Neuroendocrine aspects of the serotonergic hypothesis of depression

https://doi.org/10.1016/S0149-7634(89)80056-9Get rights and content

This review examines the role of serotonin (5-hydroxytryptamine, 5-HT) in depression. Dysfunction of serotonergic neurons has been implicated as one of the causes of endogenous depression. Since serotonergic neurons innervate the hypothalamus and these neurons send collaterals to several other brain areas, it is possible that hypothalamic sites which control hormone secretion receive the same serotonergic afferents that innervate other limbic areas in the brain. Several investigators have devised neuroendocrine challenge tests measuring the effect of 5-HT agonists on plasma cortisol and prolactin in depressed patients. These tests help to identify dysfunctional 5-HT neurons, and are a “window into the brain.” The secretion of cortisol and prolactin is increased predominantly by 5-HT1 receptors. However, changes in 5-HT2 receptors have also been implicated in depression. Results from our laboratory and by others suggest that brain serotonergic neurons stimulate renin and vasopressin secretion by activation of 5-HT2 receptors. Therefore, the renin and vasopressin response to 5-HT agonists should be included in neuroendocrine tests of serotonergic function in affective disorders. Since antidepressants produce a decrease in the density of 5-HT2 receptors, renin and vasopressin could be used to evaluate the antidepressant potential of new drugs.

References (199)

  • CrunelliV. et al.

    Effects of d- and l-fenfluramine on striatal homovanillic acid concentrations in rats after pharmacological manipulation of brain serotonin

    Pharmacol. Res. Commun.

    (1980)
  • De CeballosM.L. et al.

    Prenatal exposure of rats to antidepressant drugs down-regulates beta-adrenoceptors and 5-HT2 receptors in cerebral cortex

    Neuropharmacology

    (1985)
  • DiggoryG.L. et al.

    Decreased 5-HT2 but not 5-HT1 receptor binding in cortex of rat after chronic administration of dothiepin

    Neuropharmacology

    (1985)
  • DumuisA. et al.

    A 5-HT receptor in the central nervous system, positively coupled with adenylate cyclase, is antagonized by ICX 205 930

    Eur. J. Pharmacol.

    (1988)
  • EisonA.S. et al.

    Serotonergic mechanisms in the behavioral effects of buspirone and gepirone

    Pharmacol. Biochem. Behav.

    (1986)
  • EuvrardC. et al.

    Biochemical assessment of the central 5-HT agonist activity RU 24969 (a piperidinyl indole)

    Eur. J. Pharmacol.

    (1980)
  • FeldmanS. et al.

    Paraventricular nucleus serotonin mediates neurally stimulated adrenocortical secretion

    Brain Res. Bull.

    (1987)
  • FeldmanS. et al.

    Effect of central serotonin depletion on adrenocortical responses to neural stimuli

    Exp. Neurol.

    (1984)
  • FishbeinD.H. et al.

    Impulsivity, aggression, and neuroendocrine responses to serotonergic stimulation in substance abusers

    Biol. Psychiatry

    (1989)
  • FontaineR. et al.

    Fluoxetine in the treatment of obsessive compulsive disorder

    Prog. Neuropsychopharmacol. Biol. Psychiatry

    (1985)
  • FullerR.W. et al.

    Elevation by fenfluramine of 3,4-dihydroxyphenylacetic acid in brain and of corticosterone and prolactin in serum of fenfluramine-treated rats

    Pharmacol. Res. Commun.

    (1981)
  • FullerR.W. et al.

    Interactions of trazodone with serotonin neurons and receptors

    Neuropharmacology

    (1984)
  • FuxeK. et al.

    Further evidence that methergoline is a central 5-hydroxytryptamine receptor blocking agent

    Neurosci. Lett.

    (1978)
  • GilbertF. et al.

    Activation of the 5-HT1A receptor subtype increases plasma ACTH concentration

    Eur. J. Pharmacol.

    (1988)
  • GlaserT. et al.

    Buspirone: action on serotonin receptors in calf hippocampus

    Eur. J. Pharmacol.

    (1983)
  • HaganR.M. et al.

    Effect of the 5-HT3 receptor antagonist, GR38032F, on responses to injection of a neurokinin agonist into the ventral tegmental area of the rat brain

    Eur. J. Pharmacol.

    (1987)
  • HaleemD.J. et al.

    8-OH-DPAT increases corticosterone but not other 5-HT1A receptor-dependent responses more in female rats

    Eur. J. Pharmacol.

    (1989)
  • HaseyG.M. et al.

    Neurotransmitter metabolites and endocrine responses in depression

    Prog. Neuropsychopharmacol. Biol. Psychiatry

    (1985)
  • HoyerD. et al.

    Molecular pharmacology of 5-HT1 and 5-HT2 recognition sites in rat and pig brain membranes: radioligand binding studies with [3H]5-HT, [3H]8-OH-DPAT, (−)[125I] iodocyanopindolol, [3H]mesulergine and [3H]ketanserin

    Eur. J. Pharmacol.

    (1985)
  • HoyerD. et al.

    Identification of serotonin 5-HT3 recognition sites by radioligand binding in NG108-15 neuroblastoma-glioma cells

    Eur. J. Pharmacol.

    (1987)
  • HoyerD. et al.

    Serotonin receptors in the human brain. I. Characterization and autoradiographic localization of 5-HT1A recognition sites. Apparent absence of 5-HT1B recognition sites

    Brain. Res.

    (1986)
  • HoyerD. et al.

    5-HT1D receptor-mediated inhibition of forskolin-stimulated adenylate cyclase activity in calf substantia nigra

    Eur. J. Pharmacol.

    (1988)
  • InvernizziR. et al.

    D- and 1-isomers of fenfluramine differ markedly in their interaction with brain serotonin and catecholamines in the rat

    Eur. J. Pharmacol.

    (1986)
  • IovinoM. et al.

    Effect of substances influencing brain serotonergic transmission on plasma vasopressin levels in the rat

    Eur. J. Pharmacol.

    (1985)
  • JohnstonJ.P.

    Some observations upon a new inhibitor of monoamine oxidase in brain tissue

    Biochem. Pharmacol.

    (1968)
  • KantG.J. et al.

    Comparison of stress response in male and female rats: Pituitary cyclic AMP and plasma prolactin, growth hormone and corticosterone

    Psychoneuroendocrinology

    (1983)
  • KoenigJ.I. et al.

    Stimulation of corticosterone and beta-endorphin secretion in the rat by selective 5-HT receptor subtype activation

    Eur. J. Pharmacol.

    (1987)
  • AdvisJ.P. et al.

    Serotonergic control of prolactin release in male rats

    Life Sci.

    (1979)
  • AlperR.H. et al.

    Activation of serotonin2 (5-HT2) receptors by quipazine increases arterial pressure and renin secretion in conscious rats

    J. Pharmacol. Exp. Ther.

    (1987)
  • AroraR.C. et al.

    Serotonergic measures in the brains of suicide victims: 5-HT2 binding sites in the frontal cortex of suicide victims and control subjects

    Am. J. Psychiatry

    (1989)
  • AzmitiaE.C. et al.

    An autoradiographic analysis of the differential ascending projections of the dorsal raphe and median raphe nuclei in the rat

    J. Comp. Neurol.

    (1978)
  • BarbieriC. et al.

    Effect of fenfluramine on prolactin secretion in obese patients: Evidence for serotonergic regulation in man

    Clin. Endocrinol.

    (1983)
  • BarofskyA.-L. et al.

    Dorsal raphe-hypothalamic projections provide the stimulatory serotonergic input to suckling-induced prolactin release

    Endocrinology

    (1983)
  • BattagliaG. et al.

    3,4-methylenedioxy methamphetamine and 3,4-methylenedioxyamphetamine destroy serotonin terminals in rat brain: quantification of neurodegeneration by measurement of [3H]paroxetine-labeled serotonin uptake sites

    J. Pharmacol. Exp. Ther.

    (1987)
  • BecuD. et al.

    Serotoninergic involvement in the cimetidine-induced prolactin release

    Endocrinology

    (1983)
  • BjorklundA. et al.

    5,7-Dihydroxytryptamine: Improvement of its selectivity for serotonin neurons in the CNS by pretreatment with desipramine

    J. Neurochem.

    (1975)
  • BleichA. et al.

    The role of serotonin in schizophrenia

    Schizophr. Bull.

    (1988)
  • BrownfieldM.S. et al.

    Brain serotonin depletion alters the vasopressin secretory response to osmotic stimulation and the plasma levels of angiotensin II to hypovolemia

    Soc. Neurosci. Abstr.

    (1987)
  • BrownfieldM.S. et al.

    Neuropharmacological characterization of serotonergic stimulation of vasopressin secretion in conscious rats

    Neuroendocrinology

    (1988)
  • CaligarisL. et al.

    Involvement of neurones containing 5-Hydroxytryptamine in the mechanism of prolactin release induced by oestrogen

    J. Endocrinol.

    (1974)
  • Cited by (62)

    • Sex differences in Corticotropin-releasing factor receptor-1 action within the dorsal raphe nucleus in stress responsivity

      2014, Biological Psychiatry
      Citation Excerpt :

      In addition to sex differences in CRFr1 localization and GABAergic responses to CRF, this suggests that 5-HT neurons in females require a greater depolarizing stimulus to generate neuronal firing and subsequent 5-HT release, even at baseline. Compared with males, this might translate to 5-HTergic hypofunction in females, an underlying risk factor for the development of affective disorders during stress exposure (81,82). Overall, these studies revealed intriguing sex differences in behavioral and physiological effects of CRFr1 antagonist and CRF in the DR, which were mechanistically associated with sex differences in receptor co-expression and divergent electrophysiological responses to CRF in 5-HTergic neurons.

    • The effects of paroxetine and tianeptine on peripheral biochemical markers in major depression

      2002, Progress in Neuro-Psychopharmacology and Biological Psychiatry
    View all citing articles on Scopus
    View full text