Abnormal Neurotransmitter Release Underlying Behavioral and Cognitive Disorders: Toward Concepts of Dynamic and Function-Specific Dysregulation

Sarter, Martin; Bruno, John P; Parikh, Vinay

doi:10.1038/sj.npp.1301285

Cited by 100Neuroscience and Neuropharmacology ResearchNeurotransmitter Receptor Influence on BehaviorGenetics and Neurodevelopmental Disorders

Abnormal Neurotransmitter Release Underlying Behavioral and Cognitive Disorders: Toward Concepts of Dynamic and Function-Specific Dysregulation

Sarter, Martin, Bruno, John P, Parikh, Vinay·2007·Neuropsychopharmacology

DOI 10.1038/sj.npp.1301285

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Abstract

Abnormalities in the regulation of neurotransmitter release and/or abnormal levels of extracellular neurotransmitter concentrations have remained core components of hypotheses on the neuronal foundations of behavioral and cognitive disorders and the symptoms of neuropsychiatric and neurodegenerative disorders. Furthermore, therapeutic drugs for the treatment of these disorders have been developed and categorized largely on the basis of their effects on neurotransmitter release and resulting receptor stimulation. This perspective stresses the theoretical and practical implications of hypotheses that address the dynamic nature of neurotransmitter dysregulation, including the multiple feedback mechanisms regulating synaptic processes, phasic and tonic components of neurotransmission, compartmentalized release, differentiation between dysregulation of basal vs activated release, and abnormal release from neuronal systems recruited by behavioral and cognitive activity. Several examples illustrate that the nature of the neurotransmitter dysregulation in animal models, including the direction of drug effects on neurotransmitter release, depends fundamentally on the state of activity of the neurotransmitter system of interest and on the behavioral and cognitive functions recruiting these systems. Evidence from evolving techniques for the measurement of neurotransmitter release at high spatial and temporal resolution is likely to advance hypotheses describing the pivotal role of neurotransmitter dysfunction in the development of essential symptoms of major neuropsychiatric disorders, and also to refine neuropharmacological mechanisms to serve as targets for new treatment approaches. The significance and usefulness of hypotheses concerning the abnormal regulation of the release of extracellular concentrations of primary messengers depend on the effective integration of emerging concepts describing the dynamic, compartmentalized, and activity-dependent characteristics of dysregulated neurotransmitter systems.

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The limited therapeutic, pro-cognitive efficacy of AChE inhibitors appears to be an expected finding when considering that inhibition of AChE is not capable of restoring or augmenting the phasic glutamatergic-cholinergic interactions which mediate defined cognitive operations.
“The limited therapeutic, pro-cognitive efficacy of AChE inhibitors (e.g., Pepeu and Giovannini, 2009) appears to be an expected finding when considering that inhibition of AChE is not capable of restoring or augmenting the phasic glutamatergic-cholinergic interactions which, as will be described below, mediate defined cognitive operations (see also Sarter and Bruno, 2002; Sarter et al, 2007).”
From Modes and models of forebrain cholinergic neuromodulation of cognition (2011) · cites this paper as Sarter et al, 2007

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Modes and models of forebrain cholinergic neuromodulation of cognition
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Restoration of dopamine release deficits during object recognition memory acquisition attenuates cognitive impairment in a triple transgenic mice model of Alzheimer’s disease
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Authors: Sarter, M., Bruno, J. P., & Parikh, V.
Affiliations: University of Michigan (US)
The Ohio State University (US)
Corresponding author: Sarter, Martin
ORCID: Sarter, Martin
Bruno, John P
Parikh, Vinay
Venue: Neuropsychopharmacology
Publisher: Springer Science and Business Media LLC
Published: 2006-12-13
Volume: 32
Issue: 7
Pages: 1452-1461
ISSN: 0893-133X (ISSN-L)
1740-634X
DOI: 10.1038/sj.npp.1301285
OpenAlex: W2090966001
Cited by: 100
References: 125
Citations by year: 2026: 6 · 2025: 16 · 2024: 11 · 2023: 8 · 2022: 9 · 2021: 8 · 2020: 5 · 2019: 2 · 2018: 3 · 2017: 2 · 2016: 4 · 2015: 1 · 2014: 3 · 2013: 2 · 2012: 3
FWCI: 0.41
Type: journal article
Language: en
Open access: closed
Licence: www.springer.com/tdm (tdm)
Locations: Neuropsychopharmacology (publishedVersion)
PubMed (publishedVersion)
Funders: National Institute of Mental Health (KO2MH10172, R01MH063114, R01MH057436, MH 057436, MH073600, MH 063114, R03MH073600)
National Institute on Drug Abuse (DA019502, R01DA019502)
National Institute of Neurological Disorders and Stroke (NS37026, R01NS037026)
Topics: Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neurotransmitter Receptor Influence on Behavior
Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetics and Neurodevelopmental Disorders
Keywords: neurotransmitter release, neurotransmitter dysregulation, behavioral disorders, cognitive disorders, neuropsychiatric disorders, neurodegenerative diseases, extracellular neurotransmitter concentrations
MeSH terms: Animals, Mental Disorders, Brain, Brain Chemistry, Cognition Disorders, Humans, Synaptic Transmission, Neurotransmitter Agents

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Abnormal Neurotransmitter Release Underlying Behavioral and Cognitive Disorders: Toward Concepts of Dynamic and Function-Specific Dysregulation

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