Regulation of cortical acetylcholine release: insights from in vivo microdialysis studies

Abstract

Acetylcholine release links the activity of presynaptic neurons with their postsynaptic targets and thus represents the intercellular correlate of cholinergic neurotransmission. Here, we review the regulation and functional significance of acetylcholine release in the mammalian cerebral cortex, with a particular emphasis on information derived from in vivo microdialysis studies over the past three decades. This information is integrated with anatomical and behavioral data to derive conclusions regarding the role of cortical cholinergic transmission in normal behavioral and how its dysregulation may contribute to cognitive correlates of several neuropsychiatric conditions. Some unresolved issues regarding the regulation and significance of cortical acetylcholine release and the promise of new methodology for advancing our knowledge in this area are also briefly discussed.

Figure 1

Graph showing the number of papers published over the last 25 years using the search terms ‘acetylcholine’ and ‘microdialysis’ as indexed in the U.S. National Library of Medicine’s PubMed online (www.ncbi.nlm.nih.gov/pubmed). The figure charts the appearance of microdialysis as a tool for the measurement of in vivo acetylcholine release in the 1980’s followed by a rapid increase in the early 1990’s and leveling off in the latter half of that decade. *Although 2009 data were not yet complete as of this figure, an apparent current downward trend may reflect the emergence of alternative, biosensor-based approaches with enhanced spatial and temporal resolution.

Figure 2

A few sources of basal forebrain afferent regulation of cortical ACh release with putative neurotransmitter(s) involved and functional significance. The source of cortical ACh is from magnocellular cholinergic neurons distributed among several contiguous basal forebrain structures, including the nucleus basalis magnocellularis (NBM), ventral pallidum (VP) and substantia innominata (SI). Although cholinergic innervation of the cortical mantle is diffuse, reciprocal input derives from a few selected areas, including prefrontal (PFC) and agranular insular (AIC) cortices. Limbic brain regions providing input to the basal forebrain include medium spiny neurons of the nucleus accumbens (nAcc) and parts of the amygdala. Diencephalic and brain stem afferent regulation of the BFCS derives largely from monoamines (MA) and associated components of the ascending reticular activating system (ARAS) and from peptidergic (including orexin/hypocretin; Ox/Hcrt) neurons of the hypothalamus.