Article
Role of 5-HT in stress, anxiety, and depression

https://doi.org/10.1016/0091-3057(95)02135-3Get rights and content

Abstract

There are conflicting results on the function of 5-HT in anxiety and depression. To reconcile this evidence, Deakin and Graeff have suggested that the ascending 5-HT pathway that originates in the dorsal raphe nucleus (DRN) and innervates the amygdala and frontal cortex facilitates conditioned fear, while the DRN-periventricular pathway innervating the periventricular and periaqueductal gray matter inhibits inborn fight/flight reactions to impending danger, pain, or asphyxia. To study the role of the DRN 5-HT system in anxiety, we microinjected 8-OH-DPAT into the DRN to inhibit 5-HT release. This treatment impaired inhibitory avoidance (conditioned fear) without affecting one-way escape (unconditioned fear) in the elevated T-maze, a new animal model of anxiety. We also applied three drug treatments that increase 5-HT release from DRN terminals: 1) intra-DRN microinjection of the benzodiazepine inverse agonist FG 4172, 2) intra-DRN microinjection of the excitatory amino acid kainic acid, and 3) intraperitoneal injection of the 5-HT releaser and uptake blocker d-fenfluramine. All treatments enhanced inhibitory avoidance in the T-maze. d-Fenfluramine and intra-DRN kainate also decreased one-way escape. In healthy volunteers, d-fenfluramine and the 5-HT agonist mCPP (mainly 5-HT2C) increased, while the antagonists ritanserin (5-HT2A2C) and SR 46349B (5-HT2A) decreased skin conductance responses to an aversively conditioned stimulus (tone). In addition, d-fenfluramine decreased, whereas ritanserin increased subjective anxiety induced by simulated public speaking, thought to represent unconditioned anxiety. Overall, these results are compatible with the above hypothesis. Deakin and Graeff have suggested that the pathway connecting the median raphe nucleus (MRN) to the dorsal hippocampus promotes resistance to chronic, unavoidable stress. In the present study, we found that 24 h after electrolytic lesion of the rat MRN glandular gastric ulcers occurred, and the immune response to the mitogen concanavalin A was depressed. Seven days after the same lesion, the ulcerogenic effect of restraint was enhanced. Microinjection of 8-OH-DPAT, the nonselective agonist 5-MeO-DMT, or the 5-HT uptake inhibitor zimelidine into the dorsal hippocampus immediately after 2 h of restraint reversed the deficits of open arm exploration in the elevated plus-maze, measured 24 h after restraint. The effect of the two last drugs was antagonized by WAY-100135, a selective 5-HT1A receptor antagonist. These results are compatible with the hypothesis that the MRN-dorsal hippocampus 5-HT system attenuates stress by facilitation of hippocampal 5-HT1A-mediated neurotransmission. Clinical implications of these results are discussed, especially with regard to panic disorder and depression.

References (112)

  • S.D. Iversen

    5-HT and anxiety

    Neuropharmacology

    (1984)
  • B.J. Jones et al.

    Microinjections of methyl-β-carboline-3-carboxylate into the dorsal raphe nucleus: Behavioural consequences

    Pharmacol. Biochem. Behav.

    (1986)
  • R.S. Kahn et al.

    Serotonin and anxiety revisited

    Biol. Psychiatry

    (1988)
  • G.A. Kennett et al.

    Central serotonergic responses and behavioral adaptation to repeated immobilisation: The effect of the corticosterone synthesis inhibitor metyrapone

    Eur. J. Pharmacol.

    (1985)
  • G.A. Kennett et al.

    Enhancement of some 5-HT-dependent behavioral responses following repeated immobilization in rats

    Brain Res.

    (1985)
  • G.A. Kennett et al.

    Antidepressant-like action of 5-HT1A agonists and conventional antidepressants in an animal model of depression

    Eur. J. Pharmacol.

    (1987)
  • S.M. Korte et al.

    Adrenal hormones in rats before and after stress-experience effects of ipsapirone

    Physiol. Behav.

    (1992)
  • Y. Kuroda et al.

    Differential effect of subchronic dexamethasone treatment on serotonin-2 and beta-adrenergic receptors in rat cerebral cortex and hippocampus

    Neurosci. Lett.

    (1993)
  • E. Maru et al.

    Effects of median raphe nucleus lesions on hippocampal EEG in the freely moving rat

    Brain Res.

    (1979)
  • C.R. McKittrick et al.

    Serotonin receptor binding in a colony model of chronic stress

    Biol. Psychiatry

    (1995)
  • P.A. Nausieda et al.

    Modification of central serotonergic and dopaminergic behaviours in the course of chronic corticosteroid administration

    Eur. J. Pharmacol.

    (1982)
  • J.J. O'Connor et al.

    Serotoninergic depression of auditory evoked responses recorded in the rat hippocampus: Effect of repeated buspirone treatment

    Brain Res.

    (1992)
  • A.M. Odwyer et al.

    Treatment of major depression with metyrapone and hydrocortisone

    J. Affect. Dis.

    (1995)
  • B.W.M.M. Peeters et al.

    Involvement of corticosteroids in the processing of stressful life-events. A possible implication for the development of depression

    J. Steroid. Biochem. Mol. Biol.

    (1994)
  • B.W.M.M. Peeters et al.

    The involvement of glucocorticoids in acquired immobility response is dependent on the water temperature

    Physiol. Behav.

    (1992)
  • S. Pellow et al.

    Validation of open: closed arm entries in the elevated plus-maze as a measure of anxiety in the rat

    J. Neurosci. Methods

    (1985)
  • J.S. Popova et al.

    Changes in 5-HT1 receptors in different brain structures of rats with isolation syndrome

    Gen. Pharmacol.

    (1990)
  • N. Sakai et al.

    Inhibitory modulation of long-term potentiation via the 5-HT1A receptor in slices of the rat hippocampal dentate gyrus

    Brain Res.

    (1993)
  • C. Sandi et al.

    Corticosterone enhances long-term retention in one-day-old chicks trained in a weak passive avoidance learning paradigm

    Brain Res.

    (1994)
  • B. Shapira et al.

    Prolactin response to fenfluramine and placebo. Challenge following maintenance pharmacotherapy withdrawal in remitted depressed

    Biol. Psychiatry

    (1993)
  • B. Söderpalm et al.

    Effects of 5-HT1A agonists and l-5-HTP in Montgomery's conflict test

    Pharmacol. Biochem. Behav.

    (1989)
  • S.D. Targum et al.

    Fenfluramine provocation of anxiety in patients with panic disorder

    Psychiatry Res.

    (1989)
  • G.K. Aghajanian

    Central 5-HT receptor subtypes: Physiological responses and signal transduction mechanisms

  • H. Anisman et al.

    The impact of Stressors on immune and central neurotransmitter activity: Bidirectional communication

    Rev. Neurosci.

    (1993)
  • E.C. Azmitia

    The serotonin-producing neurons of the midbrain median and dorsal raphe nuclei

  • L.I. Backus et al.

    Behavioral evidence for a functional interaction between central 5-HT2 and 5-HT1A receptors

    Br. J. Pharmacol.

    (1990)
  • A. Baum et al.

    Control of intrusive memories as possible determinants of chronic stress

    Psychosom. Med.

    (1993)
  • M.J. Bickerdike et al.

    Social isolation attenuates rat forebrain 5-HT release induced by KCl stimulation and exposure to novel environment

    Behav. Pharmacol.

    (1993)
  • R.J. Blanchard et al.

    Ethoexperimental approaches to the study of defensive behavior

  • P. Blier et al.

    Modification of the serotonin system by the antidepressant treatments: Implications for the therapeutic response in major depression

    J. Clin. Psychopharmacol.

    (1987)
  • M. Briley et al.

    Neurobiological mechanisms involved in antidepressant therapies

    Clin. Neuropharmacol.

    (1993)
  • M. Carli et al.

    8-Hydroxy-2-(di-n-propylamino)tetralin impairs spatial learning in a water maze: Role of postsynaptic 5-HT1A receptors

    Br. J. Pharmacol.

    (1992)
  • D.T. Chalmers et al.

    Corticosteroids regulate brain hippocampal 5-HT1A receptor mRNA expression

    J. Neurosci.

    (1993)
  • D.T. Chalmers et al.

    Regulation of hippocampal 5-HT1A receptor gene expression by dexamethasone

    Neuropsychopharmacology

    (1994)
  • S.C. Cheetham et al.

    Brain 5-HT1 binding sites in depressed suicides

    Psychopharmacology (Berlin)

    (1990)
  • J. Connell et al.

    5-HT2 receptors and anxiety

    Behav. Pharmacol.

    (1995)
  • A. Coppen

    The biochemistry of affective disorders

    Br. J. Psychiatry

    (1967)
  • C. De Montigny et al.

    Effects of antidepressant treatment on 5-HT neurotransmission

  • J.W.F. Deakin et al.

    5-HT and mechanisms of defence

    J. Psychopharmacol.

    (1991)
  • J.F.W. Deakin et al.

    5-HT receptor subtypes and the modulation of aversion

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