Inhibitory effects of tandospirone, a 5HT 1A agonist, on medial vestibular nucleus neurons responding to lateral roll tilt stimulation in rats

Inhibitory effects of tandospirone, a 5HT 1A agonist, on medial vestibular nucleus neurons responding to lateral roll tilt stimulation in rats
of 4
All materials on our website are shared by users. If you have any questions about copyright issues, please report us to resolve them. We are always happy to assist you.
Related Documents
  Brain Research 910 (2001) 195– Short communication Inhibitory effects of tandospirone, a 5-HT agonist, on medial 1A vestibular nucleus neurons responding to lateral roll tilt stimulation inrats *Taku Amano, Muhammad Akbar, Hiroaki Matsubayashi, Masashi Sasa  Department of Pharmacology ,  Hiroshima University School of Medicine ,  Hiroshima  734  - 8551,  Japan Accepted 6 June 2001 Abstract An electrophysiological study was performed using chloral hydrate-anesthetized rats to determine whether tandospirone, a 5-HT 1A agonist, affects neuronal activities of the medial vestibular nucleus (MVN), since serotonergic innervation and 5-HT receptors are 1A present in this nucleus. Tandospirone applied microiontophoretically at a current of 20–60 nA caused an inhibition of tilt-induced firing of  a -type neurons, which showed increased and decreased firing with lateral tilt ipsilateral and contralateral to the recording site,respectively, along with that of   b -type neurons which exhibited the reverse responses to ipsilateral and contralateral tilt stimulation. Theinhibition was antagonized during simultaneous, iontophoretic application of WAY-100635 (20–60 nA), a 5-HT receptor antagonist, 1A although WAY-100635 alone rarely affected spontaneous or tilt-induced firing in either type of neurons. These results suggest thattandospirone acts on a 5-HT receptor to inhibit transmission of otolith information to  a - and  b -type MVN neurons.  ©  2001 Elsevier 1A Science B.V. All rights reserved. Theme :   Neurotransmitters, modulators, transporters, and receptors Topic :   Serotonin receptor Keywords :   Tandospirone; WAY-100635; Lateral roll tilt; 5-HT ; Medial vestibular nucleus neuron 1A The vestibular nucleus receives serotonergic innervation dihydrogen citrate) is an anti-anxiety drug with a selectivefrom the dorsal raphe nucleus and has 5-HT and 5-HT 5-HT receptor agonist activity [10,19,20,23]. This drug 1A 1B 1A receptors [2,13,15,16,18]. We have previously demonstra- is also expected to be effective for motion and spaceted that neurons in the lateral vestibular nucleus are sickness probably by inhibiting or modulating excessiveinhibited by serotonin via 5-HT receptors [12]. The information to MVN neurons from the semicircular canal 1A medial vestibu1ar nucleus (MVN) neurons receiving and/or otolith.otolith information were previously classified into eight Although our previous study has demonstrated that thetypes according to the responses to the lateral tilt stimula- neurons activated by vestibular nerve stimulation aretion, mainly composed of   a  and  b  types:  a -type neurons inhibited by serotonin and a 5-HT agonist, 8-OH-DPAT, 1A exhibit an increase and decrease in firing in response to the vestibular nerve conveys input from both thelateral roll tilt stimulation ipsilateral and contralateral to semicircular canal and otolith [12]. Therefore, electro-the recording site, respectively, and b -type neurons exhibit physiological studies were performed to determine whetherthe opposite responses [22]. Tandospirone or not tandospirone affects the MVN neurons responding(3a a ,4 b ,7 b ,7a a -hexahydro-2-(4-(4-(2-pyrimidinyl)-1-pipe- to lateral tilt stimulation, mainly on a - and b -type neurons.razinyl)-butyl)-4,7-methano-1 H-iso-indole-1,3(2  H  )dione- Male Wistar rats weighing 250–350 g (Charles RiverJapan, Tokyo) were used. All procedures were done inaccordance with  Guidelines for the Use of Laboratory * Corresponding author. Tel.:  1 81-82-257-5140; fax:  1 81-82-257-  Animal at Hiroshima University School of Medicine . Rats 5144.  E  - mail address : (M. Sasa).  were anesthetized with chloral hydrate (300 mg/kg, i.p.) 0006-8993/01/$ – see front matter  ©  2001 Elsevier Science B.V. All rights reserved.PII: S0006-8993(01)02698-1  196  T  .  Amano et al .  /   Brain Research  910 (2001) 195  – 198  and fixed in a stereotaxic instrument which was attached to NEC, and Daiichi Ikagaku, Tokyo, Japan) was first tiltedthe goniometer after tracheal cannulation. Part of the 20 8 ipsilateral to the recording site at a rate of 5 8  /s, pausedcranium and the dura mater were removed for insertion of for 10 s there, and then returned to the srcinal horizontala recording electrode. All pressure points and surgical position at the same angular speed. After a 10-s pause inwounds were locally anesthetized using 8% lidocaine spray the horizontal position, the apparatus was then tilted 20 8 repeatedly throughout the experiment. Additional doses contralateral to the recording site as described above.(50 mg/kg, i.p.) of chloral hydrate were given when These procedures were repeated twice before and duringrequired. Body temperature was maintained at 36.5– microiontophoretic application of the respective drugs.37.5 8 C with a heating pad placed beneath the animal. Each micropipette of the seven-barreled micropipettes wasSingle neuron activities in the MVN (11.5–12.8 mm filled with 20 mM tandospirone (Sumitomo, Osaka, Japan),posterior to bregma, 0.5–1.0 mm lateral to the midline, 10 mM WAY-100635 (Sigma, St. Louis, MO, USA), 1005.4–6.8 mm from the cortical surface) [17] were mM sodium glutamate (Kanto Chemical, Tokyo, Japan).extracellu1ar1y recorded with a glass-insulated silver wire These drugs were microiontophoretically applied to themicroelectrode (electrical resistance: approximately 1–2 immediate vicinity of the target neuron being recordedM V ) attached along a seven-barreled micropipette. The using a four-channel Micro Constant Current Supply (S-5spikes were amplified for display on an oscilloscope (VC- 125B, Nihon Kohden, Tokyo, Japan) 1 min prior to tilt9; Nihon Kohden, Tokyo, Japan) and continuously re- stimulation and for a total of 4 min. The significance of corded with a recticorder (RJG-4124; Nihon Kohden, differences between the tilt-induced firing rate/s for 10 s inTokyo, Japan) using a pulse counter and a discriminator the second trial before and during the drug application in(DSE-325P; DIA Medical System, Tokyo, Japan). each neurons was examined using paired Student’s  t  -test,A computer-controlled goniometer (PC-9801RA21, and that of differences between the two groups before and Fig. 1. Effects of microiontophoretic application of tandospirone (60 nA) alone and concomitant application of WAY-100635 (60 nA) with tandospirone(60 nA) on lateral tilt-induced firing of  a (A) and b (B) type neurons in medial vestibular nucleus. Blocks: time during application of respective drug. Thelower trace indicates the position of the goniometer.  T  .  Amano et al .  /   Brain Research  910 (2001) 195  – 198   197 during drug application was also tested. Each value of the Therefore, tandospirone-induced inhibition was suggestedgroups were obtained from the mean tilt-induced firing to be mediated by 5-HT receptors located on the MVN 1A rate/s during lateral tilt at 20 8  for 10 s in each neuron. neurons. However, the results that WAY100635 did notResults in each group before the drug application were completely reverse the tandospirone-induced inhibition,compared with those during microiontophoretic application may be due to the partial agonistic activity of thisof tandospirone alone or concomitant application with antagonist [1,4]. The inhibitory role of a 5-HT receptor 1A WAY-100635. Data were expressed as percentage of the in vestibular nucleus neurons has been also reported bycontrol before drug application. Johnston et al. and Licata et al. [9,14]. 5-HT -receptor- 1A The effects of tandospirone were examined on  a - and mediated inhibition has also been found in the lateral b -type neurons, as shown in Fig. 1A,B, respectively. vestibular nucleus neurons activated by vestibular nerveMicroiontophoretic application of tandospirone at current stimulation [12]. Antivertigo drugs such as diphenhydra-of 20–60 nA inhibited spontaneous firing in both type mine, diphenido1, and betahistine inhibited neuronal ac-neurons. The tilt-induced firing of both neurons was also tivities in the lateral vestibular nucleus and MVN, proba-inhibited during microiontophoretic application of tandos- bly inhibiting excessive impulses from the semicircularpirone up to 60 nA (Fig. 1A,B). Such significant ( P , 0.01) canal and/or otolith to the neurons and thereby controllingreduction of tilt-induced firing by tandospirone was ob- dizziness [11,21,24]. Thus, tandospirone is suggested to beserved in nine of 10  a -type neurons and all 14  b -type effective for treatment of vertigo, at least when due toneurons examined, although the firing in the remaining one excessive inputs to the MVN neurons and/or functional a -type neuron was unaffected. The means of tilt-induced imbalance of the right and left peripheral vestibular organsfiring in 10  a -type and 14  b -type neurons significantly [3,25,26].( P , 0.01) decreased to 42.6 6 10.6 and 24.1 6 5.0% duringapplication of tandospirone, respectively (Table 1). Appli-cation of WAY-100635, a 5-HT receptor antagonist, 1A Acknowledgements alone up to 100 nA did not significantly affect the tilt-induced firing in either  a - and  b -type neurons. However,Authors are grateful to Dr. Y. Harada, a president of concomitant application of WAY-100635 (20–60 nA)Hiroshima University, For valuable suggestion and finan-resulted in antagonizing against the inhibition by tandos-cial support in making computer-operated goniometer.pirone of the tilt-induced firing of both  a - and  b -typeThis study was carried out as a part of ‘Announcement forneurons. In the presence of WAY-100635 (20–60 nA), thespace utilization’ promoted by Japan space Forum. Themean of tilt-induced firing rate/s with tandospirone (20–Authors wish to thank the Research Facilities for Labora-60 nA) was significantly ( P , 0.01) increased to 88.4 6 15.0tory Animal Sciences, Hiroshima University School of and 58.4 6 7.2% in  a  ( n 5 10) and  b  ( n 5 14) type neurons,Medicine for use of their equipment and Sumitomorespectively (Table 1).Pharmaceuticals Co., for a gift of tandospirone.Previous studies have demonstrated that tandospironeand serotonin inhibit the activities of hippocampal pyrami-dal neurons that receive excitatory cholinergic input from References the medial septal nucleus by acting on 5-HT receptors 1A [8]. Similar inhibitory effects of tandospirone have been [1] M.B. Assie, W. Koek, Effects of 5-HT1A receptor antagonists on obtained in the dorsal raphe nucleus [7]. In the present hippocampal 5-hydroxytryptamine levels: (S)-WAY100135, but not study, the inhibition of   a - and  b -type MVN neurons WAY100635, has partial agonist properties, Eur. J. Pharmacol. 304 receiving input from otolith was also obtained by tandos- (1996) 15–21. pirone. The tandospirone-induced inhibition was antagon-  [2] N.M. Barnes, T. Sharp, A review of central 5-HT receptors and their ized by WAY-100635, a 5-HT receptor antagonist [5,6].  function, Neuropharmacology 38 (1999) 1083–1152. 1A Table 1Effects of microiontophoretic application of tandospirone alone and with WAY-100635 on lateral tilt-induced firing of vestibular nucleus neuronsPercent Tandospirone Way-100635 Way-100635of control (20–60 nA) (20–60 nA)  1 tandospironeNeuron type a  100 42.6 6 10.6* 108.6 6 18.1 88.4 6 15.0** a a b n 5 10 (9/10) (0/10) (7/9)Neuron type b  100 24.1 6 5.0* 72.9 6 9.3 58.4 6 7.2** a a b n 5 14 (14/14) (0/14) (12/14)Each value represents the mean percentage 6 S.E.M. of spikes/s induced by lateral tilt stimulation in MVN neurons. a Number of neurons inhibited by tandospirone/number of neurons tested. b Number of neurons antagonized by WAY-100635/number of neurons tested.* P , 0.01, significantly different from control; ** P , 0.01, significantly different from the value with of tandospirone alone.  198  T  .  Amano et al .  /   Brain Research  910 (2001) 195  – 198  [3] N. Dieringer, W. Precht, Modification of synaptic input following medial vestibular nucleus neurons in the rat, Neurosci. Lett. 154unilateral labyrinthectomy, Nature 269 (1977) 431–433. (1993) 195–198.[4] J. Dunlop,Y. Zhang, D.L. Smith, L.E. Schechter, Characterization of [15] M.C. Miquel, E. Doucet, C. Boni, S. El Mestikawy, L. Matthiessen,5-HT1A receptor functional coupling in cells expressing the human G. Daval, D. Verge, M. Hamon, Central serotonin1A receptors:5-HT1A receptor as assessed with the cytosensor microphysiometer, respective distributions of encoding mRNA, receptor protein andJ. Pharmacol. Toxicol. Methods 40 (1998) 47–55. binding sites by in situ hybridization histochemistry, radioim-[5] A. Fletcher, E.A. Forster, D.J. Bill, G. Brown, I.A. Cliffe, J.E. munohistochemistry and autoradiographic mapping in the rat brain,Hartley, D.E. Jones, A. McLenachan, K.J. Stanhope, D.J. Critchley, Neurochem. Int. 19 (1991) 453–465.K.J. Childs, V.C. Middlefell, L. Lanfumey, R. Corradetti, A.M. [16] J.M. Palacios, C. Waeber, D. Hoyer, G. Mengod, Distribution of Laporte, H. Gozlan, M. Hamon, C.T. Dourish, Electrophysiological, serotonin receptors, Ann. NY Acad. Sci. 600 (1990) 36–52.biochemical, neurohormonal and behavioural studies with WAY- [17] G. Paxinox, C. Watson, in: The Rat Brain in Stereotaxic Coordi-100635, a potent, selective and silent 5-HT1A receptor antagonist, nates, 2nd Edition, Academic Press, Sydney, 1986.Behav. Brain Res. 73 (1996) 337–353. [18] F. Radja, A.M. Laporte, G. Daval, D.Verge, H. Gozlan, M. Hamon,[6] E.A. Forster, I.A. Cliffe, D.J. Bill, G.M. Dover, D. Jones, Y. Reilly, Autoradiography of serotonin receptor subtypes in the centralA. Fletcher, A pharmacological profile of the selective silent 5- nervous system, Neurochem. Int. 18 (1991) 1–15.HT1A receptor antagonist, WAY-100635, Eur. J. Pharmacol. 281 [19] H. Shimizu, N. Karai, A. Hirose, T. Tatsuno, H. Tanaka, Y.(1995) 81–88. Kumasaka, M. Nakamura, Interaction of SM-3997 with serotonin[7] R. Godbout, Y. Chaput, P. Blier, C. de Montigny, Tandospirone and receptors in rat brain, Jpn. J. Pharmacol. 46 (1988) 311–314.its metabolite, 1-(2-pyrimidinyl)-piperazine — I. Effects of acute [20] H. Shimizu, T. Tatsuno, A. Hirose, H. Tanaka, Y. Kumasaka, M.and long-term administration of tandospirone on serotonin neuro- Nakamura, Characterization of the putative anxiolytic SM-3997transmission, Neuropharmacology 30 (1991) 679–690. recognition sites in rat brain, Life Sci. 42 (1988) 2419–2427.[8] A. Hirose, M. Sasa, A. Akaike, S. Takaori, Inhibition of hippocam- [21] T. Takatani, J. Ito, I. Matsuoka, M. Sasa, S. Takaori, Effects of pal CA1 neurons by 5-hydroxytryptamine, derived from the dorsal diphenhydramine iontophoretically applied onto neurons in theraphe nucleus and the 5-hydroxytryptamine1A agonist SM-3997, medial and lateral vestibular nuclei, Jpn. J. Pharmacol. 33 (1983)Neuropharmacology 29 (1990) 93–101. 557–561.[9] A.R. Johnston, B. Murnion, D.S. McQueen, M.B. Dutia, Excitation [22] S. Takeshita, M. Sasa, K. Ishihara, H. Matsubayashi, K. Yajin, M.and inhibition of rat medial vestibular nucleus neurones by 5- Okada, R. Izumi, K. Arita, K. Kurisu, Cholinergic and glutamatergichydroxytryptamine, Exp. Brain Res. 93 (1993) 293–298. transmission in medial vestibular nucleus neurons responding to[10] Y. Kataoka, K. Shibata, A. Miyazaki, Y. Inoue, K. Tominaga, S. lateral roll tilt in rats, Brain Res. 840 (1999) 99–105.Koizumi, S. Ueki, M. Niwa, Involvement of the dorsal hippocampus [23] R. Tsuji,Y. Ohno, A. Hirose, H. Shimizu, H. Tanaka, M. Nakamura,in mediation of the antianxiety action of tandospirone, a 5-hydroxy- Effects of tandospirone, a 5-HT1A receptor-related anxiolytic, ontryptamine1A agonistic anxiolytic, Neuropharmacology 30 (1991) the pressor response elicited by stimulation of the posterior hypo-475–480. thalamus in cats, Arch. Int. Pharmacodyn. Ther. 311 (1991) 131–[11] A. Kawabata, M. Sasa, T. Kishimoto, S. Takaori, Effects of anti- 143.vertigo drugs on medial vestibular nucleus neurons activated by [24] H. Unemoto, M. Sasa, S. Takaori, J. Ito, I. Matsuoka, Inhibitoryhorizontal rotation, Jpn. J. Pharmacol. 55 (1991) 101–106. effect of betahistine on polysynaptic neurons in the lateral vestibular[12] T. Kishimoto, T. Yamanaka, T. Amano, N. Todo, M. Sasa, 5-HT1A nucleus, Arch. Otorhinolaryngol. 236 (1982) 229–236.receptor-mediated inhibition of lateral vestibular nucleus neurons [25] T. Yamanaka, T. Amano, M. Sasa, T. Matsunaga, Prednisoloneprojecting to the abducens nucleus, Brain Res. 644 (1994) 47–51. excitation of medial vestibular nucleus neurons in cats, Eur. Arch.[13] L. Lanfumey, M. Hamon, Central 5-HT(1A) receptors: regional Otorhinolaryngol. 252 (1995) 112–118.distribution and functional characteristics, Nucl. Med. Biol. 27 [26] T.Yamanaka, M. Sasa, T. Amano, H. Miyahara, T. Matsunaga, Role(2000) 429–435. of glucocorticoid in vestibular compensation in relation to activation[14] F. Licata, G.L. Volsi, G. Maugeri, F. Santangelo, Excitatory and of vestibular nucleus neurons, Acta Otolaryngol. Suppl. 519 (1995)inhibitory effects of 5-hydroxytryptamine on the firing rate of 168–172.
Similar documents
View more...
Related Search
We Need Your Support
Thank you for visiting our website and your interest in our free products and services. We are nonprofit website to share and download documents. To the running of this website, we need your help to support us.

Thanks to everyone for your continued support.

No, Thanks