The serotonergic and noradrenergic systems of the hippocampus: their interactions and the effects of antidepressant treatments

Abstract

Previous reviews have well illustrated how antidepressant treatments can differentially alter several neurotransmitter systems in various brain areas. This review focuses on the effects of distinct classes of antidepressant treatments on the serotonergic and the noradrenergic systems of the hippocampus, which is one of the brain limbic areas thought to be relevant in depression: it illustrates the complexity of action of these treatments in a single brain area. First, the basic elements (receptors, second messengers, ion channels, ...) of the serotonergic and noradrenergic systems of the hippocampus are revisited and compared. Second, the extensive interactions occurring between the serotonergic and the noradrenergic systems of the brain are described. Finally, issues concerning the short- and long-term effects of antidepressant treatments on these systems are broadly discussed. Although there are some contradictions, the bulk of data suggests that antidepressant treatments work in the hippocampus by increasing and decreasing, respectively, serotonergic and noradrenergic neurotransmission. This hypothesis is discussed in the context of the purported function of the hippocampus in the formation of memory traces and emotion-related behaviors.

Introduction

The initial observation which has shown that classical antidepressant drugs increase the synaptic concentration of two central neurotransmitter, serotonin (5-HT) and noradrenaline (NA), has stimulated numerous studies these last decades. The first drug commercialized in the late 1950's for the treatment of depression was iproniazid, an inhibitor of the enzyme monoamine oxidase (MAO). The concentrations of 5-HT and NA are increased in the brain by blocking their degradation by MAO. Since this original discovery, many other MAO inhibitors (MAOIs) have been shown to be clinically effective for the treatment of depression. Tricyclic antidepressant drugs (TCAs) were shown to share the property of blocking the reuptake of NA and 5-HT, albeit with different potencies. Their therapeutic efficacy was thereby thought to be related to the prolongation of the synaptic action of these neurotransmitters [483]. Subsequently, selective inhibitors of either 5-HT reuptake (e.g., citalopram, fluoxetine, paroxetine) or NA reuptake (e.g., maprotiline, oxaprotiline) were shown to display antidepressant efficacy as well 381, 416. Some antidepressant drugs were found to act directly at 5-HT or adrenergic receptors. For example, mianserin and the purported antidepressant drug idazoxan 337, 353, 450increase NA output by blocking α₂-adrenergic autoreceptors 103, 116, 253, 376. Furthermore, antidepressant drugs of the azapirone family (e.g., buspirone, gepirone) act as partial agonists at the level of 5-HT_1A receptors [372]. Although the above effects on the noradrenergic and serotonergic systems are observed following acute administration, long-term treatments are required with any of these drugs in order to achieve clinical efficacy.

It was proposed that there might be two types of depressions linked with decreases in either NA or 5-HT neurotransmission [272]. In `noradrenergic' depression, patients would have low pretreatment levels of NA metabolites (e.g., MHPG) and this parameter would normalize upon clinical improvement. Furthermore, these patients would have rapid elevation of mood when administered a NA releaser (amphetamine) and exhibit a good antidepressant response to NA reuptake blockers. On the other hand, in `serotonergic' depression, patients would have low pretreatment levels of 5-HT metabolites (e.g., 5-HIAA), and present a lack of response to amphetamine but a favourable response to 5-HT reuptake blockers. However, this hypothesis was not supported by clinical findings, and antidepressant agents inhibiting either 5-HT or NA reuptake are equally effective and are not selective for subtypes of depression 109, 491.

It is crucial at this point to determine why pharmacological strategies directed primarily at either the 5-HT or NA systems are equally effective in relieving the symptoms of depression. This review discusses and compares several elements of the 5-HT and NA systems as being potential targets for antidepressant treatments. Emphasis is put on the interaction between these two systems and on one brain structure of interest in the study of depression, the hippocampus. In the second part of this review, the issue of the effects of antidepressant treatments on the 5-HT and NA systems of the hippocampus is more specifically addressed.