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

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 activitydependent characteristics of dysregulated neurotransmitter systems.

Detection of the Moderately Beneficial Cognitive Effects of Low-Dose Treatment with Haloperidol or Clozapine in an Animal Model of the Attentional Impairments of Schizophrenia

“…In this context, it is noteworthy that we also demonstrated that the consequences of AMPH pretreatment and -challenge on cholinergic activity did not manifest in control animals not performing the attention task. Therefore, the present results may not generalize to a test of the effects of the antipsychotic treatments in interaction with AMPH pretreatment and -challenges on other behavioral or cognitive operations that do not, or not to the same degree, depend on cortical cholinergic activity (see also Sarter et al, 2007). Furthermore, we hypothesized that the frozen cortical cholinergic input system in AMPH-pretreated and -challenged animals resulted from a disruption of limbictelencephalic circuitry (Goto and Grace, 2005;Homayoun and Moghaddam, 2006) involving, as a major final pathway, the projection from the nucleus accumbens to the cholinergic basal forebrain (Neigh et al, 2004;NeighMcCandless et al, 2002;Zmarowski et al, 2005Zmarowski et al, , 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

“…This view contrasts with the widespread practice of assessing drug effects on neurotransmitter release, or with the status of neurotransmitter systems in animal models, in animals that remain passive or even anesthetized, and in the absence of recruitment of the neuronal system of interest (Sarter et al, 2007).…”

Restoration of dopamine release deficits during object recognition memory acquisition attenuates cognitive impairment in a triple transgenic mice model of Alzheimer's disease

“…Another possible basis of the DA dysfunction during the acquisition stage is related to the influence of cholinergic transmission over neurotransmitters release, including DA. Acetylcholine dysfunction, which has been widely reported in the AD pathology, leads to altered cholinergic stimulation of nicotinic acetylcholine receptors, which modulates DA release in cortical projections (Sarter et al 2007;Martorana et al 2009). Infusion of Ab 1 -40 impairs the DA release evoked by the administration of cholinergic agonists (carbachol and nicotine) by retrodialysis in the nucleus accumbens (Preda et al 2008).…”