Introduction

It has been known for centuries that the berries, roots and leaves of Atropa belladonna and other plants of the Solanaceous family cause disturbances in memory and orientation and, increasing the doses, cause hallucination and delirium.71 For a long time, the latter effects attracted more attention that the subtle effects on memory.113 However, the retrograde amnesia following atropine intoxication was noted and reported also in the past. According to Muccioli,13 patients poisoned with atropine become "idiots". It is interesting that in its "Toxicology" handbook this author already recommended pilocarpine, for its actions on the vagus, as a good antidote for atropine intoxication.

It took a long time to demonstrate that the amnesic effects of atropine and scopolamine, the active ingredient contained in Atropa belladonna, Hyosciamus niger, and Datura stramonium, depended on their blockade of the actions of brain acetylcholine on muscarinic receptors. The first systematic investigation of the effects of belladonna alkaloids on cognition was made by Macht.114 He reported that after a dose as low as 0.05 mg the rats were unable to solve a familiar maze. No neurochemical mechanism was proposed for this effect, but the author was fully aware that atropine and scopolamine exerted parasympatholytic activity. The discovery of acetylcholine (ACh) in the brain by Chang and Gaddum,33 the finding that its levels in the brain increased during excitation and decreased during sedation and anaesthesia63,189 and the observations that anticholinergic agents exerted an amnesic effects46 all led to the concept that brain ACh may be involved in behavior.30

From Messengers to Molecules: Memories Are Made of These, edited by Gernot Riedel and Bettina Platt. ©2004 Eurekah.com and Kluwer Academic / Plenum Publishers.

Other steps, however, were necessary before establishing a connection between the brain cholinergic system and its muscarinic receptors with learning and memory.143 Macintosh and Obering 15 were the first to demonstrate an outflow ofACh from the cerebral cortex, provided that the superfUsing fluid contained an inhibitor of cholinesterase. The cortical cup used in their experiments was the forerunner of the microdialysis technique making it now possible to study ACh release in behaving rats. Besides showing that CNS depressants reduced ACh outflow and CNS stimulants increased it, the cortical cup experiments demonstrated that the stimulation of the reticular formation was accompanied by an increase in ACh release from the cerebral cortex, associated with an electrocortical activation. (For an extensive review of the literature see Pepeu.147 In the same years, Shute and Lewis175,176 published the first map of the cholinergic pathways in the rat brain. The map was obtained by staining the cholinesterase contained in the cholinergic neurons and fibres; it was still approximate and lacked many details. However, its general outlay was correct, as it will be shown later, and demonstrated that in the brain a network of cholinergic neurons existed from which ACh was presumably released during their activity.

Another important step towards the demonstration of the neurotransmitter role of ACh in the CNS was the observation that it was possible to stimulate 10 to 20% of neocortical101 and hippocampal18 neurons by microiontophoretic application of ACh. In the cortex the neurons were probably the deep pyramidal cells of layer V. The excitation was muscarinic in nature because it could be evoked by other muscarinic agonists besides ACh, and was selectively blocked by atropine.102 This was the first direct demonstration that muscarinic receptors existed in the CNS, and they were pharmacologically similar to those existing in the parasympathetic system.

The CNS effects of anticholinergic agents were defined as "central anticholinergic syndrome"112 and emphasis was placed on the amnesic and psychotomimetic effects, and the characteristic EEG modifications. For a long time little attention was devoted to the subtle effects on memory and no attempt was made to define the role of the brain cholinergic system in cognitive processes. In the first congress on the cholinergic mechanisms in the CNS,84 no paper presented mentioned the word memory. Only Aprison and Hingtgen6 demonstrated the involvement of a central cholinergic mechanism during drug-induced excitation in avoidance behavior. Nevertheless, even if the association between ascending cholinergic fibers, EEG activation and behavioral arousal had already been discovered, the interest in the role of the cholinergic system in movement control, sleep and wakefulness prevailed over that in the role of memory mechanisms.

Still, in the late fifties and sixties the investigation on the effects of cholinergic drugs on acquisition and retention of conditioned responses had progressively begun using more complex behavioral approaches, as shown by the already large number of references quoted by Longo112 in his exhaustive review. In the second symposium on cholinergic mechanisms, a review on cholinergic mechanisms and memory was attempted by Moss and Deutsch.132 Although the authors claimed that "the mechanisms by which atropine might affect behavior are not entirely clear" they concluded that "a full understanding of the effects of cholinergically active drugs may give some insight into certain functions of cholinergic transmission which may be necessary for normal recall of learned behaviors".

An interest in the role of brain ACh in memory was strongly enhanced by the finding that cognitive impairment and loss of forebrain cholinergic neurons are prominent and characteristic landmarks of Alzheimer's disease (AD).13 Moreover, it was shown that the blockade of muscarinic receptors by scopolamine in young normal subjects induced a cognitive impairment reminiscent of that observed in AD patients.48 Conversely, it was demonstrated that the activation of muscarinic receptors by ACh, through the increase of its extracellular levels induced by cholinesterase inhibition,186 or by direct muscarinic agonists184 may improve the cognitive deficit in AD patients. These findings triggered a large number of studies. In this chapter an attempt will be made to summarize them and present the available information on the role exerted by the central cholinergic neurons, through the activation of muscarinic receptors, on cognitive processes including attention, learning, information storage and recall.

Figure 1. Cholinergic pathways in the human brain. Dotted areas represent the most important nuclei of origin of cholinergic pathways. A: amygdala; CB: cerebellum; CC: corpus callosum; CP: caudate-putamen; DBB: diagonal band of Broca; H: hypothalamus; Hi: hippocampus; MS: medial septum; NB: nucleus basalis ofMeynert; OB: olfactory bulb; OT: olfactory tubercle; PPTN: peduncolopontine tegmental nucleus; T: thalamus; IV: fourth ventricle.

Figure 1. Cholinergic pathways in the human brain. Dotted areas represent the most important nuclei of origin of cholinergic pathways. A: amygdala; CB: cerebellum; CC: corpus callosum; CP: caudate-putamen; DBB: diagonal band of Broca; H: hypothalamus; Hi: hippocampus; MS: medial septum; NB: nucleus basalis ofMeynert; OB: olfactory bulb; OT: olfactory tubercle; PPTN: peduncolopontine tegmental nucleus; T: thalamus; IV: fourth ventricle.

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