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Reciprocal Innervation between Serotonergic and GABAergic Neurons in Raphe Nuclei of the Rat

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Abstract

Midbrain slices containing the dorsal and medial raphe nuclei were prepared from rat brain in order to study serotonergic-GABAergic interaction. The slices were loaded with either [3H] serotonin or [3H]GABA, superfused and the electrically induced efflux of radioactivity was determined. The GABAA receptor agonist muscimol (3 to 30 μM) and the GABAB receptor agonist baclofen (30 and 100 μM) inhibited [3H]serotonin and [3H]GABA release. These effects of muscimol were reversed by the GABAA antagonists bicuculline (100 μM). The GABAB antagonist phaclofen (100 μM) also antagonized the baclofen-induced inhibition of [3H]serotonin and [3H]GABA release. Phaclofen by itself increased [3H]serotonin release but it did not alter [3H]GABA overflow. Muscimol (10 μM) and baclofen (100 μM) also inhibited [3H]serotonin release after depletion of GABAergic neurons by isoniazid pretreatment. These findings indicate the presence of postsynaptic GABAA and GABAB receptors located on serotonergic neurons. The 5-HT1A receptor agonist 8-OH-DPAT (0.01 to 1 μM) and the 5-HT1B receptor agonist CGS-12066A (0.01 to 1 μM) inhibited the electrically stimulated [3H]serotonin and [3H]GABA release. The 5-HT1A antagonist WAY-100135 (1 μM) was without effect on [3H]serotonin and [3H]GABA efflux by itself but it reversed the 8-OH-DPAT-induced transmitter release inhibition. During KCl (22 mM)-induced depolarization, tetrodotoxin (1 μM) did not alter the inhibitory effect of CGS-12066A (1 μM) on [3H]GABA release, it did blocked, however, the ability of 8-OH-DPAT (1 μM) to reduce [3H]GABA efflux. After depletion of raphe serotonin neurons by p-chlorophenylalanine pretreatment, CGS-12066A (1 μM) still inhibited [3H]GABA release whereas in serotonin-depleted slices, 8-OH-DPAT (1 μM) was without effect on the release. We conclude that reciprocal influence exists between serotonergic projection neurons and the GABAergic interneurons or afferents in the raphe nuclei and these interactions may be mediated by 5-HT1A/B and GABAA/B receptors. Both synaptic and non-synaptic neurotransmission may be operative in the 5-HTergic-GABAergic reciprocal interaction which may serve as a local tuning in the neural connection between cerebral cortex and midbrain raphe nuclei.

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REFERENCES

  1. Parent, A., Descarries, L., and Beaudet, A. 1981. Organization of ascending serotonin systems in the adult rat. A radioautographic study after intraventricular administration of [3H]5-hydroxytryptamine. Neuroscience 6:115–138.

    Google Scholar 

  2. Steinbusch, H. W. M. 1981. Distribution of serotonin-immunoreactivity in the central nervous system of the rat-cell bodies and terminals. Neuroscience 6:557–618.

    Google Scholar 

  3. Kapadia, S. E., De Lanerolle. N. C., and Lamotte, C. C. 1985. Immunocytochemical and electron microscopic study of serotonin neuronal organization in the dorsal raphe nucleus of the monkey. Neuroscience 16:729–746.

    Google Scholar 

  4. Harandi, M., Aguera, M., Gamrani, H., Didier, M., Maitre, M., Calas, A., and Belin, M. F. 1987. ?-Aminobutyric acid and 5-hydroxytryptamine interrelationship in the rat nucleus raphe dorsalis: combination of radiographic and immunocytochemical techniques at light and electron microscopy levels. Neuroscience 21:237–251.

    Google Scholar 

  5. Hery, F., Faudon, M., and Ternaux, J. P. 1982. In vivo release of serotonin in two raphe nuclei (raphe dorsalis and magnus) of cat. Brain Res. Bull. 8:123–129.

    Google Scholar 

  6. Saavedra, J. P., Brusco, A., Pressini, S., and Olivia, D. 1986. A new case for the presynaptic role of dendrites: an immunocytochemical study of the N. Raphe Dorsalis. Neurochem. Res. 11:997–1009.

    Google Scholar 

  7. Chazal, G. and Ralston, H. J., II. 1987. Serotonin-containing structures in the nucleus raphe dorsalis of the cat: an ultrastructural analysis of dendrites, presynaptic dendrites, and axon collaterals. J. Comp. Neurol. 259:259–317.

    Google Scholar 

  8. Davidson, C. and Stamford, J. A. 1995. Evidence that 5-hydroxytryptamine release in rat dorsal raphe nucleus is controlled by 5-HT1A 5-HT1B and 5-HT1D autoreceptors. Br. J. Pharmacol. 114:1107–1109.

    Google Scholar 

  9. O'Connor, J. J. and Kruk, Z. L. 1992. Pharmacological characteristics of 5-hydroxytryptamine autoreceptors in rat brain slices incorporating the dorsal raphe or the suprachiasmatic nucleus. Br. J. Pharmacol. 106:524–532.

    Google Scholar 

  10. Bagdy, E. and Harsing, L. G., Jr. 1995. The role of various calcium and potassium channels in the regulation of somatodendritic serotonin release. Neurochem. Res. 12:1409–1415.

    Google Scholar 

  11. Arborelius, L., Backlund Hook, B., Hacksell, U., and Svenson, T. H. 1994. The 5-HT1A receptor antagonist (S)-UH-301 blocks the (R)-8-OH-DPAT-induced inhibition of serotonergic dorsal raphe cell firing in the rat. J. Neural. Transm. 96:179–186.

    Google Scholar 

  12. Hajos, M., Gartside, S. E., Villa, A. E. P., and Sharp, T. 1995. Evidence for a repetitive (burst) firing pattern in a sub-population in the dorsal and median raphe nuclei of the rat. Neuroscience 69:189–197.

    Google Scholar 

  13. Hjorth, S. and Magnusson, T. 1988. The 5-HT1A receptor agonist, 8-OH-DPAT, preferentially activates cell body 5-HT autoreceptors in rat brain in vivo. Naunyn-Schmiedeberg's Arch. Pharmacol. 338:463–471.

    Google Scholar 

  14. Sprouse, J. S. and Aghajanian, G. K. 1987. Electrophysiological responses of serotonergic dorsal raphe neurons to 5-HT1Aand 5-HT1B agonists. Synapse 1:3–9.

    Google Scholar 

  15. Starley, S. J. and Skingle, M. 1994. 5-HT1D as well as 5-HT1A autoreceptors modulate 5-HT release in the guinea-pig dorsal raphe nucleus. Neuropharmacology 33:393–402.

    Google Scholar 

  16. El Mansari, M. and Blier, P. 1996. Functional characterization of 5-HT1Dautoreceptors on the modulation of 5-HT release in the guinea-pig mesencephalic raphe, hippocampus and frontal cortex. Br. J. Pharmacol. 118:681–689.

    Google Scholar 

  17. Craven, R., Grahame-Smith, D., and Newberry, N. 1994. WAY-100635 and GR127935: efffects on 5-hydroxytryptamine-containing neurones. Eur. J. Pharmacol. 271:R1-R3.

    Google Scholar 

  18. Liu, R. J., Jolas, T., and Aghajanian, G. K. 1999. Serotonin, via receptors, induces an increase in spontaneous IPSCs in 5-HT cells of the dorsal raphe nucleus (DRN). Soc. Neurosci. Abstract 174.9.

  19. Belin, M. F., Augera, M., Tappaz, M., McRae-Degueurce, A., Bobillier, P., and Pujol, J. F. 1979. GABA-accumulating neurons in the nucleus raphe dorsalis and periaquaductal gray in the cat: biochemical and radioautographic study. Brain Res. 170:279–297.

    Google Scholar 

  20. Wang, Q. P., Ochiaia, P. G., and Nakai, Y. 1992. GABAergic innervation of serotonergic neurons in the dorsal raphe nucleus of the rat studied by electron microscopy double immunostaining. Brain Res. Bull. 29:943–948.

    Google Scholar 

  21. Wang, R. Y. and Aghajanian, G. K. 1977. Physiological evidence for habenula as major link between forebrain and midbrain raphe. Science 197:89–91.

    Google Scholar 

  22. Stern, W. C., Johnson, A., Bronzino, J. D., and Morgane, J. P. 1981. Neuropharmacology of the afferent projection from the lateral habenula and substantia nigra to the anterior raphe in the rat. Neuropharmacology 20:979–989.

    Google Scholar 

  23. Forchetti, C. M. and Meek, J. L. 1981. Evidence for a tonic GABAergic control of serotonin neurons in the median raphe nucleus. Brain Res. 206:208–212.

    Google Scholar 

  24. Gallager, D. W. and Aghajanian, G. K. 1976. Effect of antipsychotic drugs on the firing of dorsal raphe cells. II. Reversal by picrotoxin. Eur. J. Pharmacol. 39:357–364.

    Google Scholar 

  25. Ferraro, G., Montalbano, M. E., Sardo, P., and La Grutta, V. 1996. Lateral habenular influence on dorsal raphe neurons. Brain Res. Bull. 41:47–52.

    Google Scholar 

  26. Tao, R., Ma, Z., and Auerbach, S. B. 1996. Differential regulation of 5-hydroxytryptamine release by GABAA and GABAB receptors in midbrain raphe nuclei and forebrain of rats. Br J. Pharmacol. 119:1375–1384.

    Google Scholar 

  27. Krogsgaard-Larsen, P., Frolund, B., Jorgensen, F. S., and Schousboe, A. 1994. GABAA receptor agonists, partial agonists, and antagonists. Design and therapeutic prospects. J. Med. Chem. 37:2489–2505.

    Google Scholar 

  28. Kerwin, R. W. and Pycock, C. J. 1979. The effect of some putative neurotransmitters on the release of 5-hydroxytryptamine and ?-aminobutyric acid from slices of the rat midbrain raphe area. Neuroscience 4:1359–1365.

    Google Scholar 

  29. Bagdy, E., Solyom, S., and Harsing, L. G., Jr. 1998. Feedback stimulation of somatodendritic serotonin release: a 5-HT3 receptor-mediated effect in the raphe nuclei of the rat. Brain Res. Bull. 45:203–208.

    Google Scholar 

  30. Iversen, L. L. and Kelly, J. S. 1975. Uptake and metabolism of ?-aminobutyric acid by neurones and glial cells. Biochem. Pharmac. 24:933–938.

    Google Scholar 

  31. Harsing, L. G., Jr. and Zigmond, M. J. 1997. Influence of dopamine on GABA release in striatum: Evidence for D1-D2 interactions and non-synaptic influences. Neuroscience 77:419–429.

    Google Scholar 

  32. Harsing, L. G., Jr., Sershen, H., and Lajtha, A. 1992. Dopamine efflux from striatum after chronic nicotine: evidence for autoreceptor desensitization. J. Neurochem. 59:48–54.

    Google Scholar 

  33. Mefford, N. N. 1981. Application of high performance liquid chromatography with ]electrochemical detection to the neurochemical analysis: measurement of catecholamines, serotonin and metabolites in rat brain. J. Neurosci. Methods 3:207–224.

    Google Scholar 

  34. Rowley, H. L., Martin, K. F., and Marsden, C. A. 1995. Determination of in vivo amino acid neurotransmitters by high performance liquid chromatography with ophthalaldehyde-sulphite derivatisation. J. Neurosci. Methods 57:93–99.

    Google Scholar 

  35. Starke, K. 1987. Presynaptic alpha adrenoceptors. Rev. Physiol. Biochem. Pharmac. 107:73–146.

    Google Scholar 

  36. Pineyro, G. and Blier, P. 1996. Regulation of 5-hydroxytryptamine release from rat midbrain raphe nuclei by 5-hydroxytryptamine1D receptors: Effect of tetrodotoxin, G protein inactivation and long-term antidepressant administration. J. Pharm. Exp. Ther. 276:697–707.

    Google Scholar 

  37. Middlemiss, D. N. and Fozard, J. R. 1983. 8-Hydroxy-2-(di-npropylamino) tetralin discriminates between subtypes of the 5-HT1 recognition site. Eur. J. Pharmacol. 90:151–153.

    Google Scholar 

  38. Neale, R. F., Fallon, S. L., Royar, W. C., Wasley, J. W. F., Martin, L. L., Stone, G. A., Glaester, B. S., Sinton, C. M., and Williams, M. 1987. Biochemical and pharmacological characterization of CGS-12066A, a selective 5-HT1B agonist. Eur. J. Pharmacol. 136:1–9.

    Google Scholar 

  39. Abellan, T., Jolas, T., Aghajanian, G. K., and Artigas, F. 1997. GABA-serotonin interactions in the dorsal raphe nucleus of the rat: role of GABAB receptors. Soc. Neurosci. Abst. 907.9.

  40. Limberger, N., Spaeth, L., and Starke, K. 1986. A search for receptors modulating the release of ?-[3H]aminobutyric acid in rabbit caudate nucleus slices. J. Neurochem. 46:1109–1117.

    Google Scholar 

  41. Waldmeier, P. C. and Baumann, P. A. 1990. Presynaptic GABA receptors. Ann. NY Acad. Sci. 604:136–151.

    Google Scholar 

  42. Hashimoto, T. and Kuriyama, K. 1997. GABAA receptor-mediated K(+)-evoked GABA release from globus pallidus-analysis using microdialysis. Neurochem. Inter. 30:247–252.

    Google Scholar 

  43. Ennis, C. and Minchin, M. C. 1993. Modulation of GABAA-like autoreceptor by barbiturates but not by steroids. Neuro-pharmacology 32:355–357.

    Google Scholar 

  44. Vizi, E. S. and Kiss, J. P. 1998. Neurochemistry and pharmacology of the major hippocampal transmitter systems: synaptic and nonsynaptic interactions. Hippocampus 8:566–607.

    Google Scholar 

  45. Shen, R. Y. and Andrade, R. 1998. 5-Hydroxytryptamine2 receptor facilitates GABAergic neurotransmission in rat hippocampus. J. Pharm. Exp. Ther. 285:805–812.

    Google Scholar 

  46. Behzadi, G., Kalen, P., Parvapassu, F., and Wiklund, L. 1990. Afferents to the median raphe nucleus of the rat: retrograde choleratoxin and wheat germ-conjugated horseradish peroxidase tracing and selective D-[3H]aspartate labelling of possible excitatory amino acid inputs. Neuroscience 37:77–100.

    Google Scholar 

  47. Hajos, M., Richards, C. D., Szekely, A. D., and Sharp, T. 1998. An electrophysiological and neuroanatomical study of the medial prefrontal cortical projection to the midbrain raphe nuclei in the rat. Neuroscience 87:95–108.

    Google Scholar 

  48. Scatton, B., Serrano, A., Rivot, J. P., and Nishikawa, T. 1984. GABAergic inhibitory influence on striatal serotonergic transmission exerted in the dorsal raphe as revealed by in vivo voltametry. Brain Res. 305:343–352.

    Google Scholar 

  49. Nishikawa, T. and Scatton, B. 1985. Inhibitory influence of GABA on central serotonergic transmission. Involvement of the habenulo-raphe pathways in the GABAergic inhibition of ascending cerebral serotonergic neurons. Brain Res. 331:81–90.

    Google Scholar 

  50. Vizi, E. S. 2000. Role of high-affinity receptors and membrane transporters in nonsynaptic communication and drug action in the CNS. Pharmacol. Rev. 52:63–89.

    Google Scholar 

  51. O'Hearn, E. and Molliver, M. E. 1984. Organization of raphecortical projections in the rat: a quantitative retrograde study. Brain Res. Bull. 13:709–726.

    Google Scholar 

  52. Harsing, L. G., Jr., Kiraly, I., and Bagdy, E. 1999. Reciprocal innervation between serotonergic and GABAergic neurons in the raphe nuclei of the rat. Soc. Neurosci. Abst. 481.9.

  53. Loizou, L. 1969. Projections of the nucleus locus coeruleus in the albino rat. Brain Res. 15:563–566.

    Google Scholar 

  54. Pineyro, G. and Blier, P. 1999. Autoregulation of serotonin neurons: role in antidepressant drug action. Pharmacol. Rev. 51:533–591.

    Google Scholar 

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Authors and Affiliations

  1. Institute for Drug Research, Ltd., Budapest, Hungary

    Erzsebet Bagdy & Istvan Kiraly

  2. Institute for Drug Research, Ltd., Budapest, Hungary

    Laszlo G. Harsing Jr.

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Bagdy, E., Kiraly, I. & Harsing, L.G. Reciprocal Innervation between Serotonergic and GABAergic Neurons in Raphe Nuclei of the Rat. Neurochem Res 25, 1465–1473 (2000). https://doi.org/10.1023/A:1007672008297

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