ReviewRegulation of cortical acetylcholine release: Insights from in vivo microdialysis studies
Introduction
It has now been roughly a century since the identification of acetylcholine (ACh) as a neurotransmitter in the mammalian central nervous system, and some six decades since Richter and Crossland published their findings on the relationship between physiological state and brain ACh content [126]. With the advent of the cortical cup and push–pull cannula techniques in the 1960s and 1970s, investigators were able to go beyond post-mortem measurement of ACh content and directly measure levels of this neurotransmitter in the living brain. It was the introduction of modern in vivo microdialysis and its widespread application beginning in the 1980s, however, which revolutionized our understanding of the physiological, pharmacological and behavioral mechanisms underlying ACh release. For example, early studies on the relationship between anesthesia and brain ACh content generally large increases peaking when the animal was sacrificed 30–60 min post-anesthesia (e.g. [40]). The first microdialysis studies using the same or similar anesthetics showed virtually the opposite effect—i.e. anesthetics produce a rapid decrease in brain ACh efflux (e.g. [75]). While the original studies may have correctly interpreted their results—that anesthesia increased post-mortem brain ACh content by inhibiting its ‘liberation’, in vivo microdialysis was important in eliminating a significant intervening level of inference between ACh measurement and the phenomenon of interest—the effect of a manipulation on ACh release. The improved temporal and spatial resolution of microdialysis over its predecessors, and its ready applicability to awake, behaving animal models converged with clinical literature on the postulated role of the cholinergic system in several neurodegenerative and neuropsychiatric conditions. This combination of factors led to a rapid increase in studies using microdialysis to study ACh release in the mammalian brain (Fig. 1).
Thus, ACh release has been measured using a variety of techniques in numerous parts of the central nervous system, with the functional significance of that dependent variable inferred on the basis of the anatomical source of ACh, the brain region where it is being measured, and the pharmacological or behavioral independent variable employed to invoke (or inhibit) release. The reader is referred elsewhere for a more exhaustive overview of all of these factors [121], which is far beyond the scope of this review. Rather, this paper will focus primarily on studies of ACh release in the mammalian cerebral cortex. Furthermore, because much of what we know about the nature of cortical ACh release has derived from in vivo microdialysis studies over the past two decades, this will form the basis for much of this review. Finally, we will conclude with a brief discussion of some current issues in the field of cortical ACh release and how they may be resolved by the next generation of tools for the measurement of cortical ACh release.
Section snippets
Microdialysis measurement of ACh: release versus efflux
ACh release represents the presynaptic component of endogenous cholinergic neurotransmission in the brain. ACh release follows a series of presynaptic electrical and signaling cascades (including sodium channel-dependent depolarization and calcium-dependent vesicular docking) culminating in the quantal elevation of synaptic ACh concentrations. Efflux, as measured extrasynaptically by in vivo microdialysis is a dependent measure reflecting a summed correlate of release, degradation and
Regulation of cortical ACh release by basal forebrain afferents: linking function with anatomy
Mammalian forebrain cholinergic neurons have been broadly grouped into four clusters, using the nomenclature of Mesulam et al. [94]: the first three subgroups (Ch1-3) consist of neurons in the medial septum and vertical and horizontal limbs of the diagonal band of Broca, and provide cholinergic innervation of the hippocampus and olfactory bulb. While some reports in rodents suggest that a portion of cholinergic innervation of the medial prefrontal cortex additionally arises from the diagonal
Cortical ACh release in neuropsychiatric disorders
Given the involvement of cortical cholinergic neurotransmission in arousal and attention, a potential role of altered ACh release has been hypothesized for a number of neuropsychiatric conditions characterized, at least in part, by cognitive dysfunction. Cortical ACh release in some of these disorders derives from a strong empirical and conceptual basis, stemming from human clinical literature as well as a robust animal literature demonstrating that cortical ACh release is increased in a manner
Basal cortical ACh release: what is it, what drives it and what does it mean?
‘Basal’ cortical ACh efflux is a physiological phenomenon that can be defined as the cortical ACh release measured by the microdialysis technique in the absence of any systematic behavioral or pharmacological manipulation. The term basal implies nothing regarding the behavioral status of the animal, only the lack of a controlled independent variable. In the non-anesthetized preparation, then, basal efflux may be measured in an animal which is asleep or awake, moving or motionless, or any
Conclusions
Measurement of ACh release represents the most direct indicator of the presynaptic component of cholinergic transmission in the cerebral cortex. In vivo microdialysis studies over the past three decades have allowed for the emergence of a tremendous amount of new information regarding the pharmacological regulation of ACh release, the role of the corticopetal cholinergic system in normal behavioral and cognitive processes, and the pathological correlates of dysregulated cholinergic transmission
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