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.