonist FG 7142 (an anorectic) (reduces apetite)
- $120 for 100 mg
- antipsychotic drug haloperidol (0.15, 0.9 mg/kg, i.p.) blocked FG 7142
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, 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 μM) 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 μM) 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.
Stimulation of cortical acetylcholine release following blockade of ionotropic glutamate receptors
In vivo microdialysis techniques were used to determine the ability of glutamate receptors within the nucleus accumbens to trans-synaptically modulate the basal forebrain cortical cholinergic system. Rats were implanted with a dialysis probe in the medial prefrontal cortex to measure changes in cortical acetylcholine efflux and in the ipsilateral nucleus accumbens to locally manipulate glutamate receptor activity. Intra-accumbens perfusion of the broad spectrum ionotropic glutamate receptor antagonist kynurentate (1.0, 5.0 mm) led to a dose-dependent increase (maximum of 200%) in cortical acetylcholine efflux. This stimulated efflux was reproduced with the intra-accumbens perfusion of the AMPA/kainate antagonist DNQX (0.1, 0.25, 2.5 mm; maximum increase of 200%) or the NMDA antagonist D-CPP (10.0, 100.0, 200 µM; maximum increase of 400%). These results reveal a significant glutamatergic tone within the accumbens of awake rats and support the hypothesis that accumbens efferents to basal forebrain modulate the excitability of the basal forebrain cortical cholinergic system.
A Possible Role for Cholinergic Neurons of the Basal Forebrain and Pontomesencephalon in Consciousness
Nancy J. Woolf
Excitation at widely dispersed loci in the cerebral cortex may represent a neural correlate of consciousness. Accordingly, each unique combination of excited neurons would determine the content of a conscious moment. This conceptualization would be strengthened if we could identify what orchestrates the various combinations of excited neurons. In the present paper, cholinergic afferents to the cerebral cortex are hypothesized to enhance activity at specific cortical circuits and determine the content of a conscious moment by activating certain combinations of postsynaptic sites in select cortical modules. It is proposed that these selections are enabled by learning-related restructuring that simultaneously adjusts the cytoskeletal matrix at specific constellations of postsynaptic sites giving all a similar geometry. The underlying mechanism of conscious awareness hypothetically involves cholinergic mediation of linkages between microtubules and microtubule-associated protein-2 (MAP-2). The first reason for proposing this mechanism is that previous studies indicate cognitive-related changes in MAP-2 occur in cholinoceptive cells within discrete cortical modules. These cortical modules are found throughout the cerebral cortex, measure 1–2 mm2, and contain approximately 103–104cholinoceptive cells that are enriched with MAP-2. The subsectors of the hippocampus may function similarly to cortical modules. The second reason for proposing the current mechanism is that the MAP-2 rich cells throughout the cerebral cortex correspond almost exactly with the cortical cells containing muscarinic receptors. Many of these cholinoceptive, MAP-2 rich cells are large pyramidal cell types, but some are also small pyramidal cells and nonpyramidal types. The third reason for proposing the current mechanism is that cholinergic afferents are module-specific; cholinergic axons terminate wholly within individual cortical modules. The cholinergic afferents may be unique in this regard. Finally, the tapering apical dendrites of pyramidal cells are proposed as primary sites for cholinergic mediation of linkages between MAP-2 and microtubules because especially high amounts of MAP-2 are found here. Also, the possibility is raised that muscarinic actions on MAP-2 could modulate microtubular coherence and self-collapse, phenomena that have been suggested to underlie consciousness.
Anne Marie Brady
- http://www.odonnell-lab.net/amh.htm
- http://www.smcm.edu/Psyc/FacultySites/ambrady/Documents/BradyCV0807.pdf
Sarter, M., Bruno, J.P., and Himmelheber, A.M. (1997). Cortical acetylcholine and attention: Neuropharmacological and cognitive principles directing treatment strategies for cognitive disorders. In J.E. Brioni and M.W. Decker (Eds.), Pharmacological Treatment of Alzheimer’s Disease: Molecular and Neurobiological Foundations (pp. 105-128). New York: John Wiley.
The effects of manipulations of attentional demand on cortical acetylcholine release
Himmelheber, A.M., Sarter., and Bruno, J.P. (2001). The effects of manipulations of attentional demand on cortical acetylcholine release. Cognitive Brain Research, 12, 353-370.
Effects of intra-accumbens infusions of amphetamine or cis-flupenthixol on sustained attention performance in rats
Himmelheber, A.M., Bruno, J.P., and Sarter, M. (2000). Effects of intra-accumbens infusions of amphetamine or cis-flupenthixol on sustained attention performance in rats. Behavioural Brain Research, 116, 123-133.
Increases in cortical acetylcholine release during sustained attention performance in rats
Himmelheber, A.M., Sarter, M., and Bruno, J.P. (2000). Increases in cortical acetylcholine release during sustained attention performance in rats. Cognitive Brain Research, 9, 313-325.
In vivo neurochemical correlates of cognitive processes
Bruno, J.P., Sarter, M., Arnold, H.M., and Himmelheber, A.M. (1999). In vivo neurochemical correlates of cognitive processes: Methodological and conceptual challenges. Reviews in the Neurosciences, 10, 25-48.
Effects of local cholinesterase inhibition on acetylcholine release assessed simultaneously in prefrontal and frontoparietal cortex
Himmelheber, A.M., Fadel, J., Sarter, M., and Bruno, J.P. (1998). Effects of local cholinesterase inhibition on acetylcholine release assessed simultaneously in prefrontal and frontoparietal cortex. Neuroscience, 86, 949-957.
Sustained attention performance is associated with cortical acetylcholine release in rats
Himmelheber, A.M., Sarter, M., and Bruno, J.P. (1999). Sustained attention performance is associated with cortical acetylcholine release in rats. Society for Neuroscience Abstracts, 25, 1895.
Effects of tactile stimulation on cortical ACh efflux
Himmelheber, A.M., Fadel, J., Sarter, M., and Bruno, J.P. (1997). The parallel assessment of acetylcholine efflux in two cortical areas: Effects of tactile stimulation and cholinesterase inhibition. Society for Neuroscience Abstracts, 23, 2016.
Cortical ACh efflux and attention
Bruno, J.P., Sarter, M., Himmelheber, A.M., and Katovic, N.M. (1996). Cortical acetylcholine efflux and attention. Annual Meeting of the European Behavioral Pharmacology Society, Cagliari, Italy, May 1996.
Enhancement of hippocampal cholinergic neurotransmission through 5-HT1A receptor-mediated pathways by repeated lithium treatment in rats
Enhancement of hippocampal cholinergic neurotransmission through 5-HT1A receptor-mediated pathways by repeated lithium treatment in rats
Takeshi Fujii, Katsuhiko Nakai, Yasuo Nakajima, and Koichiro Kawashima
Abstract: Hippocampal cholinergic neuronal activity is reported to be regulated, at least partly, through serotonin1A (5-HT1A) receptors. Chronic lithium treatment has been shown to alter both behavioral and neurochemical responses mediated by postsynaptic 5-HT1A receptors. We investigated whether long-term lithium treatment affects central cholinergic neurotransmission through 5-HT1A receptor-mediated pathways. Changes in acetylcholine (ACh) release induced by 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT), a 5-HT1A receptor agonist, in the rat hippocampus were measured using a microdialysis technique and a radioimmunoassay for ACh. Administration of lithium for 21 days resulted in a serum lithium concentration of 1.03 mM and caused little change in density or affinity of [3H]8-OH-DPAT binding sites in the hippocampus. The local application of 8-OH-DPAT into the hippocampus of lithium treated rats increased the ACh efflux in both the absence and the presence of physostigmine, a cholinesterase (ChE) inhibitor, in the perfusion fluid. The basal ACh efflux of lithium treated rats was not different from that of the control rats under normal conditions, but was significantly higher than that of the controls when ChE was inhibited. These results demonstrate that chronic lithium treatment increases spontaneous ACh release in the hippocampus under conditions of ChE inhibition, but not under normal conditions, and enhances cholinergic neurotransmission through 5-HT1A receptor-mediated pathways, and suggest that activation of 5-HT1A receptor function by lithium is related to the enhancement of hippocampal cholinergic neurotransmission.
On the trail of a cognitive enhancer for the treatment of schizophrenia
Atypical antipsychotics increase acetylcholine release in prefrontal cortex and hippocampus (Ichikawa et al., 2001). Olanzapine seems to be the most powerful on this mechanism as suggested by Shirazi-Southall’study (2002) on the acetylcholine efflux in rat hippocampus.
Dopamine and anatgonists
http://lansbury.bwh.harvard.edu/da_and_antagonists.htm
Adachi, Y. U., K. Watanabe, et al. (2002). "Halothane enhances acetylcholine release by decreasing dopaminergic activity in rat striatal slices." Neurochem Int 40(3): 189-93.
Attention in learning and action
mance of visual attention tasks (Arnold, Burk, Hodgson, Sarter, & Bruno, 2002; Himmelheber, Sarter, & Bruno, 2000, 2001; Kozak, Bruno, & Sarter, 2006; Passetti, Dalley, O’Connell, Everitt, & Robbins, 2000). Similarly, Apparsundaram, Martinez, Parikh, Kozak, and Sarter (2005) found increased capacity and density of choline transporters on the synaptic membranes of right medial prefrontal cortical neurons in rats performing a sustained attention task. Many of these task-induced changes in cortical cholinergic activity have also been shown to depend on input from SI/nBM.
For example, McGaughy et al. (2002) found that cholinergicspecific
SI/nBM lesions produced both deficits in behavior and
reduced acetylcholine efflux in the mPFC during performance of a
5CSRT task. In a related fashion, Gill, Sarter, and Givens (2000),
by using single unit recording during a sustained attention task in
rats, found that unilateral cholinergic deafferentation produced a
decrease in the overall firing rate of medial prefrontal neurons and
a reduced correlation between firing patterns and behavioral performance.
Taken together, these findings all support a role of basal
forebrain modulation of cortical cholinergic function, specifically
in regard to attentional processes.
The data presented in this article complement and extend these
findings by indicating that modulation of the activity of frontal and
parietal regions by cholinergic SI/nBM neurons may serve distinct
attentional functions in the context of simple associative learning.
The double dissociation in the effects of 192IgG-saporin infusions
into PPC and MFC further indicates that separate subpopulations
of SI/nBM neurons within SI/nBM are responsible for these complementary
aspects of attention. Notably, if the same SI/nBM
neurons served both functions, projecting to both PPC and MFC,
infusions of 192IgG-saporin into either of those cortical regions
would destroy the same SI/nBM neurons and hence would have
the same behavioral effects. The dissociation in lesion effects we
observed is consistent with the results of anatomical studies (Gritti,
Mainville, Mancia, & Jones, 1997; Saper, 1984), including doublelabeling
retrograde tracer studies (Bigl, Woolf, & Butcher, 1982;
Price & Stern, 1983), which show little evidence for collateralization
of axons of SI/nBM neurons and reveal very limited cortical
projection fields of individual SI/nBM neurons. At the same time,
these subpopulations of neurons, which project to vastly different
neocortical regions, are largely intermingled throughout SI/nBM,
showing little evidence of topographical organization. Finally, the
observations that both action and learning aspects of attention in
associative learning were altered in the present experiments by
CEA lesions and by disconnection of CEA from SI/nBM cholinergic
neurons in previous studies (Han et al., 1999; Holland, in
press) indicate that CEA modulates the activity of both of these
subpopulations.
Most views of attention in human information processing describe
it as a collection of interrelated processes that converge to
produce task-relevant behaviors. These processes may be event
driven (bottom up) or goal driven (top down) and may include
event detection, orienting, perceptual analysis, selection of items to
be further processed or ignored, aspects of working memory,
vigilance, decision and response selection, response production,
and others (e.g., Allport, 1989; Awh & Jonides, 2001; Egeth &
Yantis, 1997; Jonides, Lacey, & Nee, 2005; Pashler, 1998). Anatomically,
these processes are often thought to be served by networks
of brain regions, each of which may implement different
aspects of attentional processing (e.g., Posner & Dehaene, 1994;
Posner & Petersen, 1990). Our observation that selection of attention
for new learning and for directed action in associative learning
are mediated by different cortical regions is consistent with this
general statement. Whether the parietal and frontal (respectively)
systems we examined in this study relate to the parietal and frontal
attention networks described in humans remains to be seen. Many
findings suggest caution. For example, most tasks used to study
attention in humans can be characterized as assessing attention in
the selection of action rather than the selective acquisition of new
information. Nevertheless, performance in many of these tasks
produces parietal activation in humans and is impaired in patients
with parietal damage. Indeed, performance in response selection
tasks in which cue validity is manipulated (as in Experiment 1) is
typically attributed to the activity of parietal systems (e.g., Posner
& Petersen, 1990; Posner, Walker, Friedrich, & Rafal, 1984).
Similarly, in humans, MFC has been reported to be sensitive to
reward prediction error, which we relate to attention in new learning.
Potts, Martin, Burton, and Montague (2006) found that that
the event-related potential (ERP) recorded from medial frontal
locations was most positive when an unpredicted reward was
delivered and most negative when a predicted reward was omitted.
Potts et al. (2006) placed these results in the framework of a gating
hypothesis (Cohen, Braver, & Brown, 2002) whereby midbrain
dopamine neurons, which respond to prediction error, modulate
activity of MFC to allow enhanced processing of incoming information
when reward expectation is violated. Notably, this suggestion
is comparable with the function that we ascribed to PPC rather
than to MFC, in Experiment 2, in which we found no effects of
MFC lesions on the rats’ ability to use prediction error information
to enhance overshadowing in new learning. Of course, our lesions,
which were intended to selectively reduce cholinergic innervation
of MFC, likely spared MFC functions that might be modulated by
dopaminergic input to MFC. It is tempting to speculate that dopaminergic
and cholinergic modulation of cortical subregions subserve
different functions and that lesions of the dopaminergic input
to MFC might have had very different effects in our current
studies.
In this regard it is informative to place the present data within
other theoretical perspectives of cholinergic action in attention. In
particular, Sarter et al. (2005) distinguished between signal-driven
cholinergic modulation of detection processes and top-down or
cognitive modulation of detection and other aspects of information
processing. In the present context, the cue duration-dependent
response deficits observed with MFC cholinergic deafferentation
would reflect a role for MFC in the former and a role for PPC in
the latter. Notably, within Sarter et al’s (2005) framework, a major
function of prefrontal cortex in attention is to provide top-down
modulation of cholinergic innervation of other cortical areas, especially
the posterior attention system that includes PPC. Thus, the
SI/nBM–PPC projections critical to surprise-induced enhancement
of learning might themselves be modulated by projections from
MFC to PPC (both direct and indirect, via SI/nBM), which could
convey such top-down prediction error information (Nelson,
Sarter, & Bruno, 2005; Reep et al., 1994). Although the results of
Experiment 2 show that any such modulation of PPC by MFC does
not depend on intact cholinergic input to MFC, they do not
preclude the possibility that MFC serves this critical role in topdown
information processing. Thus, it would be valuable to determine
the effects on surprise-induced learning enhancements of
Second-by-second measurement of acetylcholine release in the prefrontal cortex
Second-by-second measurement of acetylcholine release in the prefrontal cortex [pdf]
http://faculty.psy.ohio-state.edu/bruno/
Microdialysis has been widely used to measure acetylcholine (ACh) release in vivo and has provided important insights into the
regulation of cholinergic transmission. However, microdialysis can be constrained by limited spatial and temporal resolution. The
present experiments utilize a microelectrode array (MEA) to rapidly measure ACh release and clearance in anaesthetized rats. The
array electrochemically detects, on a second-by-second basis, changes in current selectively produced by the hydrolysis of ACh to
choline (Ch) and the subsequent oxidation of choline and hydrogen peroxidase (H2O2) at the electrode surface. In vitro calibration of
the microelectrode revealed linear responses to ACh (R2 ¼ 0.9998), limit of detection of 0.08 lm, and signal-to-noise ratio of 3.0. The
electrode was unresponsive to ascorbic acid (AA), dopamine (DA), or norepinephrine (NE) interferents. In vivo experiments were
conducted in prefrontal cortex (PFC) of anaesthetized rats. Pressure ejections of ACh (10 mm; 40 nL) through an adjoining
micropipette produced a rapid rise in current, reaching maximum amplitude in �1.0 s and cleared by 80% within 4–11 s.
Endogenously released ACh, following local depolarization with KCl (70 mm; 40, 160 nL), was detected at values as low as 0.05 lm.
These signals were volume-dependent and cleared within 4–12 s. Finally, nicotine (1.0 mm, 80 nL) stimulated ACh signals. Nicotineinduced
signals reflected the hydrolysis of ACh by endogenous acetylcholinesterase (AChE) as inhibition of the enzyme following
perfusion with neostigmine (10 lm) attenuated the signal (40–94%). Collectively, these data validate a novel method for rapidly
measuring cholinergic transmission in vivo with a spatial and temporal resolution that far exceeds conventional microdialysis.
M Sarter
http://sitemaker.umich.edu/martin.sarter/faculty_profile
The regulation of the choline transporter has emerged as a major subject in this research. We have recently shown that attentional performance enhanced the capacity of choline transporters in the medial prefrontal cortex, and that increased intracellular choline transporter trafficking may have been responsible for the enhanced capacity of transporters to import choline into neurons. The regulation of choline transporter function by other neuronal systems, particularly the dopaminergic system, represents another focus of our research.
Our research utilizes complex behavioral methods for the assessment of attentional functions in laboratory animals, in vivo microdialysis for the measurement of transmitter release in task-performing animals, in vivo amperometric measures of acetylcholine release and choline clearance, and ex vivo neurochemical methods for the characterization of choline transporter functions.
Apparsundaram, S., Martinez, V., Parikh, V., Kozak, R., & Sarter, M. (2005). Increased capacity and density of choline transporters situated in synaptic membranes of the right medial prefrontal cortex of attentional task-performing rats. Journal of Neuroscience, 25: 3851-3856.
Sarter, M., & Parikh, V. (2005). Choline transporters, cholinergic transmission and cognition. Nature Reviews Neuroscience, 6, 48-56.
Kozak, R., Bruno, J.P. & Sarter, M. (2006). Augmented prefrontal acetylcholine release during challenged attentional performance. Cerebral Cortex, 16, 9-17.
Sarter, M. (2006). Preclinical research on cognition enhancers. Trends in Pharmacological Sciences, 27, 602-608.
Parikh, V., & Sarter M. (2006). Cortical choline transporter function measured in vivo using choline-sensitive microelectrodes: clearance of endogenous and exogenous choline and effects of removal of cholinergic terminals. Journal of Neurochemistry, 97, 488-503.
Sarter, M., Bruno, J.P. & Parikh, V. (2007). Abnormal neurotransmitter release in behavioral and cognitive disorders: toward concepts of dynamic and function-specific dysregulation. Neuropsychopharmacology, 32, 455-463.
Kozak, R., Martinez, M., Brown, H., Bruno, J.P. & Sarter M. (2007). Toward a neuro-cognitive animal model of the cognitive symptoms of schizophrenia: disruption of cortical cholinergic neurotransmission following repeated amphetamine exposure in attentional task-performing, but not non-performing, rats. Neuropsychopharmacology, 32, 2074-2088.
Briand, L.A, Gritton, H., Howe, W.M., Young, D.A., & Sarter, M. (2007). Modulators in concert for cognition: modulator interactions in the prefrontal cortex. Progress in Neurobiology, 83, 69-91
Parikh, V., Kozak, R., Martinez, V., & Sarter, M. (2007). Prefrontal acetylcholine controls cue detection on multiple time scales. Neuron, 56, 141-154.
Martinez, V., & Sarter, M. (2008). Detection of the moderately beneficial effects of low-dose treatment with haloperidol or clozapine in an amphetamine model of the attentional impairments of schizophrenia. Neuropsychopharmacology , in press.
Briand, L.A., Flagel, S.B., Garcia-Fuster, M.J., Watson, S.J., Akil, H., Sarter, M., & Robinson, T.E. (2008). Persistent alterations in cognitive function and prefrontal dopamine D2 receptors following extended, but not limited, access to self-administered cocaine. Neuropsychopharmacology, in press.
Giuliano, C., Parikh, V., Ward, J.R., Chiamulera, C., & Sarter, M. (2008). Increases in cholinergic neurotransmission measured by using choline-sensitive microelectrodes: enhanced detection by hydrolysis of acetylcholine on recording sites? Neurochemistry International, 52, 1343-1350.
Parikh, V., Man, K., Decker, M.W., & Sarter, M. (2008). Glutamatergic contributions to nAChR agonist-evoked cholinergic transients in the prefrontal cortex. Journal of Neuroscience, 28, 3769-3780.
Sarter M. (2008). The substantia innominata remains incognita: pressing research themes on basal forebrain neuroanatomy. Brain Structure & Function, in press.
More stuff
Glutamate receptors in nucleus accumbens mediate regionally selective increases in cortical acetylcholine release
Glutamate receptors in nucleus accumbens mediate regionally selective increases in cortical acetylcholine release
Amy Zmarowski 1, Martin Sarter 2, John P. Bruno
email: John P. Bruno (bruno.1@osu.edu)
The basal forebrain cortical cholinergic system (BFCS) is critical for the regulation of attentional information processing. BFCS activity is regulated by several cortical and subcortical structures, including the nucleus accumbens (NAC) and prefrontal cortex (PFC). GABAergic projection neurons from NAC to basal forebrain are modulated by Glu receptors within NAC. We previously reported that intra-NAC perfusions of NMDA or its antagonist CPP stimulate ACh release in PFC. In this experiment we determined whether this trans-synaptic modulation of cortical ACh release is evident in multi-sensory associational areas like the posterior parietal cortex (PPC).
Artificial cerebrospinal fluid (aCSF, control), NMDA (250 or 400 M), or CPP (200 or 400 M) were perfused into the NAC shell and ACh was measured in the ipsilateral PPC. Amphetamine (2.0 mg/kg, i.p), was systemically administered as a positive control in a fourth session, since it also stimulates cortical ACh release but via mechanisms known to not necessitate transmission within the NAC. Neither NMDA nor CPP increased ACh efflux in the PPC, yet both drugs increased ACh release in PFC, suggesting that NMDA receptor modulation in the NAC increases ACh in the cortex in a regionally-specific manner.
Systemic amphetamine administration significantly increased (100-200%) ACh in the PPC, suggesting that levels of ACh in the PPC can be increased following certain pharmacological manipulations. The cortical region-specific (@ PPC !PFC) modulation of ACh by NAC may underlie the linkage of motivational information with top-down controls of attention as well as guide appropriate motor output following exposure to salient and behaviorally relevant stimuli. Synapse 61:115-123, 2007.
Enhanced anterior-temporal processing for complex tones in musicians
Enhanced anterior-temporal processing for complex tones in musicians
Clinical Neurophysiology , Volume 118 , Issue 1 , Pages 209 - 220
A . Shahin , L . Roberts , C . Pantev , M . Aziz , T . Picton
Auditory responses in the anterior temporal cortex to complex musical tones are larger in musicians than non-musicians.
Neural networks in the anterior temporal cortex are activated during the processing of complex sounds. Their greater activation in musicians may index either underlying cortical differences related to musical aptitude or cortical modification by acoustical training.
Anatomical analysis of afferent projections to the medial prefrontal cortex in the rat
Anatomical analysis of afferent projections to the medial prefrontal cortex in the rat
Walter B. Hoover and Robert P. Vertes
The medial prefrontal cortex (mPFC) has been associated with diverse functions including attentional processes, visceromotor activity, decision making, goal directed behavior, and working memory. Using retrograde tracing techniques, we examined, compared, and contrasted afferent projections to the four divisions of the mPFC in the rat: the medial (frontal) agranular (AGm), anterior cingulate (AC), prelimbic (PL), and infralimbic (IL) cortices. Each division of the mPFC receives a unique set of afferent projections. There is a shift dorsoventrally along the mPFC from predominantly sensorimotor input to the dorsal mPFC (AGm and dorsal AC) to primarily ‘limbic’ input to the ventral mPFC (PL and IL). The AGm and dorsal AC receive afferent projections from widespread areas of the cortex (and associated thalamic nuclei) representing all sensory modalities. This information is presumably integrated at, and utilized by, the dorsal mPFC in goal directed actions. In contrast with the dorsal mPFC, the ventral mPFC receives significantly less cortical input overall and afferents from limbic as opposed to sensorimotor regions of cortex. The main sources of afferent projections to PL/IL are from the orbitomedial prefrontal, agranular insular, perirhinal and entorhinal cortices, the hippocampus, the claustrum, the medial basal forebrain, the basal nuclei of amygdala, the midline thalamus and monoaminergic nuclei of the brainstem. With a few exceptions, there are few projections from the hypothalamus to the dorsal or ventral mPFC. Accordingly, subcortical limbic information mainly reaches the mPFC via the midline thalamus and basal nuclei of amygdala. As discussed herein, based on patterns of afferent (as well as efferent) projections, PL is positioned to serve a direct role in cognitive functions homologous to dorsolateral PFC of primates, whereas IL appears to represent a visceromotor center homologous to the orbitomedial PFC of primates.
Muscarinic M2 and M1 Receptors Reduce GABA Release by Ca2+ Channel Modulation Through Activation of PI3K/Ca2+-Independent and PLC/Ca2+-Dependent PKC
H. Salgado, T. Bellay, J. A. Nichols, M. Bose, L. Martinolich, L. Perrotti and M. Atzori
http://jn.physiology.org.ezproxy.lib.utexas.edu/cgi/content/abstract/98/2/952
We measured pharmacologically isolated GABAergic currents from layer II/III neurons of the rat auditory cortex using patch-clamp recording. Activation of muscarinic receptors by muscarine (1 µM) or oxotremorine (10 µM) decreased the amplitude of electrically evoked inhibitory postsynaptic currents to about one third of their control value. Neither miniature nor exogenously evoked GABAergic currents were altered by the presence of muscarinic agonists, indicating that the effect was spike-dependent and not mediated postsynaptically. The presence of the N- or P/Q-type Ca2+ channel blockers -conotoxin GVIA (1 µM) or -AgaTx TK (200 nM) greatly blocked the muscarinic effect, suggesting that Ca2+-channels were target of the muscarinic modulation. The presence of the muscarinic M2 receptor (M2R) antagonists methoctramine (5 µM) or AF-DX 116 (1 µM) blocked most of the muscarinic evoked inhibitory postsynaptic current (eIPSC) reduction, indicating that M2Rs were responsible for the effect, whereas the remaining component of the depression displayed M1R-like sensitivity. Tissue preincubation with the specific blockers of phosphatidyl-inositol-3-kinase (PI3K) wortmannin (200 nM), LY294002 (1 µM), or with the Ca2+-dependent PKC inhibitor Gö 6976 (200 nM) greatly impaired the muscarinic decrease of the eIPSC amplitude, whereas the remaining component was sensitive to preincubation in the phospholipase C blocker U73122 [GenBank] (10 µM). We conclude that acetylcholine release enhances the excitability of the auditory cortex by decreasing the release of GABA by inhibiting axonal V-dependent Ca2+ channels, mostly through activation of presynaptic M2Rs/PI3K/Ca2+-independent PKC pathway and—to a smaller extent—by the activation of M1/PLC/Ca2+-dependent PKC.
- methoctramine
- muscarinic M2 receptor (M2R) antagonist
- http://the-half-decent-pharmaceutical-chemistry-blog.chemblogs.org/archives/2007/02/03/saturday-night-synthesis-methoctramine
- http://209.85.215.104/search?q=cache:BF0YbKTEcSYJ:the-half-decent-pharmaceutical-chemistry-blog.chemblogs.org/archives/2007/02/03/saturday-night-synthesis-methoctramine+methoctramine&hl=en&ct=clnk&cd=4&gl=us
- http://www.sigmaaldrich.com/catalog/search/ProductDetail/SIGMA/M105
- $100/10 mg
- Methoctramine is a selective M2 muscarinic receptor antagonist at nM concentrations. At mM concentrations, methoctramine directly inhibits the high affinity GTPase activity of G proteins. The increase in calcium and arachidonic acid release were attenuated by the M2 receptor antagonist methoctramine, but not by the M3 receptor antagonist p-fluoro-hexahydro siladifenidol.
Saturday Night Synthesis: methoctramine
This was their starting point. It's called benextramine, it's an irreversible alpha-1 antagonist: its four amino groups are all protonated at physiologic pH and, through an induced fit mechanism, force the receptor to expose four cysteines, which react with the disulfide, binding covalently.
Now, that's fine, but researchers realised this molecule has competitive antagonism on muscaric receptors as well.
So, they threw away most of the functional groups and reduced everything to a polyamine.
Such a simple backbone is what they later called the (perfect) universal template: theoretically, it could react with any receptor, it actually has specific carriers, all the amines are protonated (only if n > 3, though) so that they could react with carboxyls, hydroxyls, thiols and aromatics.
What's more, the structure is extremely flexible and easy to modify, so it is NOT a toxin.
You can, in fact, vary the distance between the amines and/or add functions to achieve selectivity.
So, there you are: a pretty easy operation. They came up with a simple polyamine, as a base, and turn it into this!
It's called, simply, Methoctramine and I'm glad to report that it's just uncanny.
Its structure can remind you of benextramine but the disulfide bond is gone, so there's no risk of covalent bonds any more.
The result is dramatic. It's, almost equa