ReviewModulation of cholinergic functions by serotonin and possible implications in memory: General data and focus on 5-HT1A receptors of the medial septum
Introduction
At a very general level, cognitive functions can be defined as an animal's capability to collect, encode, treat, store and use any kind of knowledge about its environment. Such functions are organized into a series of distributed, structurally and functionally interconnected anatomically defined modules. Schematically, one such module can be defined according to both its general structure (i.e., the different constitutive brain regions and the connectivity network enabling intra- and inter-regional information exchange) and its functional implications (i.e., the “mental” and behavioural outputs it contributes to generate). Thus, each component of this module (for instance, a particular nucleus) comprises its own neurons and its intrinsic neuronal network, but also is both the source of projection fibres sent to other components and the target of neurochemically defined afferent fibres originating in other structures of the brain. These fibres, whether efferent or afferent, can be defined at different levels of analysis, e.g., according to the type of pathway(s) to which they belong or to their neurochemical identity (e.g., cholinergic, noradrenergic, serotonergic, etc.).
Some regions of the mammalian brain receive both a serotonergic and a cholinergic innervation (e.g., the hippocampus, the cortical mantle), or comprise cholinergic nuclei that receive an extrinsic serotonergic innervation (e.g., basal forebrain nuclei, such as the septum). Providing an exhaustive neuroanatomical survey of the various serotonergic and cholinergic nuclei or targets, of the distribution of their interconnections or terminal fields, and of the various receptor sites found therein lies beyond the scope of the present review. On these matters, the reader is referred to previous publications dealing with serotonergic and cholinergic neuroanatomy, neuropharmacology and neurophysiology in the brain [3], [24], [27], [74], [111], [132], [142].
It can be briefly reminded, however, that the brain regions receiving both a serotonergic and a cholinergic innervation, whether extrinsic and/or intrinsic, encompass, among other structures, the striatum, the cortex and the hippocampus. These three regions are recognized to play a crucial role in various forms of cognitive processes, perhaps more particularly in memory functions, be it in terms of declarative-like or non-declarative-like ones.
Several studies have shown that an interaction between serotonergic and cholinergic processes in one or the other of these regions may result in physiological modifications that the manipulation of only one of these systems is unable to mimick, either qualitatively or quantitatively. The majority of the arguments demonstrating that an interaction between cholinergic and serotonergic processes have a functional relevance were obtained with neuro- and psychopharmacological approaches. For example, it was shown that, in the rat hippocampus, the release of acetylcholine by terminals originating in the medial septum and the diagonal band of Broca may be inhibited by a local activation of 5-HT1B [20], [21], [37], [96], [118], [123] and probably also 5-HT3 receptors [60]. Under the condition of a systemic activation, this release can be facilitated via the activation of 5-HT1A as well as 5-HT3 receptors, or inhibited via the activation of 5-HT1B (5-HT1D in the guinea-pig) and 5-HT4 receptors [19], [43], [73], [104]. There is also evidence that a serotonergic denervation of the hippocampus is able to facilitate the evoked release of acetylcholine in hippocampal slices [18]. In the cortex, the release of acetylcholine may be locally controlled by 5-HT1B and 5-HT3 inhibitory receptors [42], [123], whereas systemic activation of 5-HT1A and 5-HT4 receptors induces facilitatory effects [5]. Finally, in the striatum, local inhibition of the cholinergic tonus may be mediated by 5-HT1 and/or 5-HT2 receptors [61] and, under the condition of systemic activation, by 5-HT1A receptors [6].
All these receptor sites are potential neuropharmacological targets by which serotonin (5-hydroxytryptamine or 5-HT) may influence cholinergic processes and affect cognitive function, including learning and memory [36], [131].
In the present review, we will consider serotonergic–cholinergic interactions and their relevance to memory functions. In a first part, we will glance at very general approaches relying upon more or less selective lesion techniques, combined or not to intracerebral transplantations of neurochemically defined populations of fetal neurons (i.e., cholinergic and/or serotonergic). These approaches have contributed to stimulate the interest in a possible role for cholinergic–serotonergic interactions in memory functions. In a second part, we will focus on systemic drug administration approaches by presenting data showing the effects induced by systemic treatment with serotonergic compounds on cholinergic grafts, as well as after cholinergic lesions or receptor blockade. These pharmacological approaches have the advantage, among some others, of enabling an investigation of the contribution of different subtypes of receptors. Our main focus, there, will be the 5-HT1A receptor. This receptor is negatively coupled to adenylyl cyclase and to a direct activation of inwardly rectifying potassium conductance, thus contributing to membrane hyperpolarization and reducing the probability of cell firing when activated [70], [71]. Finally, based on findings of our and other laboratories, of which some are very recent [84], others yet unpublished, the last part of this review will concentrate on the possible contribution of 5-HT1A receptors of the medial septum to spatial memory encoding and consolidation. We will then discuss the extent to which this contribution may operate via an action mediated by septohippocampal cholinergic neurons.
Section snippets
Lesion and cell grafting approaches
For many years, experiments in behavioural neurobiology have used lesion techniques that selectively damaged well delineated regions of the brain (nuclei and/or pathways) in order to assess the behavioural correlates of such damage. While very useful in studying and establishing possible structure–function relationships, such approaches were of limited utility as to the understanding of the neuropharmacological regulations involved in the modulation of region- or system-specific functions. The
Systemic drug administration combined to other approaches
Approaches that have much better contributed and still contribute to the understanding of the neuropharmacological substrates of cognitively relevant cholinergic–serotonergic interactions are of the pharmacological type and rely upon receptor-targeted drug administrations. If they lack neuroanatomical selectivity when the drugs are given systemically, they have the advantage of both enabling an investigation of the contribution of various receptor subtypes and being easily combinable to other
Intracerebral drug infusion approaches: focus on 5-HT1A receptors of the medial septum
Considering the limits of lesion and psychopharmacological approaches relying upon systemic administrations of drugs or drug cocktails, and even of the combination of both, more powerful approaches, which use intraparenchymal and thus target-restricted drug administration techniques, have been developed. In experimental animals, such approaches can be carried out relatively easily in order to characterize the functional consequences of local drug infusions. It is noteworthy that also transgenic
Conclusions
The literature contains a series of experimental arguments finding their roots in histological, electrophysiological, pharmacological and behavioural research fields, and demonstrating or suggesting that, in the mammalian brain, cholinergic function may be under serotonergic modulatory influence. Furthermore, as documented and discussed herein, this modulation may have cognitive implications. These remarks, however, call several observations. First, 5-HT1A receptors are not the only ones to be
Acknowledgments
The authors express their gratitude to Mr. O. Bildstein, O. Egesi and G. Edomwonyi for their expert animal care, and to Dr. Anne Pereira de Vasconcelos for her critical reading of the final draft of this manuscript.
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