Société Belge De Physiologie et De Pharmacologie: Belgische Vereniging Voor Fysiologie En...

Archives Internationales de Physiologie et de Biochimie, 1979, 87, 119-1 53 1 I9

SOCIGTG BELGE DE PHYSIOLOGIE ET DE PHARMACOLOGIE

BELGISCHE VERENIGING VOOR FYSIOLOGIE EN FARMAKOLOGIE

RBUNION DE LIBGE, MAI 1978

A. DEMOULIN (DPpartement d’ObstPtrique et de GynPcologie, UniversitP de Li$ge, B-4020 Li2ge) .

Influence de la glande pinkale sur la fonction hypophysaire du rat in v i m ( 1 figure).

Des glandes pinkales de mouton sont dkgraisskes h I’acktone puis extraites a l’acide acktique selon la technique dkcrite par ORTS et al. (1975). La poudre rksultant de la lyophylisation du surna- geant (APP,) est soumise a une chromatographie sur Sephadex G-25 (diamktre 2.6 cm; hauteur 98 cm; milieu d’klution : acide acktique 0.1 N - 4 oC). La lecture des fractions au spectrophotomktre (280, 254 et 235 mm) rkvkle l’existence de deux composants majeurs encore trks impurs appelks : FRA (poids molCculaire ClevC) et FRB (petit poids molkculaire).

Ces fractions ont ktk testkes sur des cultures de cellules antkhypo- physaires de rats miles adultes. L’isolement des cellules et la technique de culture ont Ctk dkcrits par HOPKINS & FARQUHAR (1973). Aprks deux ou trois jours d’incubation les substances a tester sont ajoutkes aux milieux de culture pour une pkriode de prk-incubation de trois jours. Ensuite les milieux sont renouvelks par des milieux frais contenant les fractions pinCales aux mCmes concentrations et la libkration des diffkrentes hormones hypophysaires (FSH, LH, PRL et TSH) sur une pkriode de six heures est ktudike (dosage radioimmunologique) soit dans les conditions basales, soit dans les conditions de stimulation par les releasing-hormones. Dans ce dernier cas au milieu de culture sont ajoutks du LHRH et du TRH respectivement aux concentrations de

Les trois fractions ont CtC testkes h diffkrentes doses dans de multiples expkriences. La fraction native APP, n’entraine pas de

mol/litre et ]OD mol/litre.

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120 SOCIBT~ BELGE DE PHYSIOLOGIE ET DE PHARMACOLOGIE

80.

60

L O .

20

modification de la stcrttion basale de FSH mais stimule celle de LH, 188 % par rapport aux contr8les (100 %) A la dose de 62 pg/ml. La rtponse au LHRH est inhibte tant en FSH qu’en LH (respectivement 52 et 65 %) A la dose de 200 pg/ml. APP, rtduit intenskment la libtration basale et stimulte de PRL (79 % d’inhibition a la dose de 200 pg/ml en prtsence de TRH). A I’opposk, la libtration de TSH est tr2s fortement augmentke : 200 pg/ml d’APP, induisent une augmentation de 596 % (conditions basales) et 336 % (rtponse au TRH).

.

. % PRL

120

100 g

0 1 0 0625 1.25 2 5 5 10 20 LO 80 160

FRA , W m l

FIG. 1. fnjuence de FRA sur la sicrition basale de FSH, LH, TSH et PRL in vitro.

La courbe dose-rtponse de FRA dans les conditions basales (fig. I ) montre une inhibition significative de la libtration de PRL dks la dose de 1.25 pg/ml. Par contre, seules les doses tlevtes inhibent la LH et la TSH. En prCsence des releasing-hormones, A la dose de 150 pg/ml, les stcrttions de FSH, LH, PRL et TSH sont respectivement rtduites A : 22 %, 55 %, 11 % et 84 % par rapport aux contr8les (100 %).

FRB est inactive sur la PRL, induit une stimulation proportion- nelle a la dose de la stcrttion basale de FSH et LH mais est inactive ou inhibe la rtponse au LHRH. Enfin elle stimule la libkration de TSH tant basale qu’induite par le TRH.

La glande pintale contient donc des substances de poids molt- culaires suptrieurs A 5 000 qui rtduisent la libtration autonome et induite de PRL et qui inhibent la liberation des gonadotrophines induite par le LHRH. L’activitC de FRB sur les gonadotrophines

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RkUNION DE LIkGE, MA1 1978 121

et la TSH est certainement due a la presence de releasing hormone dans la glande pineale. En effet la concentration de LHRH estimke par dosage radioimmunologique dans la FRB est de 150 pg/mg de proteine.

BIBLIOGRAPHIE

HOPKINS, C. R. & FARQUHAR, M. G . (1973) J . Cell Biol. 59, 276-303. ORTS. R. L., KOCAN, K . M. & YONUSHONIS, W. P. (1975) Life Sci. 17, 531-538.

H. MAES and M. CALLENS (Laboratorium voor Neuro- en Psycho- fysiologie, Katholieke Universiteit Leuven, Campus Gasthuisberg, Herestraat, 3000 Leuven) .

Effect of local injection of norepinephrine and pentobarbital into the rat’s ventromedial hypothalamus on feeding behaviour and photophobia.

Neural blocking in the ventromedial hypothalamus (VMH) by sodium pentobarbital (SPB) injection promptly elicits feeding activities in a food-sated rat. This effect is thought to result from a transient inactivation of VMH-units which inhibit eating behaviour, thus parallelling temporarily the known hyperphagic syndrome seen after VMH-lesions. Feeding can however also be released by VMH-application of L-norepinephrine (NE) (MAES & CALLENS, 1976). As this is due to the local a-adrenergic action of NE (LEIBOWITZ, 1975), the paradox emerges that either blocking or a-stimulation, two VMH-manipulations of an at least partially opposite nature, produce similar results in terms of behavioural output. Yet, since VMH-lesions are known not only to affect food intake but also to decrease the rat’s responsiveness to fear-inducing or novel environmental stimuli, we investigated the effect of NE (compared to SPB) on the natural fear a rat has towards brightly illuminated parts of a cage.

Male albino Wistar rats were bilaterally implanted with cannulae within or around the dorsal edge of the nucleus VMH. The animals were housed individually on an inverted 12 : 12 h light-dark cycle, with food and water available ad libitum. Testing always took place during the dark period. Each test day, the rats were obser-

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122 SOCIfiT6 BELGE DE PHYSIOLOGIE ET DE PHARMACOLOGIE

29

0.27.

139.6*

22.0*

TABLE 1. Performance overview of 11 rats during ihe 15-minuie postinjection period afier bilaieral 1 pl VMH-application of saline as placebo (PLAC) 60 y sodium penio- barbital (SPB), 5 y acetylcholine (ACH) and 0.2 y L-norepinephrine (NE). NL : no latency, median undefined. * : significantly ( P < 0.005, two-tailed) different from PLAc-condition according to a Mann-Whitney U-test.

22

0.1 1

2.9

N L

I PLAC

Number of observations

Mean proportion of time spent in bright cage area . . . . . . . . . . . . . .

Mean duration of eating in sec . . . Median postinjection latency of first

eating bout in sec. , . , , , . . . . . . . .

. . . . . . . , . 33

0.10

4.4

NL

NE

28 ____

0.1 1

233.9*

2 3 . S

ved one by one for 15 min after VMH-injection in a volume of 1 p1 bilaterally, with one of next four solutions : (1) NE 0.2 y, (2) SPB 60 y, (3) acetylcholine (ACH) 5 y and (4) isotonic saline as placebo (PLAC). One half of the observation cage was brightly lit while the other half received only the reflected light. Food pellets were present in the bright area.

Results are summarized in Table I. Replicating earlier findings, SPB and NE both induced feeding behaviour within short latencies after injection into the VMH, while ACH and PLAC had no effect.

Normally, i.e. in the PLAC control condition, an animal would stay in the brightly lit half of the cage for no longer than 10% of the time. As could be expected from destructive VMH-lesion results (COLPAERT & WIEPKEMA, 1976), VMH-blocking by SPB lengthened the bright-stay up to 27 % of the 15-min period, pre- sumably alleviating the rat’s photophobia. This latter effect was apparently linked with the feeding effect since time spent in the bright area correlates well with the amount of feeding activity after SPB-injection (Spearman Y = 0.56, P < 0.01). VMH-admi- nistration of NE on the contrary had no detectable influence on the animal’s light-aversion although it was quite effective in eliciting eating behaviour. It was also found that SPB but not NE reduces temporarily scanning behaviour, a behaviour element often seen in a fear-inducing situation, e.g. when a rat is anticipating painful shock.

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RlkJNION DE LIkGE, MA1 1978 I23

Therefore, it is concluded that the rat’s VMH is not a simple “satiety centre” but contains at least two separate and neuro- chemically different circuits. One of these circuits inhibits the onset of eating and its output is cancelled by SPB-blocking as well as by a-stimulation, another circuit participates in the adequate response (e.g. scanning) to fearful (or novel) environmental stimuli, but is only affected by nonspecific SPB-blocking.

REFERENCES

COLPAERT, F. C. & WIEPKEMA, P. R. (1976) fhysiol. Behav. 5, 687-692. LEIBOWITZ, S. F. (1975) fhysiol. Behav. 14, 743-754. MAES, H. & CALLENS, M. (1976) fsychol. Belg. 16, 209-221.

H. VERMARIEN, P. BERNARD (l) and R. BOURGAIN (Laboratory of Physiology and Physiopathology, Free University Brussels V. U. B. ) .

Methodological aspects of the registration of heart vibrations on the thorax surface ( 1 figure).

Contemporary methods for the measuring of heart vibrations on the chest wall comprise auscultation, phono- and apexcardiogram. Auscultation and phonocardiogram are used for a qualitative study of the vibration pattern; apexcardiogram is used for the study of the real curve of the phenomenon, this is the geometric displacement of the thorax surface at the heart apex.

The purpose of this study is the exact registration of the heart vibrations in order to analyse the total information available on the thorax surface, i.e. a standardised quantitative measurement.

There is a need for an in depth description of the measuring system and for a correction of the inevitable errors. Important factors are the mechanical electrical behaviour of the transducer and further the mechanical coupling of the transducer to the chest wall. This implies the measurement of the transfer function and the mechanical input impedance of the transducer, and the mechanical output impedance of the thorax wall. A discussion of this problem can be found in a paper by VAN VOLLENHOVEN (1 971). Furthermore

( I ) Address : Laboratory of Gerontology, Dietics and Nutritional Science, Faculty of Medicine, State University of Ghent.

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124 S O C I ~ ~ T ~ BELGE DE PHYSIOLOGIE ET DE PHARMACOLOGIE

one must consider the characteristics of the whole electronic amplifier and filter system following the mechanical part.

A priori it is not evident which time function of this vibration phenomenon must be considered : displacement, velocity, accelera- tion or higher derivatives. Therefore we want to measure the exact spectrum of the phenomenon. Herefrom different time signals can be derived.

A first step is the registration of a time signal from which all frequencies may be extracted. Therefore a series of high-pass filters with adjustable amplification is needed.

Further it is necessary to compute the mean of a series of systoles in order to eliminate random disturbances and breathing inter- ference. Synchronic averaging using the QRS peak of the ECG as a trigger is unsatisfactory. The ECG has a much lower frequency content as compared with the considered vibration and the se- quence of the mechanical phenomena is not entirely synchronous. As a result the higher frequencies of the second heart sound appear

FIG. I . A. One only systole. B. Ten systoles averaged, QRS peak as reference. C. Ten systoles averaged, reference corrected as described in text.

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RBUNION DE LIEGE, MAI 1978 125

very weakened after synchronic averaging. These averaging errors can be eliminated by calculation of a cross correlation function. This function provides a shifting value (correction for the trigger) and a correlation value. This last parameter can be used as a discriminator for eliminating distorted periods. Figure 1 shows the results of this technique.

Finally from the averaged signal the amplitude and phase spectrum are calculated by Fast Fourier Transform. On these data the necessary corrections are performed in order to compensate the mechanical and electrical deficiencies of the measuring system. The result shows the mean spectrum of the vibrations on a theoreti- cally unloaded chest surface. This is a quantitative starting point for further study.

Further study comprises the determination of the number of transducers (necessary and sufficient) in order to describe the vibration pattern on the chest wall, as well as their optimal location.

Such type of standardised technique is essential for automatic diagnosis by computer and for deriving more information from external vibrations in connection with the mechanical performance of the heart.

REFERENCE

VAN VOLLENHOVEN, E. (1971) Med. & Biol. Engng. 9, 365-373.

J. TROQUET (Institut Lion Fredericq, Physiologie humaine, normale et pathologique, Universitt! de LiPge).

Rotation d’un dip6le excentre dans une sphere conductrice : modele analytique du VCG.

La distribution des potentiels dkterminks a la surface d’une sphkre conductrice homogkne par un gCnCrateur dipolaire qui s’y trouve excentrk, est calculable analytiquement (FRANK, 1952). En outre, I’hypothkse faite alors, sur les caractkristiques du milieu permet de traiter une Cvolution temporelle de l’orientation dipolaire comme la juxtaposition d’ktats successifs. Une rotation uniforme et son confinement i un plan mkridien simplifient enfin le modkle de telle sorte que les informations de surface restent d’interprktation im- mkdiate et univoque.

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126 socih15 BELGE DE PHYSIOLOGIE ET DE PHARMACOLOGIE

Dans ce cas, en effet, le potentiel en un point, varie d’une manibre sinusoidale. D’autre part, a chaque instant, la nappe de potentiel ne montre Cvidemment qu’un seul maximum et un seul minimum sCparCs par une isopotentielle zCro. Les positions de I’isopotentielle zCro et des extremum ainsi que l’importance relative de ces derniers, changent en fonction de I’orientation du dipdle excentrk. Lorsque celui-ci est dirigC vers le centre, la symCtrie axiale impose des situa- tions polaires aux extremum ainsi que l’identification des iso- potentielles avec les parallbles. L’excentrement entraine pour sa part, I’inCgalitC des extremum ainsi que 1’Ccart de l’isopotentielle zero du niveau Cquatorial. Lorsque le dipdle excentrC devient per- pendiculaire au rayon de la sphbre, les extremum sont alors Cgaux et opposCs sur un mtme hkmisphbre tandis que I’isopotentielle zCro suit le miridien qui se trouve a 900 de celui sur lequel Cvoluent les extremum et qui appartient au plan de symCtrie caractkristique de I’orientation considtrke.

Depuis GABOR & NELSON (1954), I’information des nappes de potentiel peut Ctre condensie en une sCrie de moments d’ordre croissant dont les termes supirieurs a 1 sont ici attribuables au seul excentrement puisque le gCnCrateur se limite a un dipale. Parallb- lement, la sCrie des potentiels isochrones mis en place par le dipdle sur chaque mCridien peut Ctre dCcomposCe par analyse harmonique (KNEPPO el al., 1966). Le contenu en harmoniques (h”, n 2 2) significatives (2 10 % de la fondamentale h,) croit avec l’excentrement qui peut alors Ctre retrouvk 9 partir des coefficients de h, et de h,.

Bref, jusqu’a ce niveau de complexitC, il reste possible d’identifier en permanence le gCnCrateur riel a son Cquivalent calculC au dCpart de I’information pariitale. Une prise en compte d’aspects plus repri- sentatifs du corps et du coeur enrichit le plus souvent les donnies superficielles en ClCments que I’on peut certes encore diduire, mais dont I’expression manque de spCcificitC avec, pour conskquence, une rCsolution incomplbte ou arbitraire du gCnCrateur Cquivalent.

BIBLIOG RA PHIE

FRANK, E. (1952) J . Appl. Physics 23, 1225-1228. GABOR, D. & NELSON, C. V. (1954) J . Appl. Physics 25, 413-416. KNEPPO, P., SZATHMARY, V. & RUTTKAY-NEDECKY, I. (1966) Proc. 7rh Infernat.

Colloquium Vectocardiographicum, pp. 51-57. Swets & Zeitlinger, Am- sterdam 1970.

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RBUNION DE L I ~ G E , MAI 1978 127

J. MANIL, F. COLIN (l) and R. H. BOURGAIN (Laboratorium Fysio- logie en Fysiopathologie, Eenheid Neuro- en Psychofysiologie V.U.B. & ( I ) Laboratoire de Physiologie GPnPrale U.L.B.).

Comparative analysis of the respective usefulness of the ECoG (EEG) and somatosensory EP’s to assert brain damage during anoxia ( 1 figure).

In previous experiments (MANIL et al., 1978) it was found that the somesthetic cortical evoked potentials (EP’s) demonstrated a characteristic reversible pattern during hypoxia, it could thus be used advantageously as a functional criterion either in brain ische- mia or in generalized hypoxia.

We therefore compared the diagnostic value of the spontaneous electrocorticogram (ECoG) and the EP’s.

In the following experiments acute and repetitive anoxic episodes of increasing duration were induced in adult curarized rabbits. The ECoG, the EP, the EKG and the cortical oxygen tissue pressure (Tpo,) were recorded simultaneously. Typical results are reproduced in Figure 1 during an anoxia period of 2 min.

In 1, the ECoG demonstrates a normal frequency, the EP has the PIP2N shape with a peak to peak amplitude of 150 pV, and 50 pV for PI.

In 2, 15 seconds after the onset of the anoxia (dark arrow) ECoG and EP are still normal, bradycardia however is present.

In 3 and 4, 25 sec after onset of anoxia an epileptic pattern of a duration of 30 sec has appeared. During this interval two different phases are observed within the EP’s : a phase E, (in 3) where P2 has disappeared and where the EP has only one positive sharp wave of increased amplitude (100 pV) and a phase E2 (in 4) where the EP is also a positive wave with high amplitude (200 pV) but enlarged. The bradycardia persists during the anoxia.

The epileptic episod is followed by a disappearance of the spontaneous activity, the ECoG flattened completely. This interval during which the EcoG remains flat was continued for 65 sec ( 5 , 6, 7). During this interval two phases were observed in the EP’s : in the first phase F1 1 ( 5 ) the EP is a high voltage (200 pV) positive slow wave and in the second phase F1 2 (6,7) the EP decreases in amplitude (to 35 pV in 7). A moderate tachycardia appears now with a subde- nivellation of the ST segment.

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128 SOCIBTB BELGE DE PHYSIOLOGIE ET DE PHARMACOLOGIE

Anoxia 2 min

1 ‘2 3 ECOG- c*ccc*r~

EKG HtO(l0HHHt

10 11 12

-b.w+l-- - 11.5 vntt”tl”l lttw#+M -!! 11.5 tJ tJ +L 5Oms.c

FIG. 1.

During reoxygenation (white arrow) starting 2 min after the onset of the anoxia, the spontaneous cortical activity reappers 30 sec following reoxygenation (8). An epileptic episode is observed with a duration of 30 sec. The ECoG normalizes within 75 sec (9), the EP has also recovered his normal initial waveforni but of lowered amplitude (10 : 90 pV). This amplitude normalize after 6 min of reoxygenation (1 1). A normal EKG is only found after 7 min of reoxygenation (1 2).

(1) The cortical function returns to normal as long as the evoked potential has not been completely erased so long as the spontaneous activity flatened for more than 1 min.

(2) The EP’s enable us to distinguish different successive phases during the epileptic pattern as well as in the flat ECoG.

(3) The EP bring us additional information about permanent cortical disturbances not detected by the ECoG.

The EP is a more valuable index than the ECoG (EEG) in eva-

In conclusion : after anoxia

luating the cortical brain function.

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R ~ U N I O N DE LIBGE, MAI 1978 129

REFERENCE

MANIL, J., COLIN, F. & BOURGAIN, R. H. (1978) in Oxygen Transport lo Tissue (SILVER, A., ERECINSKA, M. & BICHER, H. I., eds) vol. 3, pp. 508-515. Plenum Publishing Corporation, New York & London.

Ph. DE WITTE and Fr. HUYBRECHTS-AMEELS (Laboratoire de Neuro- physiologie, U. C.L., 1200 Bruxelles Woluwk-St-Lambert) . Effects of painful footshock on self-stimulation behaviour of rats and influence of naloxone on this behaviour.

In a study on the effect of a painful footshock on the self-stimulation behaviour in the rat, we observed that the mean duration of bar pressing for self-stimulation increases with the incrementation of the footshock voltage. Furthermore, the incrementation of the brain stimulation, at the postero-lateral part of the hypothalamus, depends on the rewarding value elicited by the hypothalamic stimulation. The less the intracranial stimulation is rewarding, the more the animal increases the brain stimulation, and vice-versa. It was temptly then to establish a causal relationship between these two phenomena. Two hypotheses had to be considered.

The first hypothesis, supported by MAYER & LIEBESKIND (1974), attempted to explain analgesia to peripheral stimuli by central stimulation through the closing of a spinal cord gate. The fact that no real analgesia was found with stimulation of the postero-lateral hypothalamus does not seem to support this hypothesis.

According to the second hypothesis, an aversive state could be reduced by the elicitation of a positive state induced by rewarding brain stimulation. In this way, the activation of the rewarding brain system does not strictly alleviate algesia but could better facilitate the acceptance of aversive stimuli. The fact that the self- stimulation behaviour increases when animal received naloxone HCI (morphine antagonist) subcutaneously shows a possible relationship between the facilitation of acceptance of aversive stimuli during stimulation of the postero-lateral part of the hypothalamus and addictive agents such as morphine.

REFERENCE

MAYER, D. J. & LIEBESKIND, J. C. (1974) Bruin Res. 68, 73-94.

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130 soc18~6 BELGE DE PHYSIOLOGIE ET DE PHARMACOLOG~E

P. VAN CANEGHEM, G. DEBY-DUPONT, R. GOUTIER, C. DEBY et Z. M. BACQ (Laboratoire de Biochimie appliquke, UniversitP de Li2ge).

Relations entre facteurs antioxydants et acides gras essentiels chez le rat.

Chez la souris, la toxicitk aigue du diphknylpicrylhydrazyl, radi- cal libre stable, augmente considkrablement durant la carence en acides gras essentiels (EFA) (DEBY et al., 1973). Nous avons mesurk chez le rat carencC en EFA, outre le taux global de substances antiradicalaires du foie, certains facteurs particuliers intervenant dans les micanismes de dkfense antioxydants et antiradicalaires, a savoir le glutathion rkduit (GSH), la peroxydase du glutathion (G-POD), la B-transfkrase du glutathion (G-STr), la rkductase du glutathion (G-Red) et la dismutase de I’anion superoxyde (SOD).

La chute du taux global des substances hydrosolubles antioxy- dantes et antiradicalaires atteint environ 68 %’ par rapport aux timoins. I1 y a une diminution significative de la G-POD dans le foie, le sang et les muscles, ainsi qu’une diminution de la G-STr dans le foie, mais non dans la rate, le sang et le muscle. La G-Red est Cgalement diminu6e dans le foie, ainsi que le GSH. Par contre I’activiti de la SOD n’est modifike dans aucun des organes examinCs (foie, rate, muscle, cerveau). Nous n’avons not6 aucune modification enzymatique dans le cerveau.

Les modifications ne correspondent que partiellement ri celles que CHOW et al. (1973) et CHOW (1977) ont observkes chez le rat carenck en a-tocophkrol.

BIBLIOGRAPHJE

CHOW, C. K. (1977) Internat. J . Vit. Nutr. Res. 47, 268-273. CHOW, C. K. , REDDY, K. & TAPPEL, A. L. (1973) J . Nutr. 103, 618-624. DEBY, C., BENMILOUD, M. & MAGOTTEAUX, G . (1973) C. R. SOC. Biol. Filiales

167, 1700-1703.

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R6UNlON DE LIkGE, MA1 1978 131

J. M. GVDFKAIND et C. VERAART (l) (Lahoratoire de Neurophysio- logie, UCL-54.49, 1200 Bruxelles) . Modification de I’excitabilitC des neurones du corps genouillk lateral mise en Cvidence par I’analyse quantitative des champs sensoriels : arguments en faveur de I’intervention de I’acCtylcholine dans la mediation d’influences non-rktiniennes.

La stimulation sensorielle somatique peut faciliter les rCponses CvoquCes visuelles au niveau du corps genouillC latCral (GODFRAIND & MEULDERS, 1969; MEULDERS & GODFRAIND, 1969). On croit gCnCralement que la formation rCticulCe mCsencCphalique relaie les influx somesthisiques pour influencer les neurones genouillCs soit directement par facilitation postsynaptique, soit indirectement par disinhibition. Quel que soit le micanisme de la facilitation, certains auteurs ont proposC d’admettre que le mCdiateur impliquk serait l’acetylcholine; pour d’autres, il s’agirait plutBt d’un effet mCdiC par la noradrenaline (voir rCf. dans BURKE & COLE, 1978).

L’intervention possible de l’acktylcholine dans ces effets facili- tateurs a CtC testCe sur quatre chats anesthCsiCs au chloralose (80 mg/kg), paralyses au moyen d’un mClange de gallamine triethio- dide (7.5 mg kg-’ h-’ et de D-tubocurarine (0.5 mg kg-I h-l) et prCtraitCs par une injection intraveineuse de mtthylnitrate d’atropine (4 mg/kg).

La stimulation visuelle a Ctt effectuCe en prisentant une image lumineuse, de facon systimatique, en une sCrie de positions dans une portion approprite du champ visuel. Le stimulus conditionnant consistait en un choc Clectrique appliquC au niveau de l’un des quatre membres, quelques dizaines de millisecondes avant I’allu- mage ou I’extinction de I’image lumineuse. La dktermination quantitative des champs rCcepteurs visuels, effectuie avec ou sans stimulation conditionnante, Ctait rCalisCe automatiquement au moyen d’un ordinateur PDP-12 (VERAART, 1976). Les antagonistes de I’acCtylcholine (atropine 3 mg/kg; mCcamylamine 0.5 mg/kg) ont CtC administrks par voie intraveineuse.

L’effet de la stimulation somatique a pu Ctre dCterminC quanti- tativement pour 15 neurones parmi les 35 qui ont CtC enregistrks dans le corps genouillC 1atCral. Dans 11 cas, la reponse visuelle Ctait facilitee et, dans 2 cas, elle etait inhibCe. L’Ctude de I’Cvolution du

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( I ) Chercheur qualifie du FNRS (Belgique).

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champ rkcepteur visuel en fonction de la stimulation somatique avant et aprbs I’injection des antagonistes cholinergiques a permis d’effec- tuer les observations suivantes : I ) aprbs injection d’atropine, on a not6 une diminution de I’itendue du champ ricepteur visuel et la disparition de la facilitation induite par stimulation somatique; 2) aprbs injection subskquente de mkcamylamine, on a observe une Iigbre diminution du champ ricepteur visuel sous I’influence de la stimulation somatique.

En conclusion, ces rksultats sont en faveur de I’hypothbse selon laquelle le systbme facilitateur ascendant, qui influence I’excitabilitk des neurones du corps genouillk lateral, utilise I’acktylcholine comme mkdiateur et met principalement en jeu des rkcepteurs de type muscarinique.

BIBLIOGRAPHIE

BURKE, W. & COLE, A. M. (1978) Rev. Physiol. Biochem. Pharmacol. 80, 105-

GODFRAIND, J. M. & MEULDERS, M. (1969) Exp. Brain Res. 9, 183-200. MEULDERS, M. & GODFRAIND, J . M. (1969) Exp. Bruin Res. 9, 201-220. VERAART, C. (1976) Dews Proc. 2, 157-162.

166.

S. MERTENS DE WILMARS and C. VERAART (l) (Laboratoire de Neu- rophysiologie, U.C.L.-S4.49, Av. Hippocrate 54, 1200 Bruxt Iles) . Relations between statistical properties of spontaneous activity of lateral geniculate neurons and their anatomo-physiological features.

Diverging with most of the usual ways to study spontaneous activity, involving generaly neuronal models of discharges generated by computers, the aim of this work was 10 to investigate spontaneous activity of visual cells on basis of statistical methods, 20 to search for a possible correlation between statistical parameters of spontaneous activity and physiological features of the same neurons.

Cats were anaesthetized with N20 and paralysed by continuous infusion of a mixture of Flaxedil and Toxiferine (toxiferine dichlo- ride, Hoffman-LaRoche). The visual background was maintained

(I) Chercheur qualifik du FNRS (Belgium).

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RBUNION DE LIEGE, M A I 1978 133

at an appropriate level of luminance (between 1 and 100 Cd/m2) by means of a large diffuse screen placed in front of the animal. The eyes were prepared following usual methods. Neurons were extracellularly recorded in the lateral geniculate body and in the perigeniculate nucleus. After a rapid determination of visual response characteristics, neuronal spontaneous activity was conti- nuously recorded in a steady background, until neuron was dead.

Ten penetrations were performed on five animals. Of the 59 recorded cells, 23 discharged during a sufficient time to accumulate a suitable amount of data (from 1 000 to 130 000 intervals). A majority of these lay in the lateral geniculate. For each of them, the following anatomo-physiological data were determined : position of the visual receptive field (azimut and elevation), response latency and ON or OFF type, sustained or transient character. Analysis of spontaneous activity mainly concerned statistical distributions of interspike intervals, a test of stationarity and the joint interval distribution. Four different patterns of statistical distribution of intervals were identified, namely : hyperbolic, exponential, gaussian and plurimodal. The prefered interval, mean (p) and standard deviation (0) were determined for each pattern.

A successful attempt was made to approximate the first three distributions by means of a theoretical model founded on the Gamma distribution :

where : a = ( p / ~ ) ~ and Q = p/02.

The possible existence of nonstationarity in the sample of data related to a given cell was investigated. The selected way to deal with nonstationarity was to segment the sample of data and to compute, for each individual segment, the mean interval. The sample was said to be stationary if the temporal evolution of the mean might go out of a confidence interval whose limits were :

2 p + M + r n s ( M + m ) 5------- 4 2(M - m)

where ,u is the mean related to all the sample, M and m are respectively the maximum and the minimum mean values related to the segments, s is the standard deviation of the means related to the segments. According to this criterion, the spontaneous activity of

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134 SOClkTJ? BELGE DE PHYSlOLOGlE ET DE PHARMACOLOGIE

43 % of the neurons was nonstationary. To deal with serial de- pendence among adjacent intervals, the joint interval distributions were used. In the related scatter diagrams, abscissa and ordinate respectively represent each interval and the succeeding one. For these geniculate neurons, three different patterns were observed. In order to estimate the independence between intervals, the regression lines related to the means of the preceeding or of the succeeding intervals were computed (RODIECK et a/ . , 1962).

Comparing these different physiological and statistical measures, no definite relations appeared between stationarity on the one hand and intervals distribution or independence on the other. In contrast, independence and mean firing rate were strongly correlated (0.90) whereas the parameter e of the theoretical model was well correlated with independence (0.83). Finally, considering the physiological data, cells with sustained visual responses generaly exhibited a hyperbolic intervals distribution (small value of a in the model), while transient neurons were either exponential or gaussian (larger value of a), according to the non-plurimodal patterns of the statistical distribution of intervals.

REFERENCE

RODIECK, R. W., KIANG, N.Y.4. & GERSTEIN, G. L. (1962) Biophys. J . 2, 351-368.

J. SCUVBE-MOREAU, P. FISCHER and A. DRESSE (Institut de Patho- logie, B23, Laboratoire de Pharmacologie, UniversitC de Ligge, 8-4000 Sart Tilman par Li2ge 1 ) .

Inhibitory effect of tricyclic antidepressant drugs on spontaneous activity of noradrenergic neurons. Relation with blood and brain concentrations (4 figures).

Introduction.

Several groups of drugs affect both behaviour and metabolism of monoamines (SEIDEN et al., 1975; GREEN & GRAHAME-SMITH, 1976). Amongst the possible sites of interaction between drugs and mono- aminergic neurons, the reuptake of transmitter amines, which is the major mechanism for their inactivation, (WHITBY et a/., 1961) can be

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REUNION DE LIEGE. MA.I 1978 135

blocked by different drugs. Tricyclic antidepressants are characterized by an inhibitory effect on the uptake of noradrenaline (NA) and 5-hydroxytryptamine (SHT) by nerve endings (HERTTING et al., 1961; AXELROD et al., 1962; GLOWINSKI & AXELROD, 1964; Ross & RENYI, 1967).

Secondary aminated antidepressants are more potent inhibitors of NA uptake than their tertiary aminated analogues (CARLSSON et a/., 1969; HAMBERGER & TUCK, 1973; Ross & RENYI, 1975a & b).

Electrophysiological techniques make it possible to study the influence of this inhibition on the spontaneous activity of central neurons.

In this work, we limited our study to the noradrenergic neurons of Locus coeruleus (L.C.) located in the dorsal part of the pons and almost exclusively constituted of NA containing cells. Each cell of the L.C. has multiple connections in particular with the molecular layer of the cerebral cortex and the PurkynE cells of the cerebellum (UNGERSTEDT, 1971; MAEDA & SHIMIZU, 1972; DRESSE, 1972; LINDVALL er al., 1978). We have performed a quantitative study of the effect of five tricyclic antidepressants on the spontaneous activity of Locus coeruleus. In a parallel work, blood and brain concentrations of imipramine and chlorimipramine were determined by gas chromatography.

Materials and methods.

Male Wistar rats weighing 200-300 g, are anaesthetized with chloral hydrate (400 mg/kg i.p.). The spontaneous discharge of the noradrenergic cells of L.C. is recorded by stereotaxically implanted nickel-chrome microelectrodes, at the following coordinates : P. 2 mm, L. 1.2 mm from the Lambda and H. 6 mm under the cerebellum surface. Before lowering the electrode, a small bone flap is removed and the transverse venous sinus is tied and cut. Electrode signals are passed through an impedance adapter and an amplifier and displayed on a Tektronix oscilloscope. Signals are also passed in an electronic amplitude discriminator and counted by a digital counter. After a baseline firing rate has been recorded during a first control period of at least ten minutes, the drug is perfused into the jugular vein by means of a perfusion pump with a flow of 6 ml/h. Perfusion is stopped when the frequency of discharge has dropped

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136 socrt% BELGE DE PHYSIOLOGIE ET DE PHARMACOLOGIE

under 50 % of the control rate during one minute, and it is possible to determine for each substance the dose required for inhibition of firing to 50 % of baseline rate (IDso). The activity of the cell is still recorded during a third period as long as it is possible to maintain the recording of the cell. At the end of the experiment, animals are perfused with a solution of formaldehyde 4 % and the brains are removed for histological control. The drugs studied are the dibenza- zepine derivatives : norimipramine (secondary aminated), imipramine and chlorimipramine (the tertiary aminated analogues) and the dibenzocycloheptadiene derivatives : nortriptyline (secondary aminated) and amitriptyline (tertiary aminated). All drug doses refer to the base form of the substance. In another series of experiments, rats were perfused in the same conditions but without recording of activity. The perfusion is stopped when the animals have received the dose necessary to reduce to 50 '% the firing rate of L.C. as determined previously. Blood and brain are removed either immediately after perfusion or 60 or 120 minutes after.

a

b

FIG. la, b. Spontaneous acfivify of Locus coeruleus neurons. Photo from the oscilloscope : (a) high speed of sweeping : 500 psec/div.; (b) speed of sweeping : 1 sec/div.

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R ~ U N I O N DE L I ~ C E , MAI 1978 137

Determination of concentrations are made for imipramine and chlorimipramine by gas chromatography after extraction by diethylether at pH 1 I (chromatographe Carlo Erba Fractovap 2301 AC, recor- der Houston omniscribe, capillary column SE 30, carrier gas H2 5 ml/min, detector NPSD to 250 "C, injector to 25OoC, oven t o

200 "C). At least six animals are used in each experiment.

Results.

Locus coeruleus neurons have a stable firing rate characterized by a low frequency of 1-3 spikes/sec (Fig. la, b). This activity cor- responds with the description of GRAHAM & ACHAJANIAN (1971).

Slow perfusion of the tricyclic antidepressant drugs decreases progressively the spontaneous rate of discharge of these N A neurons, without influence on the amplitude. When the perfusion is stopped at a frequency of 50 % of the control activity, the inhibitory effect of the drug persists during several minutes. Recovery to the control frequency seems to be very slow (Fig. 2). In a few cells which could be recorded during more than 50 min after perfusion, there is a slow increase in frequency and a tendency of recovery towards predrug firing rate (Fig. 3).

Locus coerulus Norimipramine 1 Mean freq./lO sec

Norimipramine 0.1 mg kg-1 min-10.037

FIG. 2. Effect of intravenous perfusion of norimipramine on the firing rate of a noradrenergic cell. Perfusion is stopped at a depression of 50 'A of the control rate. Flow 6 ml/h.

There is a great difference in potency between the five tricyclic antidepressants tested, the secondary aminated derivatives being more potent than the tertiary aminated ones. So, the ID, for norimipramine is 0.29 mg/kg while the ID,, for chlorimipramine is 3.08 mg/kg.

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Lccus cceruleus Nortriptyline Mean freq./lO sec

FIG. 3 . Effect 0 j i . v . perfusion of nortriptyline on thefiring rate o j a L.C. neuron. There is a tendency of recovery towards predrug firing rate.

The mean doses required for inhibition of firing to 50 % of the control rate are represented in Table I . The order of activity is norimipramine > nortriptyline > imipramine > amitriptyline > chlorimipramine.

TABLE I. ID6,, : mean doses required (mg/kg 5 SE) for inhibition of firing to 50 % of base line rate. n = number of animals. IC,, : concentrations producing 50 % inhibition on the uptake of [3H] L-NA in crude synaptosome preparations of the rat midbrain-hypothalamus region (from Ross & RENYI, 1975).

Compound

Norimipramine . . . . . . . . . . Nortriptyline . . . . . . . . . . . . Imipramine . . . . . . . . . . . . . Amitriptyline . . . . . . . . . . . Chlorimipramine . . . . . . . .

0.29 i 0.02

0.66 i 0.06

1.30 5 0.11

1.42 f 0.24

3.08 & 0.30

n I c 6 0 (PM)

0.0033

0.013

0.028

0.054

0.060

In parallel to this study, other rats were perfused with the doses of imipramine and chlorimipramine determined above and the blood and brain levels were measured immediately after perfusion, and 60 and 120 min after. These results are represented in Figure 4.

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RBUNION DE LIBGE, MAI 1978 139

5001

2OM

IOM

la

2c

IC

ng/Q of ml 50001

FIG. 4. Plasma, blood cells arid brain concentrations of imipramine and chlorimipramine after i .v . perfusion of the doses necessary to reduce to 50 % the frequency of discharge of L.C. neurons (imi. : total dose 1.3 mg/kg; chlorimi. : total dose 3.08 mg/kg).

Discussion.

Our results show that the spontaneous firing rate of noradrenergic neurons may be influenced by the tricyclic antidepressant drugs used in therapeutic. There is a quantitative difference in this activity : antidepressants having a secondary amine in the side chain (norimipramine and nortriptyline) are more potent inhibitors than their respective tertiary amine analogues (imipramine, amitriptyline and chlorimipramine). These results are in good agreement with the experiences performed in vilro by Ross & RENYI ( I 975) on the uptake of tritiated NA by synaptosome preparations (see Table I). We also confirm the results obtained by NYBACK et a/. (1975). Perfusion of the drug instead of single injections has the advantage to get more stable blood levels and to produce a progressive inhibitory effect. It is interesting to note that this test presents a great sensitivity compared to the behavioural tests commonly used in screening for antidepressant activity (SIMON, 1965; KINNARD et al., 1966).

It is generally admitted that the reduction of the rate of firing by antidepressants is due to an accumulation of neurotransmitter at the synaptic level, and thus to a stimulation of postsynaptic receptors which in turn may decrease the activity of the presynaptic neurons by a feed-back mechanism mediated by a multineuronal loop.

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It is also possible that this inhibitory effect is mediated by a noradrenergic recurrent collateral with or without interneurones or by stimulation of presynaptic inhibitory receptors (CEDARBAUM & AGHAJANIAN, 1977).

In our experimental conditions, it is difficult to establish relations between the blood and brain concentrations of imiprz mine and chlorimipramine and the effectiveness of the drug. It is only possible to say that at the concentrations found after 60 min these antidepressants are still active since there is no recuperation after this time.

Norimipramine was perfused in the same conditions but the active concentrations were under the limit of detection of the method of dosage (20 nglml). There was no trace of formation of norimipramine by metabolism after i.v. perfusion of imipramine and chlorimipramine but it is however possible that non detectable but active norimipramine was formed.

Conclusion.

This test presents a great sensitivity to the drugs studied. It allows to demonstrate a different effectiveness between the two types of tricyclic antidepressants. In the future, it would be interesting to study the effect of other antidepressant drugs in this test and to repeat the same experiences on other neuronal systems, in particular on tryptaminergic neurons.

Acknowledgments

LETIHON for his photographic assistance.

3.4526.75.

We thank Ms. MOSSAY-BREEUR for the histological work and Mr.

This work has been realized thanks to a subvention of FNRS no

REFERENCES

AXELROD, J . , HERTTING, G . & POTTER, L. (1962) Nature (London) 194, 297. CARLSSON, A,, CORRODI, H., FUXE, K . & HOKFELT, T. (1969) Eur. J . Pharmacol.

CEDARBAUM, J. M . & AGHAJANIAN, G. K. (1977) Eur. J . Pharmacol. 44,375-385. DRESSE, A. (1972) Rev. Neurol. 127, 241-251. GLOWINSKI, J. & AXELROD, J . (1964) Nature (London) 204, 1318-1319. GRAHAM, A. W. & AGHAJANIAN, G. K. (1971) Nature (London) 234, 100-102. GREEN, A. R. & GRAHAME-SMITH, D. G. (1976) Nature (London) 260, 487-491. HAMBERGER, B. & TUCK, J . R. (1973) Eur. J . Clin. Pharmacol., Vol. 5 , 229-

5, 367-373.

235.

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REUNION DE LIEGE, MAI 1978 141

HERTTING, G . , AXELROD, J . & WHITBY, L. G. (1961) J . Pharmacol. Exp. Ther.

KINNARD, W. J . , BARRY, H . 111 , WATZMAN, N . & BUCKLEY, J . P. (1966) in Proc. 1st Inl. Symp. Antidepressant Drugs (GARATTINI, S. & DUKES, M., eds) pp. 89-98. Excerpta Medica Foundation, Milan.

LINDVALL, O., BJORKLUND, A. & DIVAC, I. (1978) Brain Res. 142, 1-24. MAEDA, I . & SHIMIZU, N . (1972) Brain Res. 36, 19-35. NYBACK, H. V., WALTERS, J . R. , AGHAJANIAN, G . K . & ROTH, R. H . (1975)

Ross, S. B. & RENYI, A. L. (1967) Life Sri. 6, 1407-1415. Ross, S. B. & RENYI, A. L. (1975, a) Acra Pharmacol. Toxicol. 36, 382-394. Ross, S. B. & RENYI, A. L. (1975, b) Acta Pharmacol. Toxicol. 36, 395-408. SEIDEN, L. S., MAC PHAIL, R. C. & OGLESBY, M. W. (1975) Fed. Proc. 34,

SIMON, P. (1965) Therapie, XX, 1123-1 147. UNGERSTEDT, U . (1971) Acta Physiol. Scand. 82, Suppl. 367, 1-48. WHITBY, L. G. , AXELROD, J . & WEIL-MALHERBE, H . (1961) J . Pharmacol. Exp.

134, 146-153.

Eur. J . Pharmacol. 32, 302-312.

1823-1 831.

Ther. 132, 193-201.

G . MARECHAL, L. PLAGHKI et M. COLSON-VAN SCHOOR (Laboratoire de Physiologie GPnPrale, Universitk Catholique de Louvain, 1200 Bruxelles) . CPK et CT dans les muscles striks.

La creatine totale (CT, somme de la crkatine et de la phospho- rylcrkatine) reste constante dans le muscle, quel que soit le rythme de la stimulation. Ceci contraste avec I’effet important qu’exerce la stimulation sur les concentrations des substrats de la glycolyse ou des oxydations. Cependant, la concentration en C, est propor- tionnelle a la force isomitrique maximale ou le taux de production de la chaleur de maintien. Ce fait suggkre que la concentration en C, et I’activitC maximale de la CPK pourraient Ctre Ctroitement con- tr6lCes dans le muscle striC. Nous avons donc CtudiC les relations entre la CPK et la C, dans trois diffkrents cas :

a) RPgPnPration. - Les muscles sont dissCquCs, CmincCs en mor- ceaux de 1 mm3, et greffks isotopiquement. Le jour suivant I’opCra- tion, la CPK et la C, ont diminuC de 1 a 3 04 des valeurs contrhles (muscles homolatCraux). Puis ils augmentent durant 240 jours, pendant que les muscles rkgenkrent. Les muscles redeviennent fonctionnels de 30 A 60 jours aprks I’opCration. La CPK augmente plus vite que la C, : leur rapport ne reste donc pas constant. Leur relation est dCcrite par I’Cquation de puissance :

r = 0.99 (CPK) 10.7 ( c T ) 1 . 5 5 ( 1 )

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142 socr8~8 BELGE DE PHYSIOLOGIE ET DE PHARMACOLOGIE

Cette Cquation est la m&me pour les trois muscles CtudiCs : gas- trocnkmien et soleus de rat, gastrocnimien de grenouille. Les contr6les de ces trois muscles sont reprbentks par la meme Cquation.

b) PhylogPnie. - La CPK et la C, ont CtC analysCes dans les muscles d’animaux adultes : gastrocntmiens de grenouille (n = 36), ALD (n = 6) et PLD (n = 6) de poulet, soleus (n = 18) et gastroc- nCmiens (n = 48) de rats, soleus (n = 6) et gastrocnkmiens (n = 6 ) de souris, muscles paravertkbraux (n = 24) de chiens et d’hommes (n = 35) . Les muscles lents ont moins de C, que les muscles rapides. Cependant, la CPK n’est pas une fonction IinCaire de la C,, mais une fonction de puissance, exactement dkcrite par 1’Cquation (1)

c) Ontogenie. - Les muscles gastrocnimiens et solCaires de rats ont CtC analysts depuis leur naissance jusqu’au 44e jour. L’accrois- sement en CPK devient plus rapide que celui en C, 3 jours (gastroc- nkmien) et 6 jours (soleus) aprQ la naissance. Pour les deux muscles, (I’un rapide et I’autre lent), la CPK est une fonction de puissance de la CT, mais elle est diffkrente de 1’Cquation (1). Elle est dCcrite par :

(r = 0.94).

(CPK) = 1.43 (CT)*.O6 (2) r = 0.98

d) Conclusions. - Dam les muscles adultes, I’activitC de la CPK est Ctroitement couplie a la concentration de la C,. A la suite d’une perturbation puissante (i.e. Cminqage), ce systhme reste Ctroitement couplb, et il rCgCn6re selon une trajectoire qui passe d’abord par un type <( muscle lent )) vers un type (( muscle rapide n. L’activitC de la CPK ou la concentration en C, pourrait bien donc refliter I’Ctat de modulation du muscle en diffkrentiation. Dans le muscle en croissance cependant, la trajectoire qui porte le nouveau-nC vers I’adulte est diffirente, la CPK croissant plus vite, quasi avec le carrC de la C,. Le rCglage du mkcanisme qui assure la relation CPK-C, du muscle en croissance est donc diffdrent de celui du muscle adulte.

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REUNION DE LIBGE, MAI 1978 I43

E. VANDENBUSSCHE, J. WEYTJENS and M. CALLENS (Laboratorium voor Neuro- en Psychofysiologie, Katholieke Universiteit Leuven, Campus Gasthuisberg, Herestraat, 3000 Leuven) . The influence of light and dark adaptation on the size of the receptive fields of the lateral geniculate neurons ( 1 figure).

Recently, VIRSU et al. (1977) demonstrated a rather small incre- ment in the size of the receptive field (RF) centre of lateral geniculate body neurons with low levels of background illumination. In the light of the conflicting data published by POGGIO et al. (1969) and MAFFEI & FIORENTINI ( 1 972) concerning the attenuation of the inhibitory influence of the surround mechanism with decreasing background illumination, it is important to re-examine the influence of light and dark adaptation on the size of the RF centre of the geniculate body neurons.

Methods commonly used to estimate the size of a RF are either threshold or sensitivity measurements. Threshold methods are good estimators of the absolute size of the RF, a sensitivity method on the contrary gives a more relative estimation. Both methods use a small spot (Spot-Test) to test the whole RF in a systematical way, or centred spots of increasing sizes (Area-Test). Since for our problem a relative estimation of the RF size is sufficient, we used the sensitivity methods.

In chronical prepared cats, the extracellular activity of 36 geniculate neurons was recorded using the spot- and area-tests at different conditions of background illumination but constant photo- contrast (spot/background illuminance = 10 : 1). The intensity of the stimuli was varied by means of neutral density filters. The dia- meter of the small spot in the spot-test was 0.50, in the area-test, the spotdiameter gradually increased fiom 0.2" to 19".

As a representative example, Figure 1 summarizes the results of the presentation of the spot- and area-test to an off-centre neuron. It was found that, in contrast with the area-test (Fig. 1, B), the spot-test (Fig. I , A) demonstrates a clear effect of the background illuminance on the RF centre size as we would expect from the retinal data (BARLOW et al., 1957). The variability in the RF centre size estimated by the area-test during different background illuminations is probably due to the way the RF centre size has been estimated from the spatial response profiles (for instance because only the maximum was used).

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144 SOCI6TE BELGE DE PHYSIOLOGIE ET DE PHARMACOLOGIE

FIG. 1. The influence of lighr adaptation on the receptive field centre size of a geniculare body off-neuron. A : Spot test, spotdiameter 0 . 5 O . B. Area-test, the spotdiameter was varied from 0 . 2 O to 1 9 O . C : Spatial response profile.

Background illuminations are indicated in the graphs. Photoconstrast : stimulus/ background, 10 : I .

In spite of the broad variation in the background illumination the slope of the descending side of the different spatial response profiles (Fig. 1, C) remains relatively stable. These data are in contradiction with an attenuation of the inhibitory influence of the surround mechanism by decreasing background illumination, and support the conclusion from the area-test that the R F centre size is independent of the background illumination.

These data suggest that the constancy of the R F centre size during drastic variations in the light adaptation is only assured when both centre and surround mechanisms are simultaneously activated.

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REUNION DE LIEGE, MA1 1978 I45

The constancy of the RF centre size then would be the result of regulatory interactions between the centre and surround mechanisms.

The paradoxical results obtained with the spot- and area-test could be accounted for by the artificial nature of a small spot as a stimulus to activate the neurons of the lateral geniculate body in an appropriate way.

REFERENCES

BARLOW, H. B., FITZHUGH, R. & KUFFLER, S. W. (1957) J. Physiol. (London)

MAFFEI, L. & FIORENTINI, A. (1972) J . Neurophysiol. 35, 65-72. 137, 338-354.

POGGIO, G . F., BAKER, F. H., LAMARRE, Y. & RlVA SANSEVERINO, E. (1969) J. Neurophysiol. 32, 892-9 15.

VIRSU, V., LEE, B. B. & CREUTZFELDT, 0. D. (1977) Exp. Brain Res. 27, 35-50.

G . A. ORBAN, H. KENNEDY and H. MAES (Laboratorium voor Neuro- en Psychofysiologie, Katholieke Universiteit Leuven, Carripus Gasthuisberg, Herestraat, 3000 Leuven) . Horizontal organization of velocity characteristics in area 18 of the cat.

Velocity response curves of area 18 neurons with peripheral receptive fields ( RFs) were described by ORBAN & CALLENS (1977). At these eccentricities (over 10" from fixation point) two types of curves were found : velocity sensitive neurons (83 u/o) have a curve which can be described as a high pass filter for velocity and velocity specific neurons (13 u/o) which are tuned to an optimal velocity and which can be described as a narrow band filter for velocity. The present experiments were undertaken to extend this study to the whole of area 18, especially to parts with more central projections. Since the boundary between areas 17 and 18 is the projection of the vertical meridian (VM), which includes by definition the fixation point, the study implies a determination of this boundary. The two guides which can be followed to define the 17-18 boundary are the cytoarchi tectonics and the retinotopic organization. We have made oblique penetrations from area 17 to area 18 at different antero-posterior levels. In such a penetration the R F moves first

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inward (in area 17) and later outward (in area 18) (HUBEL & WIESEL, 1965). At the end of the penetrations two electrolytic lesions were made, which allowed reconstruction of the penetration on coronal brain sections.

Cortical neurons were recorded in anaesthetized (N,O/O,) paralysed cats. Their R F were plotted and classified with hand held stimuli according to KATO et al. (1978). According to these classifi- cation criteria all cell types (including HCI & HCII) of area 17 are also present in area 18. Velocity response curves (0.75/sec - 7000/sec) were prepared in a pseudo multihistogram way. The results suggest a double organization of velocity characteristics in area 18. Neurons with RFs close to the projections of the VM have a third type of velocity response curves resembling a broad band filter for velocity. As the fields move away from the VM the curves progressively change from a broad band curve to a high pass curve. Second, at more posterior levels (projections closer to the fixation point) the proportion of velocity specific neurons (narrow band cells) increases. The cells with slow optima reach higher responses than at more anterior levels. With respect to the 17/18 border the velocity response curves change rather steeply from the area 17 curves which resemble low pass filters for velocity to the broad band curves of area 18. At more posterior levels due to the greater proportion of slow narrow band neurons, the transition between 17 and 18 may be less clear. The changes in velocity response curves fit very well with the retinotopic separation between 17 and 18. The agreement between the electrophysiological border and the cytoarchitectonic border is not perfect but falls within the 1 mm suggested by TUSA et al. (1978).

REFERENCES

HUBEL, D. H. & WIESEL, T. N. (1965) J. Neurophysiol. 28, 229-289. KATO, H. , BISHOP, P. 0. & ORBAN, G. A. (1978) J . Neurophysiol. 41, 1071-

ORBAN, G . A. & CALLENS, M. (1977) Exp. Brain Res. 30, 125-140. TUSA, R. J. , PALMER, L. A. & ROSENQUIST, A. C. (1978) J . Comp. Neurol. 177,

1095.

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RBUNION DE L I ~ G E . MAI 1978 147

E. GODAUX, J.-E. DESMEDT, M. GENIN et P. DEMARET (Unite‘ de Recherche sur le Cerveau, U.L.B., I15 Boulevard de Waterloo, Bruxelles) . La signification des unites phasiques observees dans le mouvement balistique.

Le concept d’unitis phasiques concerne des unites qui seraient mises en jeu dans une activitk musculaire rapide et pas dans la mCme activite effectuie plus lentement (GRANIT et al., 1956). Nous avons mis en doute la validit6 de ce concept dans la contraction isomb trique. Toute unitC activke dans une contraction isomitrique peut Ctre activee dans une contraction en rampe isomitrique quoique son seuil soit plus ClevC dans ce dernier cas (DESMEDT & GODAUX, I977a & b). Cependant, lors d’un mouvement isotonique d’abduction de I’index, nous avons trouvC des unites motrices du premier inter- osseux dorsal qui ne dkchargent pas mCme lorsque le mouvement atteint son amplitude maximale mais qui sont facilement activkes si le mCme mouvement est rialis6 suivant le mode balistique. Ces unites semblent mCriter le qualificatif de phasique. NCanmoins, toutes ces unitis (( phasiques )) sont activees dans le mouvement lent lorsque celui-ci s’effectue contre une risistance adequate.

Une etude quantitative est nkcessaire si ces (( unitks phasiques )) ont des propriCtCs riellement particulikres par rapport aux unites non phasiques. On peut determiner le seuil balistique (en degrCs de diplacement angulaire) de chaque unite par I’amplitude du mouvement en deGa de laquelle I’uniti n’est jamais prksente et au-deli de laquelle elle dicharge toujours. Les seuils balistiques des unites phasiques sont plus grands que les seuils balistiques des unites non phasiques. D’une faGon ginkale, I’ordre d’activation des unites dans le mouvement balistique isotonique se fait suivant le (< principe de grandeur )) puisqu’une excellente correlation lie les seuils balistiques des unites a leurs seuils isomitriques en rampe dont le rangement suivant les tailles des unites motrices est bien Ctabli (MILNER-BROWN et al., 1973).

REFERENCES

DESMEDT, J . E. & GODAUX, E. (1977, a) Nature (London) 267, 717-719. DESMEDT, J . E. & GODAUX, E. (1977, b) J . Physiol. (London) 264, 673-693. CRANIT, R. , HENATSCH. H.-D. & STEG, G . (1956) Acta Physiol. Rand. 37,

114-126. MILNER-BROWN, H. S., STEIN, R. B. & YEMM, R . (1973) J . Physiol. (London)

230. 371-390.

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J. DAMAS, Z. M. BACQ (l), N. MOREL (2) (*) et T. GODFRAIND (2)

(Physiologie humaine, norrnale et pathologique, Institut Le‘on Fredericq (I) et Laboratoire de Biochimie applique‘e, Universite‘ de Li2ge; (2) Laboratoire de Pharmacodynarnie gine‘rale et de Pharrnacologie, Universite‘ Catholique de Louvain) . Reponse aux catbcholamines chez le rat carence en acides gras essentiels.

Les acides gras essentiels correspondent a la famille des acides gras non saturCs en w6 (AAES-JerRGENSEN, 1961). Parmi eux se ran- gent les prkcurseurs des prostaglandines de types 1 et 2. 11s sont principalement renfermks dans les phospholipides membranaires et, a ce titre, peuvent conditionner les proprittCs physico-chimiques des membranes. Aussi, avons-nous recherche si, independamment de leur incapacitC a former des prostaglandines, les rats deficients en acides gras essentiels (BONTA et al., 1974; BULT & BONTA, 1976) ne prCsentent pas une modification de la rCactivitC vasculaire aux catCcholamines.

Nous utilisons des rats Lewis soumis a un regime dCpourvu d’acides gras essentiels, fournis par la firme TNO (Rent, Holland). Leur appauvrissement en ce type d’acides gras a CtC chimiquement vCrifiC (VAN CANEGHEM et al., 1979).

a) La rCactivitC a l’adrhaline, a l’isoprinaline et au calcium de I’aorte isolCe a CtC examinCe in vitro. La concentration (ED,) de noradrknaline qui provoque une contraction Cgale a la moitie de la contraction maximale est du mCme ordre de grandeur pour les aortes provenant de rats normaux et de rats carencCs : respectivement 0.9 k 0.13 x et 1.4 f 0.29 x La force de contraction dCveloppCe est identique. Le pA2 de la phentolamine vaut 7.77 pour les aortes normales; 7.64 pour les aortes de rats dificients. Au niveau des aortes dCpolarisCes par le KCl, I’ED,,, du CaCI, est respectivement de 5.5 & 0.4 x M et de 6.6 i 0.6 x

M. Enfin, la relaxation de I’aorte isolCe provoquke par l’isoprinaline est identique dans les deux cas : 15 % chez les rats normaux et 16 % chez les rats carends, 1’ED5,, de I’isoprCnaline Ctant respectivement de 2.6 x et 2.9 x

b) Chez les rats anesthCsiCs au pentobarbital (30 a 45 mg/kg), le niveau de la pression artirielle de repos est de 12.27 & 0.93 cm

(*) Aspirant du FNRS (Belgique).

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RkUNION DE LIkGE, MA1 1978 149

Hg chez les rats normaux; de 11.4 f 1.45 cm Hg chez les rats carencks.

La noradrknaline (0.5 pg/kg) provoque, dans les deux groupes, une ClCvation Cquivalente de la pression artirielle de 18.8 1.03 % (normaux) et de 18.2 -l 1.07 (carencks). L’adrCnaline (0.3 pg/kg) entraine une chute de la pression artCrielle de 25.1 4.01 % (normaux) et de 17.5 rt 12.9 % (carencks). A plus fortes doses, elle provoque une rCponse biphasique du mCme ordre de grandeur dans les deux groupes.

Enfin chez les rats carencCs comme chez les rats normaux, la guanithidine entraine une hypersensibilitk aux catkcholamines (CESSION-FOSSION, 1965) du mCme ordre de grandeur.

En conclusion, la rCactivitC aux catkcholamines des rats carencks en acides gras essentiels ne prCsente aucune altiration par rapport aux animaux normaux.

REFERENCES

AAES-JBRGENSEN, E. (1961) Physiol. Rev. 41, 1-51. BONTA, I. L., CHRISPIJN, H. , NOORDHOEK, J . & VINCENT, J. E. (1974) Prosta-

BULT, H. & BONTA, I. L. (1976) Nature (London) 264, 449-451. CESSION-FOSSION, A. (1965) Arch. int. Pharmacodyn. 158, 45-58. VAN CANEGHEM, P., DEBY-DUPONT, G., GOUTIER, R., DEBY, C. & BACQ, Z. M .

glandins 5, 495-503.

(1979) Arch. internat. Physiol. Biochim. 87, 130.

C. DEBY, G . DEBY-DUPONT, Z. M. BACQ et P. VAN CANEGHEM (Laboratoire de Biochiniie Appliquke, UniversitP de Li2ge).

Inhibition naturelle des biotransformations de I’acide arachidonique (1 figure).

L’injection intra-vasculaire d’acide arachidonique (AA) au lapin est suivie d’une hypotension artkrielle permettant de mesurer approximativement la conversion de ce prCcurseur en substances prostanoides ( LARSSON & ANGGARD, 1973). Une sensibilisation prkalable est indispensable pour obtenir des rCponses significatives (abaissements de 40-50 % de la pression initiale) au moyen de doses d’AA amenant des concentrations plasmatiques qui ne sont pas trop supirieures A celles pouvant apparaitre naturellement chez le lapin.

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150 SOCIfiTfi BELGE DE PHYSIOLOGIE ET DE PHARMA.COLOG1E

Deux facteurs apparaissent indispensables pour obtenir une grande sensibiliti ti I’AA : un certain degrC d’himolyse (hCmoglobinCmie entre 0.3 et 0.7 mg/ml de plasma), et I’hCparinisation (5 mg/kg d’hiparine) (DEBY et al., 1974). Au moyen d’une telle prkparation, il est courant d’obtenir des rCponses significatives avec des doses d’AA comprises entre 25 et 35 pg/kg. Des rksistances peuvent cependant apparaitre; elles sont gCnCralement en rapport avec la prCsence de phCnomttnes inflammatoires (affections cutankes) ou infectieux (infections intestinales); elles s’accompagnent d’une ClCvation marquCe du taux d’haptoglobine; I’injection intra- musculaire d’essence de t6rCbenthine fait apparaitre, dans les 24 heures, une forte rksistance i I’AA accompagnant une Clkvation importante du taux d’haptoglobine (DEBY et al., 1978).

D’autre part, SAEED et al. (1977) ont dCcrit un effet inhibiteur du plasma de divers Mammifhes, attribuk 51 des globulines a2; ces inhibiteurs exercent notamment leur action sur la conversion in vitro de I’AA en prostaglandines; leur taux plasmatique augmente fortement dans les jours qui suivent I’injection de glucocorticoides (SAEED et al., 1977).

Ces proteines inhibitrices ne sont pas les haptoglobines ; utilisant la fraction microsomiale de vCsicules siminales de taureau comme enzyme, selon une technique dCcrite prCcCdemment (DEBY et al., 1971), nous n’avons observk aucun effet inhibiteur exercC par I’haptoglobine purifiie par I’un de nous, selon la technique de BETLACH & MCMILLAN (1972).

Nous avons vCrifiC si I’effet sensibilisateur de I’hCparine, que nous n’avons pas su expliquer jusqu’i prCsent, est dO a une action sur les inhibiteurs plasmatiques (fig. 1).

La priparation des lapins par injections de glucocorticoides les rend particulittrement rksistants i I’effet hypotenseur de I’AA. Si, d’une part, I’injection intra-veineuse d’hydrocortisone ( 10 mg/kg), ne modifie pas, dans les minutes qui suivent, la rCponse a I’AA d’un lapin sensibilisk par les techniques dCcrites plus haut, un traitement prolong6 par ce glucocorticoide fait apparaitre une risistance considkrable i I’AA.

Des lapins miles, pesant entre 2.1 et 2.5 kg, ont recu 0.5 mg par kg et par jour d’hydrocortisone; les tests d’hypotension arachidonique, aprtts sensibilisation par himolyse et hkparinisation, ont CtC pratiquCs sur 4 groupes de 3 lapins, ayant subi respectivement ce traitement pendant 24, 48, 72 et 96 heures.

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RfiUNION DE LIhGE, MA1 1978 151

FIG. I . Histogrammes; A : plasmas de lapins avant tout traitement; B : 60 min aprPs injection d‘hkparine, C : 70 min aprPs hkparine et I0 min aprPs injection de sang hkmo- lysk q s . pour obtenir une concentration plasmatique de 0.5 mglml d’hhmoglobine.

Ordonnkes : rendement de la conversion enzymatique de I’AA en prostanoldes, en % des essais temoins (microsomes vesiculaires de taureau). I . Moyenne de 3 plasmas congeles provenant de lapins sensibles B I’AA. 2. Moyenne de 3 plasmas congeles provenant de lapins resistants B I’AA. 3. Moyenne des plasmas frais provenant des memes lapins qu’en 1. 4. Moyenne des plasmas frais provenant des m&mes lapins qu’en 2.

Alors que la dose moyenne d’AA nicessaire pour obtenir une chute de 50% Ctait de 30 pg/kg chez les tCmoins, elle Ctait de 120 pg/kg pour les lapins trait& pendant 24 h et respectivement de 240, 430 et 420 pg/kg pour les groupes traitis durant 48, 72 et 96 heures.

Des lapins, manifestant une hypersensibilitt a I’AA aprb traitement par I’hCparine et I’hCmolyse, ont CtC perfusCs par 30 ml de plasma provenant de lapins donneurs rendus rksistants par traitement de 4 jours a I’hydrocortisone (0.5 mg/kg et par jour); sur six receveurs ainsi trait& deux sont devenus rCsistants dans les 10 minutes qui ont suivi la transfusion du plasma.

En conclusion, la sensibilitk du lapin A I’AA va de pair avec un certain degrC d’hCmolyse (hkmoglobinCmie entre 0.3 et 0.7 mg/ml

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152 SOClkTk BELGE DE PHYSIOLOGIE ET DE PHARMACOLOGIE

de plasma) et I’hCparinisation, qui (( neutralisent )) des facteurs inhibiteurs apparaissant notamment au cours de phinomhes inflammatoires ou infectieux.

Le traitement durant plusieurs dizaines d’heures, par glucocor- ticoi’des, fait apparaPtre un Ctat rCfractaire, vraisemblablement do A la stimulation de la production de ces inhibiteurs.

Nous remercions la firme UPJOHN de Puurs (Belgique) qui nous a gracieusement fourni la PGE, ntcessaire A nos essais.

BIBLIOGRAPHIE

BETLACH, C. J. & MCMILLAN, D. E. (1972) Anal. Biochem. 49, 103-108. DEBY, C., DESCAMPS, M., BINON, F. & BACQ, Z.-M. (1971) C. R. SOC. Biol.

DEBY, C., BARAC, G . & BACQ, Z.-M. (1974) Arch. int. Pharmacodyn. 208,

DEBY, C., VAN CANEGHEM, P. & BACQ, Z.-M. (1978) Biochem. Pharmacol.

LARSSON, C. & ANGGARD, E. (1973) J. Pharmac. Pharmacol. 25, 653-655. SAEED, S. A., MCDONALD-GIBSON, W. J., CUTHBERT, J., COPAS, J. L., SCHNEI-

DER, C., GARDINER, P. J., BUTT, N. M. & COLLIER, H. 0. J. (1977) Nature (London) 270, 32-36.

Filiales 165, 2465-2468.

363-364.

27, 613-615.

J. DAMAS et R. MARCELLE (Institut Lion Fredericq, Physiologie humaine, normale et pathologique, Universitt de LiPge) . Modifications du bronchospasme anaphylactique du cobaye par deux anti-inflammatoires non steroidiens : L.8027 et indomethacine

Nous avons examink I’influence de deux anti-inflammatoires non stkrofdiens, I’indomCthacine et le L.8027, sur les broncho- spasmes anaphylactique et histaminique du cobaye. Les agents bronchospastiques (ovalbumine 5 %, histamine 1 %) sont adminis- trCs sous forme d’aerosols A des cobayes de souche Hartley, sensi- bilisis trois A quatre semaines auparavant au moyen d’ovalbumine de poule. Les cobayes, anesthCsiCs au pentobarbital sodique (1 mg/l00 g), sont trachCotomisCs et soumis A diffirentes mesures de mCcanique ventilatoire. Le dClai d’apparition du bronchospasme est estimC par la mesure continue des variations de la pression transpulmonaire pendant I’interruption iterative du courant aCrien selon MARCELLE (1976). Ce dClai est d’autant plus court que I’intensitC de la rCactivitC bronchique est marqde.

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R ~ U N I O N DE L I ~ G E , MAI 1978 153

L’indomithacine (6 mg/kg, 15 min auparavant) ne modifie pas significativement la survenue des riactions bronchiques, anaphylactique (-0.75 f 0.43 %) ou histaminique. Le L.8027 (1.5 mg/kg) n’influence pas I’action bronchospastique de l’histamine; par contre, lors de I’inhalation continue d’ovalbumine, il prolonge significativement le dtlai d’apparition du bronchospasme anaphylactique (+ 112.3 10.54 %; n = 8; P < 0.05). En d’autres termes, il accroit la quantiti d’antigkne nicessaire pour diclencher cette riponse, dont le seuil s’avkre relevi.

A ces doses, les deux anti-inflammatoires suppriment la contraction bronchique provoquie par I’acide arachidonique (250 pg/ kg), inject6 par voie intraveineuse.

Lors de la riaction anaphylactique, diffirents midiateurs sont libirks a partir du poumon (Revue in PIPER, 1977). L‘indomttha- cine supprime la formation des prostaglandines (PG) et leur libiration, ce qu’objective I’inhibition de I’action bronchique de I’acide arachidonique. Par contre, elle accroit la libiration d’histamine et de SRS-A (ENGINEER et al., 1978). Elle riduit Cgalement les effets de la SRS-A et de la bradykinine (BERRY & COLLIER, 1964). Comme aprbs indomithacine, ni l’action bronchique de l’histamine ni I’apparition du bronchospasme anaphylactique ne sont modifiies, celui-ci dipendrait, en ordre principal, de l’intervention de I’histamine. Le L.8027 diminue la libiration des PG, sans modifier significativement celle de l’histamine et de la SRS-A (ENGINEER & PIPER, communication personnelle). Comme le L.8027 diminue la riactivite bronchique du cobaye a I’antigkne sans influencer celle a I’histamine, les PG exercent bien, dans la riaction anaphylactique, un r d e broncho-constricteur complimentaire.

BIBLIOGRAPHIE

BERRY, P. A. & COLLIER, H. 0. J. (1964) Brit. J . Pharmacol. 23, 201-216. ENGINEER, D. M., NIEDERHAUSER, U., PIPER, P. J. & SIROIS, P. (1978) Brit. J.

MARCELLE, R. (1976) Etude de la Bronchomotricitk. ThPse, Univ. Libge. PIPER, P. J. (1977) Pharmacol. Ther. B. 3, 75-98.

Pharmacol. 62, 61-66.

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