Review
cGMP: a second messenger for acetylcholine in the brain?

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Abstract

Already 30 years ago, it became apparent that there exists a relationship between acetylcholine and cGMP in the brain. Acetylcholine plays a role in a great number of processes in the brain, however, the role of cGMP in these processes is not known. A review of the data shows that, although the connection between NO-mediated cGMP synthesis and acetylcholine is firmly established, the complexities of the heterosynaptic pathways and the oligosynaptic structures involved preclude a clear definition of the role of cGMP in the functioning of acetylcholine presently.

Section snippets

Introduction and scope of the review

As a neurotransmitter in the brain, one of the functions of acetylcholine is a role in regulating the information flow and processing during learning and memory. Although it is commonly mentioned in the literature that acetylcholine is involved in learning and memory, the precise role of acetylcholine in these processes is not known. The molecular mechanisms involved have not been unravelled and therefore it is not yet possible to detail the role of acetylcholine at this level of reductionism.

Projections from cholinergic nuclei and the relationship with neuronal NOS

Cholinergic innervation of the brain has been described in detail (Semba and Fibiger, 1989, Wainer et al., 1993, Semba, 2003, Descarries et al., 2003).The basal forebrain cholinergic neurons are found in the medial septum, the diagonal band of Broca, ventral pallidum, substantia innominata, magnocellular preoptic area and the magnocellular basal nucleus (nucleus of Meynert). The cholinergic neurons of the medial septum and the vertical and horizontal band of Broca project mainly to the

Effects of cholinergic agonists and antagonists on cGMP levels in the CNS

The first report on the effects of in vivo administration of cholinergic agonists on cGMP levels in the brain came from Ferrendelli et al. (1970), as already mentioned above. They found that 5 mg/kg oxotremorine s.c. in mice increased cGMP levels in cortex and cerebellum. In addition, they found that administration of atropine alone (60 mg/kg) had a similar effect as oxotremorine in both cortex and cerebellum, whereas after a combined administration of oxotremorine and atropine the increase in

Functional studies involving acetylcholine and cGMP

Taking into account that cholinergic innervation is found in almost all brain regions, it is to be expected that functional studies on the role of acetylcholine will be diverse in nature. Acetylcholine plays a role in thermoregulation, motor disturbances, learning and memory, locomotor activity, analgesia, and CSF secretion. Nevertheless, the number of studies connecting acetylcholine stimulated NO–cGMP signaling to function is rather small.

Hypothermia has been linked to an increase in cGMP and

Electrophysiological studies

Early electrophysiological studies on the relationship between acetylcholine and cyclic nucleotides used the technique of iontophoretic application of these substances close to identified neurons from which recordings were made. Thus, the effects of application of acetycholine, cGMP and/or cAMP were studied in Purkinje cells (Siggins et al., 1976), and pyramidal tract neurons (Stone et al., 1975, Stone and Taylor, 1977). Results in these studies were not unequivocal. Acetylcholine and cGMP

Acetylcholine release

Studies on the release of acetylcholine have been performed in vitro using slices or synaptosome preparations, and in vivo using the technique of microdialysis. The number of studies addressing the effects of cGMP or NO on acetylcholine release in vitro is not large and these experiments have been done using slices from the cortex, striatum, and/or hippocampus of different experimental animals. Taken together the findings of these studies are not unequivocal, irrespective of the animal used, as

Cholinergic innervation and cGMP synthesis in the rat brain

From the above review of the literature, it becomes clear that the data that are most important for the correct interpretation of these results are not available, i.e. the location of the cGMP response in the brain when slices or animals are challenged with muscarinic agonists or antagonists. Although some answers can be obtained by using cultured neurons (e.g. Castoldi et al., 1993), the apparent presence of polysynaptic pathways precludes unequivocal interpretation of the data obtained on

Cholinergic transmission in Alzheimer’s disease

Three lines of evidence indicate that cholinergic neurotransmission in patients with Alzheimer disease is severely disturbed. First, there is a decrease in ChAT activity in the cortical tissue of demented patients. Second, the number of cholinergic neurons in the nucleus basalis of Meynert is decreased in AD brains. Third, there is a significant correlation between postmortem reductions in cholinergic markers of the forebrain and premortem mental state scores in AD patients (Cummings et al.,

Concluding remarks

The data reviewed above indicate that there is certainly a link between cholinergic neurotransmission and cGMP synthesis. The biochemical data demonstrate that muscarinic agonists and antagonists can stimulate cGMP synthesis in different brain areas of a number of species. The problem of the localization of this response has still not been resolved. It is quite likely, and this is suggested by the data, that responding cells will be of a different type and function in the various brain areas.

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