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

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Inhibitory effects of tandospirone, a 5HT 1A agonist, on medial vestibular nucleus neurons responding to lateral roll tilt stimulation in rats
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  Brain Research 910 (2001) 195–198www.elsevier.com/locate/bres 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 :   sasa@mcai.med.hiroshima-u.ac.jp (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. 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