Basic and Applied Aspects of Vestibular Function

12. Serotonergic mechanisms in emesis

8/J1ic o.'!'iAppli,dNpcCIF ofVu6bt<1o.r FWtCu" 1H< I.C. Hw...,.N.G. Own_and VJ. Wiloon (Ed•.) e ll"", K"", Univ.,..ily Preu, H"", Kon" 1911 SEROTONERGIC MECHANISMS IN EMESIS J.B. Lucot and G.H. Crampton Department ofPharmacology, Wrighl State UniversilY, Dayton, OH 45435, U.SA. Abstract The observation that the CSF of cats which are susceptible 10 motion sickness contained lower baseline levels of 5-hydroxyindoleacetic acid, among other constituents, led to the hypothesis that serotonin inhibits emesis. The hypothesis was tested by administration of the serotonin-IA agonists busprrone and 8-0HDPAT before motion testing in cats susceplible to motion sickness. Both drugs blocked motion sickness in a dose-dependcnt fashion. To determine if these drugs blocked emesis elicited by otherstimuli, they were administered beforesubeutaneous administrationofthe aJpha.2 noradrcnergic agonist. xylazine. Bothdrugs also blocked xylazine-induced emesis. It was concluded thai stimulation ofserotoninIA receptors inhibits emesis elicited by the two stimuli and that this mechanism may e;o;en a genera) antiemetic effect Introduction Analysis of the constituenls of cerebrospinal fluid from the fourth ventricle of cats determined thatcatswhich became motion sick had lowerbaseline levels ofserotonin metabolites, dopamine metabolites, uric acid and vasopressin (Fox et ai" 1987; LUCOI and Crampton, in revision). Studies to determine which, ifany, ofthese neurotransmittersystems are involved in the emetic process were started by manipulation of serotonin receptors. Buspirone was selected as a test drug because it is a panial agonist at serotonin-IA receptors (Andrade and Nicoll, 1985; Peroutka, 1985). However, at higher doses, buspirone also stimulates presynaptic dopamine receptors (McMillen et at., 1983), raising a question regarding the mechanism of action of any antiemetic effecL This problem was resolved by testing 8-0H-DPAT for antiemetic propenies, because it is a selective agonist at serotoninIA receptors (Middlemiss and F07.ard, 1983). Two emetic stimuli were used. Provocative motion was relevant as thc neurochemical analysis had been perfonned using motion sickness susceptibility as a critical variable. Keywords: cat. motion sickness. serotonin agonists, xytazine. emesis. 108 Lucot and CrAmp(on Xylazine was usedsince ourexperiencehas been thaI it is areliableandcomparativelybenign drug stimulus for eliciting emesis. Funhcr, xyiazineand motion trigger the emetic reflex by means ofdifferent ncural pathways, thus providing information on possible anatomical sites of action (see below). Methods The motion stimulus was provided by a motor driven device resembling a Ferris wheel. Female cats rode in two Plexiglas boxes which were suspended from a 0.89 m beam that rotated ahoUla centralaxleat 17 rpm. Theboxes werccountcr·rotated soas torcmain vertical. A motion chaUenge test consisted of 30 min of rotation followed by onc min ofobservation at rest (Crampton and LUCOl, 1985). Cats received five screening tests to determine the baseline level of susceptibility, and only those wilh moderate to high susceptibilities were used for drug studies. All tests were separated by two weeks to prevent habituation to the motion stimulus. Xylazine-induced emesis was elicited by subcutaneous administration ofO.66 mg,lkg of xylazine base in a volume of 0.066 ml/kg. The female cats were different from those used in the motion studies. These subjects were administered xylazine and observed for 30 min or for 15 min after lhe last emetic episode, whichever occurred last. Tests were separated by a week to prevent habituation. Only cats which responded to this dose were used in drug studies. Wilh both motion sickness and xylazine-induced emesis, the dependent variable was retching, though in all cases retching was followed by vomiting. Buspirone was administered subcutaneously 30 min before motion testing in 20 cats. 8OH -DPATwas administered subcutaneously 15 min before motion testing in ten cats. These pre-trealrnent times were also used in xylazine tests. Both drugs were dissolved in sterile saline in an injection volume of 0.1 mllkg. Results Buspirone blocked motion sickness with an ED50 of0.41 mg/kg (Table I). The highest dose lCsted, 4 mg/kg, also blocked xylazine-induced emesis (Table 2). Buspirone was effective in blocking both emetic stimuli (LuCOI and Crompton, 1987). TabJe1. The effects of buspirone on motion sickness. Buspirone was administered subcutaneously to twenty cats 30 min before motion testing. Saline alone was administered both billore and after determination of the dose-resp:lOse CUM:t. Buspirone, mg/kg pre-vehicle 0.0625 0.25 1.0 4.0 post-vehicle Number of retching 15 12 11 5 1 14 Serotonergic Mechanisms in Emesis Table 2. The effects of buspirone and 8-OH·DPAT on retching induced by 0.66 mglkg of xylazine administered subcutaneously. Vehicle alone was administered before xylazine both before and after determination of the effects of buspirone and 8-OH-DPAT. Drug Buspirone pre-vehicle 4.0 mglkg post·vehicle 8.QH-DPAT pre·vehicle 0.01 mglkg 0.04 mglkg 0.16 mglkg 0.64 mQlkg post·vehicle Number of retching/Number tested 11 /15 5115 14/15 10/10 7110 6110 4110 1/10 10/10 109 8-0H-DPAT also blocked motion sickness. with an ED50 of O.Q1I mg/kg (Table 3). Thedose-response curve was not different from parallel when compared to thatofbuspironc (LucOl and Crampton, in revision). Xylazinc-induced emesis was prevenlCd with an ED50 of 0.056 mg/kg (Table 2). The dose-response curves for prevcnlion of xyJazine-induced emesis and for prevention of motion sickness were not different from parallel (LuCOl and Crampton, in revision). Table 3. The effects of 8-OH·DPAT on motion sickness. The 8·0H·DPAT was administered subcutaneously to ten cats 15 min before motion testing. Saline alone was administered both before and after determination of the doseresponse curve. 8-0H·DPAT, mg/kg pre-vehicle 0.002 om 0.D2 0.04 post-vehicle Number of retching 8 7 5 4 o 8 110 LUCOI and Crampton Discussion Buspirone and 8-0H-DPAT are drugs from different chemical families which have in' common only the action of stimulating scrotonin-IA receptors. Thus. stimulation of serotonin -IA receptors is likely the mechanism by which these drugs block emesis. The emetic stimuli were chosen to provide information regarding possible anatomical siles relevant to any observed antiemetic effeclS. The development of motion sickness in cal docs not requirean intact area postrema (Borison and Borison, 1986), whilcxylazinc requircs this structure to elicit emesis (Colby et al., 198 1). Further, xylazine produces emesis by stimulating a1pha-2 noradrenergic receptors, an action which can be blocked by prior administration of yohimbine (Hikasa et al.• 1986; Lucot and Crampton. 1986). However, motion sickness is not blocked by yohimbine (Lucotand Crampton, 1986). From these two lines of reasoning, we conclude that motion and xylazine use different pathways to trigger the emetic sequence. The mostparsimonious explanation for theobservation that buspirone and 8-0H-DPAT block emesis elicited through two different triggering pathways is that they are acting at some point ofconvergence of the pathways. A reasonable location for the point ofconvergence is the area of the brainstem that organizes the emetic reflex (Borison and Wang, 1949). The existence of a structure or network that orchestrates the complex series of autonomic and motorevents thatconstitute emesis is logical even though the preciseanatomical location has been questioned (Miller and Wilson, 1983). If buspirone and 8-0H-DPAT act at Lhatlevel, then they, or any other drug which stimulates serotonin-IA receptors, will block emesis elicited by other stimuli. References l. Andrade, R. and Nicoll, R.A. (1985). The novel anxiolYlic buspirone elicits a small hyperpolarization and reduces serotonin responses at putative 5-HTl receptors on hippocampal CA I pyramidal cells. Soc. Neurosci. Abstr., 11,597. 2. Borison, H.L. and Borison, R. (1986). Motion sickness reflex arc bypasses the area postrema in cats. Exp. Neurol., 92, 723-37. 3. Borison, HL and Wang, S.c. (1949). Functional localization of central co-ordinating mechanism for emesis in caL. 1. Neurophysiof., 12, 305-13. 4. Colby,E.D., McCarthy, L.E. and Borison. H.L. (1981). Emetic action of xylazine on the chemoreceptor trigger zone for vomiting in cats. 1. Vel. Pharmacol. Therap.. 4, 93-96. 5. Crampton, G.H. and LUCOI, LB. (1985). A stimulator for laboratory sLudies of motion sickness in cats. Avial. Space Environ. Med., 56.462-65. 6. Fox, R.A., Keil, L.C., Daunton, N.G., CramplOn, G.H. and Lucot, J.B. (1987). Vasopressin and motion sickness in cats. Avial.Space Environ. Med., 58,Suppl., 9, A 143-47. 7. Hikasa, Y., Takase, K., Saito. K. and Ogasawara, S. (1986). Antagonism of the emetic action ofxylazine by alpha-adrcnoccptor blocking agents.Eur. 1. Pharmacol. ,130,22935 . 8. Lucol, J.B. and Crampton, G.H. (1986). Xylazine emesis. yohimbine and motion sickness susceptibility in the cat. 1. Pharmacal. Exp. Therap.. 237, 450-55. Serotonergic Mechanisms in Emesis 111 9. Lucot,J.B. andCrampton, G.H. (1987). Buspironeblocks motion sicknessand xylazineinduced emesis in the cat. Aviat. Space Environ. Med., 58,989-91. 10. Lucot, J. and Crampton, G.H. 8-0H-DPAT suppresses vomiting in the cat elicited by motion, cisplatin, or xylazine. Pharmacol. Biochem. Behav. (In revision). 11. McMillen, B.A., Matthews, R.T., Sanghera, M.K., Shepard, P.D. and German, D.C. (1983). Dopamine receptor antagonism by the novel antianxiety drug, buspirone. J. Neurosci., 3, 733-38. 12. Middlemiss, D.N. and Fozard, J.R. (1983). 8-Hydroxy-2-(di-n-propylamino)-tetralin discriminates between subtypes of the 5-HT-I recognition site. Eur. J. Pharmacol., 90, 151-53. 13. Miller, A.D. and Wilson, V.I. (1983). 'Vomiting center' re-analyzed: An electrical stimulation study. Brain Res., 270, 154-58. 14. Peroutka, S.I. (1985). Selective interaction ofnovel anxiolytics with 5-hydroxytryptamine -IA receptors. Bioi. Psychiat., 20,971-79. ...