JOURNAL OF THE EXPERIMENTAL ANALYSIS OF BEHAVIOR 1979, 32, 463-472 NUMBER 3 (NOVEMBER)

I. V. ZAVADSKII AND THE BEGINNINGS OFBEHAVIORAL PHARMACOLOGY:AN HISTORICAL NOTE AND

TRANSLA TION

VICTOR G. LATIES

UNIVERSITY OF ROCHESTER SCHOOL OF MEDICINE AND DENTISTRY

I. V. Zavadskii, who worked in Pavlov's laboratory between 1907 and 1909, performed astudy that has many of the characteristics of modern behavioral pharmacology. He studiedthe effects of alcohol, morphine, cocaine and caffeine on the conditioned salivary reflex.A translation of his paper and some brief comments on his life are presented.Key words: Zavadskii, behavioral pharmacology, classical conditioning, morphine, alco-

hol, caffeine, cocaine, conditioned inhibition, salivary conditioning, dogs

I salute this new method and its introduction inthe study of pharmacologic problems. It is preciselybecause of the lack of a strictly objective method thatpharmacologic knowledge in the domain of the centralnervous system is still so sketchy.

-N. P. Kravkov (1908)

These words were spoken by a leading Rus-sian pharmacologist during the discussion of apaper delivered to the medical society in St.Petersburg more than 70 years ago (Zavadskii,1908a). The author of the- report was IgorVladimirovich Zavadskii, who spent the years1907 through 1909 with Pavlov. He first com-pleted his doctoral dissertation on delayed re-flexes (Zavadskii, 1 908b). Pavlov then askedhim to investigate the behavioral effects ofsome drugs, using dogs that had been trainedfor other studies. Although both he and Pav-lov regarded the results as only "preliminary,"Zavadskii himself did no more with drugs.Pharmacological studies were continued by an-other student, P. M. Nikiforovskii (1910); ashort description in English of this work hasbeen given by Anichkov (1965).

Zavadskii published only one more paperfrom Pavlov's laboratory, a pioneering investi-The translation is by Victor Jelin. It was checked by

Leonid Margolin. The late S. V. Anichkov graciouslysupplied a photocopy of Zavadskii's publication. Ithank them all. Preparation of this note was supportedin part by grants ES-01247 from the National Instituteof Environmental Health Sciences and grant MH-11752from the National Institute of Mental Health, and inpart by a contract with the U.S. Department of Energyat the University of Rochester Department of Radia-tion Biology and Biophysics and has been assigned Re-port No. 3490-1623. Reprints may be obtained fromVictor G. Laties, Department of Radiation Biology andBiophysics, University of Rochester School of Medicineand Dentistry, Rochester, New York 14642.

gation of olfaction (Zavadskii, 1909), and thenleft the field of behavior completely; no otherpublications by him appear in Kleshchova'scomprehensive bibliography of the condi-tioned reflex literature (Kleshchova, 1955). Hebecame a professor in the Department of Med-ical Diagnostics at Kazan University in 1913,participated in World War I as a physician,and ended his career as Chief of the TropicalDiseases Clinic in the city of Rostov-on-Don.He died in 1944. A short account of his lifeand his experiences with Pavlov appears in arecent collection of reminiscences of Pavlov(Zavadskii, 1967).

Is this the first paper in behavioral pharma-cology?

REFERENCESAnichkov, S. V. Pavlov's method of conditioned re-

flexes in pharmacology. In M. Ya. Mikhel'son andV. G. Longo (Eds.), Pharmacology of Conditioning,Learning and Retention. New York: Macmillan,1965, pp. 17-24.

Kleshchova, N. K. Bibliography on Conditioned Re-flexes, Vol. 1, 1901-1936. Ed. by E. G. Ayrapetjants.Moscow-Leningrad: Publishing House of the Acad-emy of Sciences, USSR, 1955.

Nikiforovskii, P. M. Pharmacological methods-in ap-plication to conditioned reflexes. Thesis, St. Peters-burg, 1910, 200 pp.

Zavadskii, I. V. An application of the method of con-ditioned reflexes to pharmacology. Toward theproblem of the effects of certain drugs (alcohol,morphine, cocaine, and caffeine) on the fuinction of

463

464 VICTOR G. LA TIES

the higher regions of the central nervous system.Proceedings of the Russian Medical Society in St.Petersburg, 1908, 75, 269-287. (a)

Zavadskii, I. V. Inhibition and dis-inhibition of con-ditioned reflexes. Thesis, St. Petersburg, 1908. 195pp. (b)

Zavadskii, I. V. Gyrus pyriformis in its relation to the

sense of smell in the dog. Proceedings of the Rus-sian Medical Society in St. Petersburg, 1909, 76,523-528.

Zavadskii, I. V. I. P. Pavlov in the laboratory. InE. M. Kreps (Ed.), I. P. Pavlov: Reminiscences byhis contemporaries. Leningrad: Academy of Sci-ences of the USSR, 1967, pp. 97-100.

AN APPLICATION OF THE METHOD OF CONDITIONED REFLEXES TOPHARMACOLOGY. TOWARD THE PROBLEM OF THE EFFECTS OF CERTAIN

DRUGS (ALCOHOL, MORPHINE, COCAINE, AND CAFFEINE) ON THE FUNCTIONOF THE HIGHER REGIONS OF THE CENTRAL NERVOUS SYSTEM

BY I. V. ZAVADSKII

From the Physiologic Section of the Imperial Institute of Experimental Medicine

This work, whose results I shall presentlyhave the honor to communicate, is the first at-tempt to use the methods of conditioned sali-vary reflexes toward the pharmacology of thehigher regions of the central nervous system.The experiments were carried on exclusively

on dogs, of which four were at our disposal.Conditioned reflexes were established as fol-

lows: in the first dog, named Strekoza (Grass-hopper), scratching served as conditioned stim-ulus, while the unconditioned stimulus wasthe pouring into the mouth of 1/4% hydro-chloric acid; in the second dog (Gordon), thesound of a whistle was associated with thefeeding of meat powder; in the third (Negr),scratching was associated with the feeding ofmeat powder; in the fourth (Russlan), scratch-ing was associated with the 1/4% hydrochloricacid poured into the mouth.

In the first two dogs, the length of the con-

ditioned stimulus was 4 minutes, while the un-conditioned stimulus was brought in only onthe fourth minute-in the first 3 minutes theconditioned stimulus was thus applied alone.In the other two dogs, the scratching lasted2 minutes, while the unconditioned stimuluswas applied 1 minute after the beginning ofscratching.The third dog (Negr) differed from the

others in that it had a so-called conditionedinhibitor. A noiseless rotator made of feath-ers, a vertuska, served as the conditioned in-hibitor. The [unreinforced] combination ofthe spinning stimulus with the scratching wasbringing about a complete inhibition of sali-vation, while the scratching alone producedabout 1 cc of saliva per minute.

In order to make it easier to visualize thecharacteristics of salivation of these dogs, Igive examples:

STREKOZA

Magnitude of Conditioned ReflexDate, month, in drops per % minute

time of Parotid Glandbeginning ofscratching TYPE OF 1st 2nd 3rd 4th 5th 6th

[i.e., the stimulus] STIMULUS Y2 min. M min. Y2 min. M min. Y2 min. 1/2 min. REMARKS

4 January10:33 Scratching 0 0 0 0 4 4 At 4th minute,

HCI poured in:45 1 0 0 1 4 4 t,

11:05 " 0 0 0 1 3 9 PI

:25 "'0 0 0 1 5 5

GORDONSubmaxillary Gland

11 January3:39 whistle 0 0 1 3 5 5 At 4th minute,

feeding meatpowder

:53 " 0 0 0 1 5 5 ''4:12 " 0 0 0 5 4 4 ":37 " 0 0 0 0 3 5 ''

AN HISTORICAL NOTE

A typical characteristic of the reflexes inthese two dogs is the delay of salivation. Theconditioned salivation does not begin immedi-ately with the application of the stimulus, butafter l1/2-2 minutes. This delay of secretiondepends on the method of associating the con-ditioned stimulus with the unconditioned one.In our cases, as stated above, the uncondi-tioned agent is superimposed to the condi-tioned one 3 minutes after the beginning ofthe latter. The conditioned salivation repre-sents an advantageous adaptation of the or-ganism, i.e., the secretory reaction occurs onlywhen there is an actual need, in the examplesabove, at the moment preceding the applica-tion of the unconditioned stimulus. Now itcan be asked, to what physiologic category ofphenomena should belong the delay of thereflex? To this question the laboratory ofProfessor I. P. Pavlov answers as follows:under the influence of the particular condi-tions of these tests, the specific action of theinitial part of the conditioned stimulus isinhibitory tlhrough the process of internalinhibition. All cases of inhibition are calledinternal when no stimulus other than theconditioned one is present. (Details about thedelay of reflexes are presented in my reportto the Russian Medical Society of St. Peters-burg, 29 November 1907, and in the disser-tation "Materials toward the Problem of theInhibition and the Spread of Inhibition ofConditioned Reflexes," 1908, St. Petersburg.)The opposite type of inhibition is called

"external" inhibition. As an example of thelatter we can mention our third dog, in whomthe association of a rotating object withscratching brings about a complete stop insalivary secretion. For instance:

NEGR

9 January3:23 scratching alone:35 scratching and rotating object:40 scratching alone

4:00 same:12 scratching and rotating object:22 scratching alone

Magnitude ofthe conditioned

reflex incc/minute.

Submaxillarygland

1.2cc0 cc

1.0cc0.9cc0cc

0.7 cc

The fourth dog, Russlan, had a reflex com-

parable to that of the dog Negr, only the

unconditioned stimulus was not meat powderbut the acid solution, and there was no condi-tioned inhibitor.

Besides the "artificial" conditioned reflexes,all the dogs presented the so-called naturalconditioned reflexes, i.e., reflexes on the sightof meat powder or of the test tube with theacid.Having acquainted ourselves with the char-

acteristics of the reflexes of all the four dogs,we shall now proceed with the description ofthe pharmacologic experiments.We have so far tested four substances out of

the abundant domain of pharmacology: alco-hol, morphine, caffeine, and cocaine.

Alcohol was instilled into the stomachthrough a feeding tube; the other substances,subcutaneously.We have eight experiments with alcohol:

five with relatively large doses, and three withsmall ones. A large dose we consider one from1.5 to 2.0 cc 96% solution per kg weight; asmall one, from .25 to .5 cc for the sameweight. For these experiments we used threedogs: Strekoza and Gordon (three experimentseach) and Negr (two experiments). Let us firstexamine the effect of large doses.

In all the five experiments, the results ob-tained were, with small individual variations,completely analogous.As soon as 5 minutes after the introduction

of alcohol, a complete disappearance was ob-served, not only of the artificial conditionedreflexes but also of the natural ones. No sali-vation was obtained from scratching, nor thewhistle, nor even from showing the meat pow-der or the acid. After 1/2, or 1 hour, the naturalconditioned reflexes were reestablished; that is,showing the stimulating substances again ac-quired the ability to produce salivation. After2, 3, or 4 hours, depending on the dog, thespecific activity of the artificial conditionedstimulus was also restored.

Besides the direct action of the alcohol, wehad also the occasion to observe an aftereffect,manifested particularly clearly with delayedreflexes. Out of four experiments (two onStrekoza and two on Gordon) three showed,the day after the instillation of alcohol, a verynoticeable intensification of salivation. Thenumber of drops of saliva increased two- tothree-fold above the norm. It is quite possiblethat this phenomenon would have also oc-curred in the fourth experiment, if this last

465

4VICTOR G. LA TIES

Table 1Scratching for 4 min: 3 min alone, in the 4th combined with the pouring in of the acidsolution. When the natural conditioned reflex was tested (showing of the test tube withthe acid solution), then the solution was poured 3½2 min after the beginning of scratching.STREKOZA Weight: 1 pood 20 lbs (Russ.) [1 pood = 40 Russ. lbs = 36 lbs avoidupois]

Magnitude of the conditioned reflex in drops.Recording every 1/2 min

Date, month, Parotid glandtime of Showing of

beginning of Ist 2nd 3rd 4th 5th 6th the test tubescratching lM min mimi min1mm2 min ½ immn min with the acid Remarks

Drops per At 11:45 36 cc 96% al-15 January ½ min cohol in 200 cc water are

11:30 1 0 0 2 3 7 - introduced through atube into the stomach[1.139 g, i.e., 1.139 g/kg].

Salivation stopped at11:52.At 11:46 30", the dog

began shaking its earsvigorously. The shakingis very frequent: 15 to20 times per minute.

11:56 0 0 0 0 0 0 0 Shaking of ears weakerand less frequent.

12:16 0 0 0 0 0 0 2 Shakingof earsceased.12:28 0 0 0 0 0 0 - Dog is standing still.1:11 0 0 0 0 0 0 101:40 0 0 0 0 0 0 -2:21 0 0 0 0 0 0 -

16 January10:17 0 0 2 7 11 1210:30 0 0 0 3 10 1010:50 0 0 3 12 10 10 > Aftereffect11:15 0 1 1 2 9 911:30 0 0 0 7 10 13 J

one had not been complicated by the illnessof the dog (Gordon): the day following theinstillation of alcohol, the animal developeda strong diarrhea, which, as it is well known,markedly lowers the magnitude of conditionedsalivary reflexes, particularly ones establishedin association with food substances.Apart from the increase in salivation, the

sequential timing of salivation should also benoted: 1) salivation begins markedly earlier-at the end of the first minute or at the be-ginning of the second, while normally thefirst drops of saliva appear almost always atthe end of the second or at the beginning ofthe third minute. 2) Very often the graph ofsalivation changed markedly and the maxi-mum rise occurred in the second and not thethird minute. The impression given by thegraph is such as if we were facing a state ofasthenia, i.e., increased irritability and rapid

fatigue. For examples of the effect of alcohol,see Tables 1 and 2.

Small doses of alcohol produced exactly thesame effect as the larger ones, except that withthe decreased amount of the drug, the disap-pearance of the artificial conditioned reflexeslasted a shorter time, while the natural reflexesdid not disappear but only diminished. After-effects after small dosages have not been ob-served. We bring as an example Table 3.Thus, to summarize, alcohol in dosages of

.25 to 2.0 cc per kilogram inhibits the activityof the higher sections of the nervous system.A preliminary stage of stimulation of saliva-tion activity has never been observed. Theaftereffects after large doses manifest them-selves in the disturbance of the functionalbalance: 1) in the predominance of stimu-lation over inhibition, and 2) in a state ofasthenia.

466

Table 2Whistle for 4 min: 3 min alone, during 4th combined with the feeding of meat powder.When the natural conditioned reflex is tested (showing of meat powder), then the powderis given 3% min after the beginning of the blowing of whistle.

GORDON Weight: 1 pood 8 lbs (Russ.) = 44 lbs avoirdupois

Magnitude of the conditioned reflex indrops per min

Date, month, Submaxillary gland Showing oftime of Soigo

beginning of 1st 2nd 3rd 4th 5th 6th the meatwhistling ½ im 12 min min 1½mm2½in min ½ min powder Remarks

0 0 1 3 5 5

0 0 0 0 0 0

0 0 0 0 0 0

0 0 0 0 0 0

Drops per½ min

At 2:05 35 cc 96% al-cohol in 200 cc wa-ter [1.34g/kg] are intro-duced into the stomachthrough a tube.

Starting at 2:07, con-tinuous and vigorous earshaking.

0 Ear shaking continuesduring the blowing ofthe whistle.When the meat pow-

der is shown to the dog,the dog looks, but doesnot move toward it-theear shaking is less fre-quent.The meat powder is

eaten only during M min-then again the earshaking begins.

- Ear shaking weakerand less frequent. Meatpowder is eaten duringa full min.

- During the blowing ofthe whistle a positive re-action as directed move-ment of the anmal.

Shaking of earsstopped.At 3:25 the dog lowers

itself on the strap offrame, and hangs with-out supporting itself onits feet.

0 0 0 0 0 0 4 drops During the blowing ofthe whistle, the dog getsup a few times, but im-mediately falls back.At showing of meat

powder, gets up andmoves toward it.

0 0 0 0 0 0

0 0 0 0 0 3

1 0 0 2 3 50 0 0 4 2 3

0 0 8 6 50 2 3 8 40 2 8 7 40 0 0 4 4

467

During whistle thedog stands up.

At 5:00 the dog istaken off the frame, andreplaced there at 7:50.

Aftereffect

5444

29 December1:53

2:30

2:53

3:15

3:45

4:254:508:008:15

30 December2:102:252:453:05

VICTOR G. LA TIES

Table 3

Scratching for 4 minutes: 3 preceding the pouring of the acid, 4th minute during thepouring. If the natural conditioned reflex is to be tested, i.e., the showing of the test tube,then the acid solution is poured not at the beginning of the 4th minute, but %, minutelater, i.e., 312 minutes from the beginning of scratching.

STREKOZA

Magnitude of the conditioned reflex indrops per Y2 min

time of Parotid gland Showing ofinitiation of 1st 2nd 3rd 4th 5th 6th the test tubescratching lf2 min 1 min 1h min Xh min 1h min 1h min with the acid Remarks

Drops per5 January lh min10:26 0 0 0 0 3 6 2510:40 0 0 0 1 9 12 - At 10:53, ten cc 96%

alcohol in 200 cc wa-ter [0.3 g/kg] are intro-duced through a stom-ach feeding tube.

After the tube is re-moved the dog licks it-self; salivation ceases at10:58.At 10:55 it begins to

shake its ears, 2-3 shakesper min.

11:03 0 0 0 0 0 0 6 Shaking of ears con-tinues, but at long in-tervals.

11:18 0 1 2 1 0 211:35 0 0 0 1 0 4 At 11:40 the shaking11:53 0 0 0 2 11 10 ceases. The dog stands12:20 0 0 0 0 6 12 quietly.

Morphine was used three times, in doses of.01 g of morphium muriaticum, instilled un-der the skin. All three experiments, with threedifferent dogs (Strekoza, Gordon, and Russ-lan), gave exactly comparable results. Ten tofifteen minutes after injection, the natural andartificial reflexes disappeared for a very longtime. The natural reflexes reestablished them-selves after 1/2 to 1 hour, the artificial ones af-ter 7 to 8 hours. Aftereffects were not observedin two of the experiments and in one were ofan indeterminate character: six applications ofthe conditioned stimulus gave four times aweakened salivation, and twice an increasedone, of the asthenic type. I report that experi-ment in Table 4.

Caffeine has been tested four times (withtwo experiments each on the dogs Gordon andStrekoza), in doses of .1 g, subcutaneously.

All four injections brought forth an increasein the size of the reflexes. A clear effect was

apparent after 10 to 15 minutes following theinjection and lasted about an hour. The co-vert phase of salivation was significantly short-ened, but the appearance of the secretory curvedid not differ from the norm, i.e., there was aclear increase in secretion at the end of the3 minutes of action of the conditioned stimu-lus. Aftereffects from caffeine have never beenobserved. Thus: Table 5.We have tested cocaine in the form of hydro-

chloric salt in doses of about one-fourth of agrain: we have eight experiments with cocaine(two on Strekoza and three each on Gordonand Negr).The effect of cocaine on conditioned sali-

vation was grossly similar to that of caffeinebut significantly less constant. Each dog re-acted to cocaine in his own peculiar way. InStrekoza, cocaine brought out effects com-pletely analogous to those of caffeine, andwe are not, therefore, reporting them. In Gor-

468

AN HISTORICAL NOTE

Table 4

GORDON

Magnitude of the conditioned reflex indrops per lh min

Date, month, Submaxillary glandtime of Meat powder

initiation of 1st 2nd 3rd 4th 5th 6th shaken forwhistle 1lh mm 1 min 12 mi 1/ min X/2 min lh min 30 sec Remarks

Drops perJ4 min

0 0 0 1 3 6

0 0 0 0 0 0

0 0 0 0 0 0

0 0

0 0

0 0

0 0 0 0

0 0 0 0

0 0 0 0

0 0 0 0 0 0

At 3:07 a solution ofmorphine hydrochlorideis injected subcuta-neously (0.01 g) [0.5 mg/kg].Beginning at 3:10, lick-

ing and salivation. At3:17 the dog vomits. At3:23 the licking and sali-vation cease.

0 The dog stands quietly.The dog pulls toward

the meat powder. Eatslazily, but does not re-

fuse it. There is no posi-tive movement at thesound of whistle.

3 The dog hangs on thestraps but does not sleep.No positive reaction atwhistle.

samesame

2 Movement toward meatpowder extremely weak.The dog is freed from

the frame, and replacedat 7:40.

- The dog stands in a

fairly alert fashion, butthere is no positive move-ment toward meat pow-der at whistle.

0 0 0 0 0 0

5 January1:18 0 0 -0 0 3 31:43 0 0 0 0 2 21:58 0 0 3 4 3 22:17 0 0 10 10 5 22:40 0 0 0 0 0 32:55 0 0 0 0 0 1

Aftereffect

don, immediately after injection, an inhibitionof secretion for from 20 to 50 minutes was

observed. Its duration was a function of thedose (in this dog, we have used dosages from.008Og to .016 g). After the inhibition, therealways followed a rise lasting about 1 to IY2

hours. An example follows (Table 6).The third dog, Negr, is interesting in that

in it one could observe the effect of cocaineon the manifestations of external inhibition.

After the injection of cocaine, the condi-tioned inhibitor lost significantly in strength

4 January2:55

3:26

3:46

4:204:505:26

7:46

8:10

469

VICTOR G. LA TIES

as to its effects: the association of the rotatorstimulation to the scratching was no longerproducing complete inhibition of salivation.

NEGR

20 January2:18 scratching alone:30 scratching and rotating object:37 scratching alone

2:46 0.016 g cocaini muriaticesubcutaneously

:55 scratching alone3:05 scratching and rotating object:11 scratching alone

Submaxillarygland

cc per minute

0.5 cc0 cc

0.7 cc

2.2 cc

0.5 cc

1.3 cc

All the above indicate that conditioned sali-vation can be used as an excellent indicator ofpharmacologic effects of various drugs on thehigher sections of the nervous system.

In conclusion, I wish to mention the effectsof the pharmacologic substances used aboveon unconditioned reflexes and to touch on

the motor reactions of the dogs. In certain ofmy experiments, a complete reversal could beobserved between the sharp reaction of thesalivary glands and minimal, hardly notice-able changes in the movements of the animal.The unconditioned reflex was measured in

two dogs only, Negr and Russlan. Within the

ble 5

EKOZA

Magnitude of the conditioned reflex indrops per I, min

Date, month, Parotid glandtime of

initiation of Ist 2nd 3rd 4th 5th 6thscratching h mi Mmi nh i mmin nin h min l min Remarks

20 January10:43 0 0 0 0 3 5 At 10:50 subcutaneous injection of10:55 0 0 0 1 4 13 0.1 g caffeini puri [4.1 mg/kg]. During11:12 0 1 3 5 10 13 the period of the experiment it was11:35 0 1 3 2 4 10 not possible to observe any change in12:00 0 0 0 0 2 7 the dog's position, or movement.

Table 6

GORDON

Magnitude of the conditioned reflex indrops per lh min

Date, month, Submaxillary glandtime of

initiation of Ist 2nd 3rd 4th 5th 6thwhistling 1mnmm 1 min min lh min lh min M, min Remarks

25 January1:55 0 0 0 0 1 3 At 2:19, 0.016 g cocaini muriatic2:10 0 0 0 0 0 4 [0.8 mg/Kg] cocaine hydrochloride in-

jected subcutaneously.

2:30 0 0 0 0 0 2 No positive motor reactionThe dog lowered himself with his

hind legs on the straps, drooping hishead.

2:50 0 0 0 0 1 2 At the beginning of the 3rd min ofthe whistle, the dog lifts himself andlooks in the direction from where themeat powder is given.

3:10 0 0 0 1 2 2 The dog is on its feet all the timethe whistle is on.

Positive motor reaction.3:33 0 2 2 2 6 5 same3:47 0 0 1 3 4 3 same4:05 0 1 1 2 3 4 same

470

AN HISTORICAL NOTE

limits of the doses used, I could not observeany particular changes in it.With regard to the behavior, or, perhaps

better, the motor reactions of the dogs, I cansay that in many cases I could find no varia-tions from the norm. In particular I observedthe following: under the effect of large dosesof alcohol, an increase in motor activity oc-curred as a rule in all dogs, manifesting itselfin the shaking of head and ears. These shak-ings began 2 to 3 minutes after the introduc-tion of alcohol and lasted, depending on thedose and the individuality of the dog, from1/4 to 2 hours. Following the stimulation thereusually followed, 11/2 to 2 hours later, a weak-ening of muscular strength, the dog hung onthe straps, and, taken off the frame, quicklyassumed a prone position.The injection of morphine, in two experi-

ments out of the total of three, produced vom-iting, while there were no other effects onmotor stimulation. In all three cases, there wasa muscular weakening and a tendency in thedogs to assume the prone position.The effect of caffeine, so sharply and clearly

acting on the conditioned activity of the sali-vary glands, did not manifest itself with anyvisible effects on the motile system.

Cocaine produced a different effect on eachof the dogs.

In Strekoza, no divergence from the normever showed itself. Immediately after the in-jection, Gordon drooped his head down andhung on the straps; later there occurred alight stimulation expressed as continuousmovements on the frame and frequent glancestoward the place where the meat powder waskept.Negr presented a similar stimulation, only

in a sharper form, which occurred shortlyafter the injection of cocaine, but without apreliminary motor inhibition.

[The paper was followed by an abstract in Ger-man that serves well as a summary.]

The reporter has initiated the applicationof the method of conditioned salivary reflexesto the investigation of the effect of alcohol,morphine, cocaine, and caffeine on the func-tions of the higher parts of the central nervoussystem. Four dogs served as experimental sub-jects. The first had a conditioned reflex built

toward scratching, established with the helpof a solution of hydrochloric acid poured intothe animal's mouth; in the second dog, a con-ditioned reflex was established to the soundof a whistle, which was produced simulta-neously with his being fed meat powder; inboth animals, there occurred a "retardation"of about 3 minutes. In the other dogs, theconditioned reflexes established were the usualones: scratching reinforced with the simulta-neous feeding of powdered meat in one caseand scratching combined with the pouring ofHC1 solution into the mouth in the other.Besides that, the next to the last animal hada conditioned inhibition from the visual areapresent.The reporter comes to the following conclu-

sions:In doses of .25 g to 2.0 g per kg weight, al-

cohol inhibits the activity of the higher partsof the central nervous system: this manifestsitself in the disappearance not only of the arti-ficial but also of the natural conditioned re-flexes. A preliminary state of excitation wasnever observed. Effects of large doses of alco-hol manifest themselves in the predominanceof the excitation activities, and a state of as-thenia. Under the effect of morphine (.01 g ofmorphium muriaticum, subcutaneously), boththe artificial and the natural conditioned re-flexes disappear for a shorter or longer period.The introduction of caffeini puri (.1 g underthe skin) brought in all the experiments astrengthening of artificial conditioned reflexes.An aftereffect of caffeine could not be ob-served. The effect of cocaine was similar tothat of caffeine, only was not so constant.Finally, the writer observed that in certaincases (e.g., with caffeine), a complete reversalbetween the strong reaction of the salivaryglands, and the barely perceptible change inthe movements of the animal could be noticed;that is, the conditioned salivary reflexes are avery sensitive indicator of those changes whichare elicited through the action of this or thatdrug on the central nervous system.

[There then followed a transcription of thediscussion of the work.]

L. P. Pavlov. Before beginning the discussionof the report, I have to say that these ex-periments have to be considered as only pre-

471

VICTOR G. LA TIES

liminary. We had on our hands some mag-nificent dogs from the experimental point ofview, giving clear, one could say stereotypicreflexes. The thought came to use them intesting certain pharmacologic substances.Since transferring these animals into otherhands would have determined a set of newconditions, I asked the distinguished re-porter to make these observations. His ex-periments constitute an initial exploration;therefore, it is clear that there can be noquestion of any definitive conclusions. Af-ter these explanations, I beg you to expressyourselves in regards to the report just read.

I. Ia. Perelzweig. I would like to ask why youuse the term "internal inhibition."

I. V. Zavadskii. In opposition to external in-hibition, where extraneous external [stim-uli] come into play.

N. P. Kravkov. I am interested to learn thatthe conditioned reflexes do not seem toweaken; neither caffeine nor alcohol seemto affect them?

I. V. Savadskii. In the doses used by us, theyare not affected.

N. P. Kravkov. In regards to your work, I sa-lute this new method and its introductionin the study of pharmacologic problems. Itis precisely because of the lack of a strictlyobjective method that pharmacologicalknowledge in the domain of the centralnervous system is still so sketchy. We knowabout stimulation and about paralysis, butany closer characterization of these phenom-ena is lacking. In our view alcohol, mor-phine, and caffeine all stimulate the centralnervous system, but we have no objectivecriteria of this. The method introduced nowdoes offer an objective approach; therefore,we salute it. Of course, we do look on yourresults as preliminary. I also think that, inmaking the analysis, we must distinguishbetween conditioned reflex changes and theother actions a drug has after complete ab-sorption.

I. V. Zavadskii. We had, of course, foreseen

this problem, and were using the weak solu-tions with these considerations in mind.

R. A. Grekker. What were the control experi-ments preceding and following your obser-vation?

I. V. Zavadskii. The control consisted in estab-lishing immediately before the experimentthat the conditioned reflex was still present.With this objective, first we produced thestimulus and then the drug was introduced.Further controls, following the experiment,were not carried out because the drug wascirculating in the organism and we had,-nomeans to know when it was eliminated. Inessence, all the previous observations con-stituted a control in regards to the experi-ment, but a comparison of figures couldonly be made with those obtained the sameday. Two different days cannot be compared,but in the limits of one day the figures ob-tained were very close.

1. P. Pavlov. I have to point out first the ex-treme sensitivity of this method, and fromthis stems its importance for pharmacologicstudies. Using minute doses of various drugs,we obtained no observable deviations in themotor activity of the animal. The animalsappeared completely normal, and neverthe-less the method of conditioned reflexesshowed a sharp change: for instance, thedisappearance of the conditioned reflex.This study makes possible a deeper charac-terization of the effect of a drug on thecentral nervous system, as it solves the prob-lem of how to interpret, in each given case,the nature of the stimulation; if it is stimu-lation in its proper sense, or whether it isa defect in function, a weakening of theaction of inhibitory centers. The questionwas resolved simply. We tried to give thesmallest doses of alcohol, and never obtaineda stimulating-effect. This has to be under-stood in the sense that, from the beginning,the effect of alcohol is a paralyzing one andnot a stimulating one.

472