Review article
Dorsal raphe vs. median raphe serotonergic antagonism. Anatomical, physiological, behavioral, neuroendocrinological, neuropharmacological and clinical evidences: Relevance for neuropharmacological therapy

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Abstract

Monoaminergic neurons located in the central nervous system (CNS) are organized into complex circuits which include noradrenergic (NA), adrenergic (Ad), dopaminergic (DA), serotonergic (5-HT), histaminergic (H), GABA-ergic and glutamatergic systems. Most of these circuits are composed of more than one and often several types of the above neurons. Such physiologically flexible circuits respond appropriately to both external and internal stimuli which, if not modulated adequately, can trigger pathophysiologic responses. A great deal of research has been devoted to mapping the multiple functions of the CNS circuitry, thereby forming the basis for effective neuropharmacological therapeutic approaches. Such lineal strategies that seek to normalize complex and mixed physiological disorders, however, meet only partial therapeutic success and are often followed by undesirable side effects and/or total failure. In light of these, we have worked to develop possible models of CNS circuitry that are less affected by physiological interaction using the models to design more effective therapeutic approaches. In the present review, we cite and present evidence supporting the dorsal raphe versus median raphe serotonergic circuitry as one model of a reliable paradigm, necessary to the clear understanding and therapy of many psychiatric and even non-psychiatric disturbances.

Introduction

The central nervous system (CNS) monoaminergic circuitry includes glutamatergic, GABAergic, noradrenergic (NA), adrenergic (Ad), dopaminergic (DA), serotonergic (5-HT), histaminergic (H) and cholinergic (ACh) systems. Although Glut vs. GABA, NA vs. 5-HT and DA vs. 5-HT antagonisms have been stated, they should not be considered as "black or white" paradigms as these systems combine in complex ways to form circuits that may either cooperate or antagonize according to physiological factors. Further, NA, Ad, DA and 5-HT nuclei are interconnected in such a way that their mixed circuits can converge for a specific physiological purpose. However, despite the above findings, a large body of neurophysiological and neuropharmacological investigation has shed much light on the physiology and pathophysiology of the CNS monoaminergic circuitry (Lechin et al., 1979b, Lechin et al., 1989, Lechin et al., 2002a). In the present review, the authors aim attempt to integrate the results of some of these studies. Our goal is to organize the great voluminous data in order to make it accessible to readers who are unfamiliar with this area of neuroscience. In addition, the data we put forward allows us to postulate an MR–5-HT vs. DR–5-HT antagonism. This should serve as an example of how new channels of understanding can facilitate access to bulky research data whose unwieldy growth has deepened an abyss between researchers and clinicians. We selected the DR–5-HT vs. MR–5-HT antagonism as an illustration because we believe that this paradigm constitutes one path among the many possibilities, for readers to approach an overwhelming number of papers emanating from neurochemical, neurophysiological, neuroendocrinological, neuroanatomical and neuropharmacological investigation. Moreover, we found evidence that all psychiatric and somatic diseases may be associated with an imbalance in this paradigm. In short, we present a summing up of the vast accumulation of data that we have studied over the last 30 years.

Section snippets

Anatomical evidence

The CNS–5-HT system includes serotonergic neurons grouped into eight nuclei located at the midline of the mesencephalic and medullary segments. The more anterior nucleus, median raphe (MR) or B8 (centralis superioris) and the dorsal raphe (DR) or B7, send axons to two well-differentiated areas dealing with distinct neuronal circuits. The MR innervates the dorsal hippocampus, medial septum, nucleus accumbens core, and several hypothalamic nuclei. The DR innervates the fronto-parietal cortex,

Catecholaminergic (NA, DA, Ad) vs. serotonergic (5-HT) interactions

Subcortical DA neurons send excitatory axons to the DR but not the MR serotonergic nucleus. This phenomenon is consistent with the fact that drugs which excite DA neurons (amphetamine, cocaine) trigger 5-HT release from DR but not MR axons (Boye et al., 2001, Costall et al., 1976, Porras et al., 2002). These findings are also consistent with the demonstration that activation or inhibition of DR and MR nuclei are followed by different physiological and pathophysiological responses and, further,

Anatomical and physiological data supporting DR vs. MR opposing roles

In this section, we summarize only a limited number of data and investigations supporting the postulated DR vs. MR opposing roles because the bulk of information is too great for discussion in a multidisciplinary review article.

Behavioral evidence of the DR vs. MR antagonism

The bulk of information dealing with this issue is so great that we refer here only to a limited number of the research papers supporting a DR vs. MR antagonism (Table 2).

Neuroendocrinological evidence

Dorsal raphe axons excite CRF–ACTH–Crt cascade, an effect mediated by 5-HT-1A postsynaptic receptors located at hypothalamic level. Circulating Crt crosses the blood–brain barrier (bbb) and exerts antagonistic activity on Crt receptors located at DR level. Prolonging this effect provokes up-regulation of the DR receptors, and exhaustion of DR–5-HT neurons (Gilbert et al., 1988, Hery et al., 2000, Kant et al., 1983, Laaris et al., 1997, Lowry et al., 2000, Mosko and Jacobs, 1975, Owens and

Neuropharmacological evidence supporting DR vs. MR antagonism

We will discuss DR vs. MR antagonism seen through the role of drugs acting at acetylcholinergic (ACh), noradrenergic (alpha-1, alpha-2), dopaminergic (DA-2), and serotonergic (5-HT-1A, 5-HT-1B/D, 5-HT-2) receptors.

Endogenous (major) depression vs. dysthymic depression

We published in 1995 two research articles dealing with the neuroautonomic profile underlying these psychiatric disorders (Lechin et al., 1995a, Lechin et al., 1995b). Major depressed patients showed raised NA + raised NA/Ad ratio + lowered p-5-HT + lowered Trp values. This abnormal profile did not change throughout orthostasis and exercise challenges. Conversely, dysthymic depressed patients showed lowered levels of all catecholamines (NA, Ad, DA) + raised levels of tryptophane, f5-HT and

Final comments

Many psychiatric and neurological disorders might find support in our postulated DR vs. MR antagonism. For example, phobic and anxiety syndromes fit well with the DR over MR predominance, whereas others such as the psychotic syndrome would be consistent with the opposite profile. Many neurophysiological and neuropharmacological evidences might support the above postulations which are based on a great deal of experimental findings sprouted from both neurochemical and neuropharmacological

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