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• (=isl^'!S-7t1OV) EFFECT CF TRANAZLILMS Qi sse-11759/iltli IMSIiKL 24d :bz &UCCAT*_ 511MLI LETEE FLSTVei117 il:ArATUS (satic&&Iiermavastits Zad space Tdaiaistratioy S p [atlas^[ llli/3! X71 Cs" 06C z5/51 4c77.:

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rarmskelnr!ya 1 teks`-koloziys,ioi_ 12, Rio_ 6, ,tune 1979, PP f0£-613

'rATZJ},AL AERONAUTICS AID SPACE ADMI:;ISTRATIONWASHINGTO'i D.C. 20546 14ARCH 1990

Ili 1'. 1 '3 V Val i ^ _cz . ^J V EPAR ; r f r, ^^.Pf^Ol:i:;a Scie^ iYi a and aea:.=..ca1j l^oi:ion Facflit^ rL^`'

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By

'!a. E. MoaksincL :chi axed 5. T. £3:inchdk&shvi.1i*

ire shat increase i. a gra;.ion of the population has entailed an ink rcvemer_t /606**

is the mea.:s of movement. Noder-: rapid transportation creases considerablerectilinear, radial and com--iez acre=eraticns that are adequate stimuli of thev°stib :ar ap}aratus. The vestibulcsonatic and vest ibulo-autonomic reactions thatoccur here are sub actively distressing and reduce the =er`oruance capacity of

both the drivers and the :assengers. This determines the urgency of a search

substances that alleviate the ranifestations of these reactions. It is

?mown that neu=ole: tics to a certain measure possess such properties (Y. Ye.

Motovilov, 1964; I. A. Yarosh, 1966; iiocdi et al., 1966; Deane et al.,Johnson et al., 19715, however the depressing effect of these substances on the

mental and psychomotor reactions makes thec not very suitable for the indicated

pur:ose (V. V. Zakusov, 1964). Isclatedworks snake it possible to hypothesize that

tranquii?zers will be effective for preventing the negative consequences of ves-

tibular stimuli (I. I. Voinova et al., 1975; Franks et al., 1962). the more sosince the directed effect on the emotional sphere by means of prescribing tran- 607quilizers can increase the performance caracity of roan (C. S. Loba,tov et al.,

1968; G. D. Glod et al., 1972; Hurst, et al., 1970). On the other hand, it is

known that the emotional factor is one of the components that plays a role in

the pathogenesis of motion sickness.

The tasks of this study were to establish in an experiment whather tranqui-

literspossess a group rroperty to increase the resistance to the effect of*Departments of Pharmacology and Otorhinolaryngclogy of the N. I. Pirogov

Odessa Medical Institute

Nwabers in margin indicate pagination in original foreign text.

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&4eG x-_ to s t iii c ,-'" tt' ti sus t 1bLar ap: arat = "ann in tel@ case O f ottia n i a

:kCsitira - yes :lt tc se=act a .remratior ^iZt: t*,e mast azi licit effect of rrc-tecticin ac, im A ac,-a:erat.icrns.

Rgthocs of S jA-V

Work wa;. Iota on OW alb ;--,c nice. Fcr adeo dat e_ stizz:ation of the labyrinth

wh, f'air:r wi3as;:^d retW_ c'' ce^tr°.f^^zg w used (A. Y. Sogatskir et al,3.a?S; L. D. amd L. S. Ivanern c. lam) which aCZCCrdinC :c K. L. Ehi:ov(1Q6^) excites the racerters and the o:rolith:c instrmert. and t ;re serLicircu:&Tca_%a:s. T i into acc—zunt the applied nature of tha study it Was necessary toobtain a.cce:eration clone to the tmnsNrtaticr_.. For this t urpcse a certri ice

was ms.:a with s^mch Jncus rotor with pcwar :2S rpas with rotaticli ra i s 11 cs.

"he ra ia: acee?aration that thus dere:orea L—as _ g and acted on the ani als inthe direction back--chest. It is 3-wwr that one cf the racuent disorders occurringueier the inf:ueaee of acce_eration is the sat of motor-cocrdinatior. disorders.

'Iberefcre in order to a%raluate tip affect of cart_ifi;ging on the :motor activityof the anal; 1-he net.hod of actenetry was t;^ that gives an eb iectivenumerical indic-a-tcr. The suer:est actometer eluipped with an alactronagreiic

counter was used.

Five mice w i th the same body veight. were placed it a drum of the centrifugeand axmsod to 3-minute rotation cloc kw ise. yixectly after this an evaluationwas made of the pronouncement and duration of reflexes (nystagnus of the torso,

tail reflex) and the rice were moved to the char.ber of the actometer, where they

stayed for 1 h. At the lst, 5th, 10th, etc. minutes the aetonetrie counter wasturned on. Thus, in 1 hour 13 reasurer"nts were made, the magnitude of eachreflected the sum of movements of five animals in 1 min. The findings were

statistically processed and from the 13 points curves were =lotted for the

motor activity of the animals under different experimental conditions.

:ha animals were divided into 5 grouts of 180 individuals each. Since in

the centrifuge and actometer 5 mice each were rlaced simultaneously, 36 experi-

ments were conducted in each group; each animal was used only once in the experi-

ment. The first group included intact mice not exposed to centrifuging, and

from the data of -hese experiments a stable curve was derived for the spontaneous

motor activity; the second group was the control--curve for the effect of

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ti1e-y IDar obaffa tta . aleriumt of nico:ita.

—1 v rslaz^ tad subs td!tces a-ra t: k3 most wise-ti used in 7ract ice a.t v`Qr1 ir.'^ ci;a^* i:3= rte' ^-^e: *^a-rcbra^te--3ar_^ati^a of -rc;an icl. e_Ani:at--deri vative of

1.4-7-re*r.odia e, Ina, nicclits--'-ithiun salt of n icot inic acid ( la. BF . I5aksimovichi. }SA«'71T, 1 3, 1?74, 1976; Ia. B. Mks 5 movich et a1., 2976; centifi-

catA of authorshiz No. 38' r1c of 2 A ,ri: 1971). the r.abstance; were given in

theca ^eutic doses %tea-rob :-2n t$--3 N6:'g, elsni^. -^._^ nicoiiia--10 u :'`kg)in the same volume of :hys:ol:ag 2 cal soluti.>n (0.k al) intrsperitersa_!- once. Atthe and oftee acute exneriaaart the aniiTals were observed for 1 month. The inta-gral ir::icas ware eonsiderad: body weight, behavior, mortality rata.

Results

S^cntansous motor activity of the intac t. rice was not stable for 1 h:already frc r. the 1. th i.inut ,e of observation it was reduced and for about 1 anhour fluct;ated in the _owast limits, and then. returned srvothly to the in'tia?amounts.

Tha results of the control series of experiments indicated that the adequate

stimulus of the vestibular apparatus shar ply disrupts the motor system of the

anira_s. 2 -ectly after centrifuging of mice they were rotated 2-3 times to the

right around the longitudinal axis; torsal and aye nystagmus were clearly mani-

fest (reaction of semicircular canals); the otolita reflex was observed (straightening

of tall ) and tremor of the extremities. Further attention was drawn to the sharp

disruption in the coordination of movements and reduction in the general motor

activity linked to the action of accelerations. A highly reliable reduction inthe number of movements was noted during the entire experiment.

Under the influence of the tranquilizers the vastibulo-spinal reflexes were

weakly pronounced, and often were missing (especially nystagmus of the torso and

tail). At the same time in these animals the motor activity remained also X608

diminished, although less than in the control. Further observations of the mice

in all grouts indicated the complete rectomation of locomotor reactions in 24 h.

No losses of body weight or increase in mortality of the anirTials were observedas compared -Lo the intact mice in the 1 month from the conducting of the ex-eriment.

3

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S ^^. _ . _ .v =i ^^' Kin

Dvnur_ies of Yotor Activity of Anina:s Number of !!eva-ents in 1 nin) under Dif-farent Conditions of nxreri rent_-- intact mica; 2--control; 4--elenium; --niCClL

Statistically processed results of t:'.+ axperinants on all five groups of

animals are :resented in table 1.

Discussion of Results

A con-arisen of the results of the conducted experiments outlined the following

laws. First: powerful (2 g) stimulation of the vestibular analy-er by centrifugingleads to disruption of the vestibulo-spinal bonds. This is accom^anied by the

appearanca :f pathological reflexes interchanging with -renounced and stable by-o-

kinesis. For 1 h after cessation of rotation the number of .movements is reduced

2-4-fold as nomnared to the actomatric index of intact animals and by the 60th

min-ate of the axreriment remains lower by more than double ( -60.95). Second: the

tranq uilizers regardless of their chemical nature shar ^ly reduce the -at.hological

hyper-reflex due to the centrifuging and noticeably diminish the subsequent hypo-

kinesia. Thus, a unique effect that is common to all the tranquilizers of protec-

ting the vastibulo-spinal bonds appears. It is possible that the effect of inter-

ruption of the interneural transmission that is inherent to tranquilizers is also

s^read on these raths. This would promote expansion of the extant ideas on the

intracentral mechanisms for the effect of tranquilizers (I. P. i,anin and L. A.A llimets, 1967; Yu. N. Furman, 1 c)74; Yu. A. A leksai,drovskiy, 1976; I. Tomkov and

K. Kirov, 1971; F. Shvet s, 1971).

However, as is easy to see on the figure, although all the emplo.-ed tranqui-

lizers possess the protective prelerties, this effect is not ex pressed to the same

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degree. &,thematical analysis of the picture given in table 2 is convincing of

this. It is ap-arer.t from it that in the first 10 min. the changes in the motor

activity in all animtils who took tranquilizers are of the sums ty^e regardlessof the en^Ioysd tranquilizer. However, already from the 15th minute individual

peculiarities of the ^reaarations begin to a-7ear. At the same time in animals

of the 4th and 5U. group the second wave drop in motor activity begins, in mice

who took me^robam.ate (third group) the motor system is stabilized. and from the

20th minute they begin to rap;.'^j emerge from the state of hypokinesia. At the

50th minute the degree of suppression of the motor activity of the mice of the

third grou- was almost two times lower than in the mice of the fourth and fifth

groups (res^eetively -18.6/ versus -31.8 ar.d - 35.6%).

There is yet another important detail. In the animals who took elenium and 610

nicolite, starting from the 50th minute a third wave of drop in motor activity

develops that is noti:oable although not sharp. In the mice who received me-

probamate there is no third wave of drop and the motor activity is generally

stabilized on a level attained by the 50th minute and is fairly close to the

amount of the actometric index of intact animals. The cited data force us to

consider that in a comparative aspect meprobamate has the most -ronounced effect

in relation to increasing the resistance to accelerations and elimination of

possible motor disorders.

Conclusions

1. Tranquilizers increase the resistance of animals to the effect of adequate

stimuli of the vestibular apparatus.

2. Meprobamate possesses the most pronounced protective properties.

References

A leksandrovskiy, Yu. A. Sostoyaniya psikhicheskoy dezad ntatsii i_ikh komnensatsi_i_(F rranichnyye nervno^sikhicheskiya rasstroystya) 1"States of :sychicDysadaptation and Their Compensation (Boundaries of Neuro-?'sychic Disorders)"^Moscow, 1976.

Bogatskiy, A. V.; Golovenko, N. Ya.; Andronati, S. A. et. al., Kosemichaskayabiol„ No. 3 ( 1970, P. 75-73.

Voinova, I. I.; Iavretskaya, E. F.; and Frivol'neva, T. F. Farmako l. i toksi-ko11t No. 6 (1975), p. 653-659.

_ --

Glod, G. D.; Belay, V. Yo., Vasil'yev, F. V.; et al., Kosmicheskaya biol., No. 4(1972), P. 77-33.

6

I

' Zakusov, V. V. Farmakol. i toksikol., No. 1 (1964), P. 107-121.

+ Klimovskava, L. D.; Ivanen;:o, L. S. K osmicheskaya biol., No. 4 (1Q 78) , p. 55 -59.

Lapin, I. P.; and Allikmets, L. A. in Sovremannvve psikhotropnyye sredtsva"modern Psychotropic Reso^^rcas" -, Moscow, 1967, No. 1, P. 97-100.

Lobastov, 0. S. Spivak, L. I.; and Fanov, B. F. Voy en. -med, sh., No. 5 (1968),n 26-28 . —

Maksimovich, Ya. B.; and Krasyun, V. I. Vrach, delo, No. 8 (1973), p• 99-101.

Maksimovich, Ya. B.; and Krasyun, V. I., In Serotonin-Brain-Drugs, Symposium.?Papers, Warszawa, 1975. p • 29-30•

Maksimovich, Ya. B.; and Krasyun, V. I. In, Sov_eshchaniye po a_ktual'nym problemampsikhofarmskologii L"Conference on Urgent Problems of Psyehoprarmscolcgy"Tartu, 1976, p. 65-68.

Maksimovich, Ya. B.; Kresyun, V. I.; Sol.ov'yev, V. G.; et al., Sintez i mekhaniz m.4qystviya fiziologicneski akti_vnykh vashch_est y "Synthesis and Mechanismof Action of F hysiologically Active Substances"_, Odessa, 1976, P. 178-179.

Motovilov, V. Ye. Vestn. otoriuo lar., No. 2 (1964), p. 14-17.

Furman, Yu. N. Vrach. delo, No. 2 (1074), p. 9-11.

Khilov, K. L. Funktsiya. organa ravnovesiya i bolazn' peredvizher.iya L"Functionof Organ of Equilibrium and Motion Sickness"_j, Leningrad, !Q6Q.

Yarosh, I. A. Voyen.-mad, zh i , No. 9 (1966), p. 88-89.

Deane, F. R.; Wood, C. D.; Graybiel, A. Aerospace Mad., Vol. 38 (1967), P. 842-445.

Franks, J. J.; Milch, L. J.; Dahl, E. V. J.A.M.A., Vol. 141 (1962), p . 263-264.

Hurst, P. M.; Radlow, B.; and Bagley, S. K. Ergonomics, Vol. 13 (1970), p. 435-444.

Johnson, W. H.; Fenton, R. S.; and Evans, A. Laryngoscope (St. Louis), Vol. 86(1976) , p. 946-954.

Shvet.s, F. Farmakodinamika lekartsv s eksperimental'noy i klinichaskoy tocy1izreni^a LF harmtcodynamis of Medicine from an Experimental and Clinical View-1'oint , Bratislava, 1971, Vol. 1.

Temkov, I.; and Kirov, K. Klinichaskaya osikhofarmakologiya"Clinical Psycho-pharmacology"], Moscow, 1971.

l

' Wood, C. D.; Graybiel , A.; and McDonOLIgh, R. Aerospaco Mc^d.. , Vol. ^7 (1 077) , p.187-

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