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Serotonin and Stress Francis Chaouloff, Ph.D., Olivier Berton, Ph.D., and Pierre Mormède, Ph.D

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Serotonin and Stress Francis Chaouloff, Ph.D., Olivier Berton, Ph.D., and Pierre Mormède, Ph.D Serotonin and Stress Francis Chaouloff, Ph.D., Olivier Berton, Ph.D., and Pierre Mormède, Ph.D. Forty-five years after its discovery, brain serotonin (5-HT) regulatory process allowing serotonergic homeostasis, is is still the subject of intense research aimed at mediated by specific neuroendocrine mechanisms. In understanding its role in stress adaptation. At the addition to the multiplicity of postsynaptic 5-HT receptors presynaptic level, numerous stressors increase nerve firing and their specific regulation by corticoids, specificity to and extracellular 5-HT at the level of serotonergic cell stressors is also underscored when considering one receptor bodies or nerve terminals. Different studies have reported type such as the 5-HT1A receptor. Stress studies should stressor- and region-specific changes in extracellular 5-HT, consider the past experience and the genetic status of a view challenged by electrophysiological and the individual as key modulators of the serotonergic neurochemical evidence for a nonspecific response of responses to stress. [Neuropsychopharmacology serotonergic neurones to stressors when activity/arousal is 21:28S–32S, 1999] © 1999 American College of taken into account. In addition, early studies indicate that Neuropsychopharmacology. Published by Elsevier Science Inc. stress-induced elevation in 5-HT synthesis, a key counter- KEY WORDS: Serotonin; Stress; Nerve firing; Release; published during that period. In the 1980s, the recogni- Synthesis; 5-HT1A Receptors tion of the first subtypes of 5-HT receptors led to stud- ies aimed at measuring the impact of acute and re- Since the discovery of serotonin (5-hydroxytryptamine, peated stressors on these targets; in parallel, key studies 5-HT) in the mammalian brain (Twarog and Page 1953), appeared that were devoted to (1) the roles of stress the effects of stress upon serotonergic systems have hormones (e.g., corticoids) in the control of central sero- been the focus of permanent research (Anisman and tonergic activity, and (2) the effects of stressors on 5-HT Zacharko 1982; Chaouloff 1993; Rueter et al. 1997). An nerve firing. Currently, numerous studies explore the overview of such research provides a reliable illustra- effects of stressors on extracellular 5-HT levels (as as- tion of the progress made in that field. Early studies sessed by the microdialysis technique) and 5-HT recep- from the 1960s focused on the effects of stressors on tor-coupled second messengers. brain 5-HT levels and synthesis. In the 1970s, drugs ren- An overview of 30 years of research on stress and dering possible the estimation of 5-HT turnover allowed 5-HT indeed favors the hypothesis that numerous com- a more detailed analysis of time- and region-dependent ponents of central serotonergic systems are sensitive to changes in serotonergic systems of stressed animals; in stressors. This result would thus fit, at first glance, with addition, reports regarding the influence of stressors therapeutic data in anxious and/or depressed patients, upon the supply of tryptophan to the brain were first data suggesting that 5-HT is an important component of the central network that provides adaptation to From the NeuroGénétique et Stress, INSERM U471, Institut Fran- stress. However, among the questions that remain re- cois Magendie, Bordeaux, France Address correspondence to: Francis Chaouloff, NeuroGénétique garding the role of 5-HT in this network, one is of par- et Stress, INSERM U471, Institut Francois Magendie, Rue Camille ticular importance: is 5-HT a fine modulator or an on- Saint Saëns, 33077 Bordeaux Cédex, France Tel/fax: 0033. or-off switch? If the former proposal is correct, one 5.57.57.37.57/52; E-mail: [email protected] Received October 12, 1998; revised January 5, 1999; accepted Jan- would expect, among other criteria, that 5-HT responds uary 20, 1999. specifically to certain stressors, both in terms of dura- NEUROPSYCHOPHARMACOLOGY 1999–VOL. 21, NO. 2S © 1999 American College of Neuropsychopharmacology Published by Elsevier Science Inc. 0893-133X/99/$–see front matter 655 Avenue of the Americas, New York, NY 10010 PII S0893-133X(99)00008-1 NEUROPSYCHOPHARMACOLOGY 1999–VOL. 21, NO. 2S Serotonin and Stress 29S tion and location, but not (or differently) to others. With the aforementioned experiments were conducted in this question in mind, this article tries to delineate the cats raises the possibility of different results in other effects of stress on key components of central serotoner- species. gic systems. EXTRACELLULAR 5-HT AND STRESS 5-HT INNERVATION AND STRESS In a recent review of the effects of different physical, When exposed to a stressor, the organism responds by metabolic, psychological, or immunological stressors two means, respectively behavioral and neuroendocri- on extracellular 5-HT levels (Rueter et al. 1997), one was nological in nature, with the latter response aimed at able to observe that extracellular 5-HT rose in most re- providing metabolic and cardiovascular adjustments gions (1) whatever the nature of the stressor applied, (through the sympathetic nervous system and the corti- and (2) without any dichotomy between nerve termi- cotropic axis) that allow an appropriate behavioral re- nals derived from the DRN on the one hand, and the sponse to the stimulus. Indeed, there is extensive evi- median raphe nucleus (MRN) on the other hand. In dence for the presence of 5-HT nerve terminals and/or keeping with the electrophysiological data mentioned 5-HT receptors in key stress-related neuroendocrine above, it was proposed that such a generalized increase (e.g., hippocampus, hypothalamus, brainstem, medulla, in extracellular 5-HT levels was primarily determined etc.) and behavioral (e.g., amygdala, striatum, hippo- by the level of activity/arousal displayed during stress campus, cortex, periaqueductal grey, etc.) regions (Chaou- (Rueter et al. 1997). Actually, the reports of positive cor- loff 1993; Graeff 1993). Moreover, serotonergic cell bod- relations between extracellular 5-HT levels and activity/ ies in the raphe nuclei receive afferents from a vast arousal support the aforementioned hypothesis (Rueter array of regions (Jacobs and Azmitia 1992), including et al. 1997). However, recent studies have shown that those mentioned above, thus allowing 5-HT nerves to injection of either lipopolysaccharide (an immunologi- receive permanent information during stress. That im- cal stressor) or corticotropin-releasing factor (a key mediate early gene expression, such as that of c-fos, is transmitter during stressful events) elicits changes in detected in these nuclei following different types of extracellular 5-HT levels and locomotor activity that do stressors (e.g., forced swim or restraint, Cullinan et al. not correlate among each other (Linthorst et al. 1995; 1995) illustrates the latter statement. Price et al. 1998). That almost all stressors have an overall stimulatory effect on extracellular 5-HT levels would argue against 5-HT NERVE CELL FIRING AND STRESS a specific effect of stress on presynaptic 5-HT tone (whether activity/arousal is taken into account or not). Electrophysiological studies in cat rostral raphe nuclei However, this view has been recently challenged by have indicated that the activity of dorsal raphe nucleus some studies claiming stressor- and site-dependent (DRN) serotonergic neurons is affected by a variety of changes in extracellular 5-HT levels (Adell et al. 1997; metabolic, psychological, or physical stressors. How- Kirby et al. 1995, 1997), including within raphe nuclei ever, in line with early findings indicating that the fir- (Adell et al. 1997). Moreover, site-dependent changes in ing rate of these neurons vary positively with activity/ extracellular 5-HT responses to a given stressor may arousal, it was reported that none of the stressors affect also be measured by altering the context (including specifically serotonergic DRN neurons when activity/ stressor controllability, Amat et al. 1998) within which arousal was taken into consideration (Jacobs and Fornal the stressor is applied (Wilkinson et al. 1996). 1991; Jacobs and Azmitia 1992). Thus, data related to se- To add to the aforementioned uncertainties as to the rotonergic DRN neurons point to a stimulatory, albeit specificity vs. nonspecificity of the presynaptic serotoner- nonspecific, effect of stressors on forebrain/midbrain gic response to stress, the following issues should be 5-HT nerve cell firing. taken into account. First, any direct comparison be- When placed in the framework of adaptation, these tween all these studies is rendered impossible due to results lead to one key question: would such a nonspec- key experimental differences that include the addition ificity apply to repeated or chronic stressors? Moreover, (or not) of a 5-HT reuptake inhibitor to allow an estima- in keeping with experimental evidence for emotionality tion of extracellular 5-HT levels, the time period (light not being one unique behavioral entity but the sum of vs. dark) during which the experiment was run, the re- multiple independent behavioral dimensions (Ramos covery period allowed between implantation of the and Mormède 1998), the hypothesis that activity/ cannula and stress exposure, the rat strain, prior hous- arousal does have a stressor-dependent behavioral sig- ing (single vs. collective) before housing the rat alone in nificance would then confer, if true, a specificity to the the experimental bowl, etc. Second, the microdialysis 5-HT nerve firing response
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