Serotonergic and Noradrenergic Neuromodulation in the Hippocampus and the Mechanism of Action of Antidepressants

  • Osamu Tajima
  • Shinichi Murata
  • Tsukasa Mitsuhashi
  • Kenichi Takemasa
Conference paper


Despite the recent explosive progress of brain imaging and molecular biology, the pathophysiology of affective disorders and the mechanism of action of antidepressant drugs remain unknown. There is no consensus about the net effect of chronic antidepressant treatment on serotonergic and noradrenergic neurotransmission, particularly noradrenergic neurotransmission. Novel antidepressants, such as selective serotonin (5-HT) reuptake inhibitors (SSRIs) or reversible inhibitors of monoamine oxidase A (RIMAs) have better side-effect profiles and wide clinical indications compared with classical tricyclic antidepressants. SSRIs such as fluoxetine, sertraline, fluvoxamine, paroxetine, and citalopram have little anticholinergic effect and have been proved to be effective not only for depression but also for obsessive-compulsive disorder, panic disorder, and eating disorder. RIMAs do not have the fatal side effect of old irreversible monoamine oxidase inhibitors, the so-called cheese effect, and among RIMAs such as moclobemide, brofaramine, and toloxatone, moclobemide has efficacy against social phobia. The clinical efficacy of these novel antidepressants against major depression, however, is not significantly different from that of classical antidepressants. The clinical choice of an antidepressant for an individual patient remains primarily based on considerations of side effects and safety rather than efficacy (Lecrubier 1993).


Eating Disorder Pyramidal Neuron Locus Coeruleus Noradrenergic Neurotransmission Chronic Antidepressant Treatment 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. Andrade R, Nicoll RA (1987) Pharmacologically distinct action of serotonin on single pyramidal neurons of the rat hippocampus recorded in vitro. J Physiol 394: 99–124PubMedGoogle Scholar
  2. Birnbaumer L (1990) G proteins in signal transduction. Annu Rev Pharmacol Toxicol 30: 675–705PubMedCrossRefGoogle Scholar
  3. Blakely RD, Berson HE, Fremau RT Jr, Caron MG, Peek MM, Prince HK, Bradley CC (1991) Cloning and expression of a functional serotonin transporter from rat brain. Nature 354: 66–70PubMedCrossRefGoogle Scholar
  4. Blier P, De Montigny C, Chaput Y (1990) A role for the serotonin system in the mechanisms of action of antidepressant treatments: preclinical evidence. J Clin Psychiatry 515: 14–20Google Scholar
  5. Brunello N, Langer SZ, Perez J, Racagni G (1994/1995) Current understanding of the mechanism of action of classic and newer antidepressant drugs. Depression 2: 119–126Google Scholar
  6. Chaput Y, De Montigny C, Blier P (1991) Pre- and postsynaptic modifications of the serotonin system by long-term administration of antidepressant treatments: an in vivo electrophysiological study in the rat. Neuropsychopharmacology 5: 219–229PubMedGoogle Scholar
  7. Cohen JD, Servan-Schreiber D (1993) A theory of dopamine function and its role in cognitive deficits in schizophrenia. Schizophr Bull 19: 85–104PubMedGoogle Scholar
  8. De Montigny C, Aghajanian GK (1978) Tricyclic antidepressants: long term treatment increases responsiveness of rat forebrain neurons to serotonin. Science 202: 1303–1306PubMedCrossRefGoogle Scholar
  9. De Montigny C, Chaput Y, Blier P (1990) Modification of serotonergic neuron properties by long-term treatment with serotonin reuptake blockers. J Clin Psychiatry 51 (Suppl B): 4–8PubMedGoogle Scholar
  10. Gilman AG (1987) G proteins: transducers of receptor-generated signals. Annu Rev Biochem 56: 615–649PubMedCrossRefGoogle Scholar
  11. Hoffman BJ, Mesey E, Brownstein M (1991) Cloning of a serotonin transporter affected by antidepressants. Science 254: 579–580PubMedCrossRefGoogle Scholar
  12. Kasper S, Lepine JP, Mendlewicz J, Montgomery SA, Rush AJ (1994/1995) Efficacy, safety, and indications for tricyclic and newer antidepressants. Depression 2: 127–137Google Scholar
  13. Köhler M, Hirschberg B, Bond TC, Kinzie JM, Marrion NV, Maylie J, Adelman JP (1996) Small-conductance, calcium-activated potassium channels from mammalian brain. Science 273: 1709–1714PubMedCrossRefGoogle Scholar
  14. Lecrubier Y (1993) Antidepressant drugs: similar but different In: Mendlewicz J, Brunello N, Langer SZ, Racagni G (eds) New pharmacological approaches to the therapy of depressive disorders. Karger, Basel (International Academy for Biomedical and Drug Research), vol 5, pp 83–910Google Scholar
  15. Madison DV, Nicoll RA (1982) Noradrenaline blocks accommodation of pyramidal cell discharge in the hippocampus. Nature 299: 636–638PubMedCrossRefGoogle Scholar
  16. McCormick DA, Pape H, Williamson A (1991) Action of norepinephrine in the cerebral cortex and thalamus: Implications for function of the central noradrenergic system. In: Barnes CD, Pompeiano O (eds) Neurobiology of the locus coeruleus. (Progress in brain research, vol 88 ) Elsevier, Amsterdam, pp 293–305CrossRefGoogle Scholar
  17. Menkes DB, Rasenick MM, Wheeler MA, Bitensky NW (1983) Guanine triphosphate activation of brain adenylate cyclase: enhancement by long-term antidepressant treatment. Science 129: 65–67CrossRefGoogle Scholar
  18. Pacholczyk T, Blakely RD, Amara SG (1991) Expression cloning of a cocaine and antidepressant-sensitive human noradrenaline transporter. Nature 350: 350–354PubMedCrossRefGoogle Scholar
  19. Scuvee-Moreau JJ, Dresse AE (1979) Effects of various antidepressant drugs on the spontaneous firing rate of locus coeruleus and dorsal raphe neurons of the rats. Eur J Pharmacol 57: 219–225PubMedCrossRefGoogle Scholar
  20. Sugrue MF (1983) Do antidepressants possess a common mechanism of action Biochem Pharmacol 12: 1811–1817CrossRefGoogle Scholar
  21. Sulser F (1984) Antidepressant treatments and regulation of norepinephrine-receptor- coupled adenylate cyclase systems in brain. Adv Biochem Psychopharmacol 39: 249–261PubMedGoogle Scholar
  22. Worley PF, Baraban JM, Snyder SH (1987) Beyond receptors: multiple second messenger systems in brain. Neurol Prog 21: 217–229Google Scholar

Copyright information

© Springer-Verlag Tokyo 1998

Authors and Affiliations

  • Osamu Tajima
    • 1
  • Shinichi Murata
    • 1
  • Tsukasa Mitsuhashi
    • 1
  • Kenichi Takemasa
    • 1
  1. 1.Department of NeuropsychiatryKyorin University School of MedicineMitaka, Tokyo 181Japan

Personalised recommendations