A study of the central effects of sympathomimetic drugs: EEG and behavioural investigations on clonidine and naphazoline

h’ruropharmaculoqy.

1975. 14. 707-714.

Pergamon

Press.

Prmted

in Gt

Britam

A STUDY OF THE CENTRAL EFFECTS OF SYMPATHOMIMETIC DRUGS: EEG AND BEHAVIOURAL INVESTIGATIONS ON CLONIDINE AND NAPHAZOLINE V. FLORIO,L. BLANCHI”and V. G. LONCXI Istituto

Superiore

di SanitB, Viale Regina (Accepted

Elena 299. Rome 00161, Italy

14 November

1974)

Summary-Theeffect of clonidine and naphazoline on the EEG and behaviour of rats, rabbits and cats, and the modifications of these effects by x-adrenolytic drugs and other compounds acting on the sympathetic system, have been studied. Clonidine and naphazoline induced behavioural depression and EEG synchronization in all animal species studied. These effects were prevented by the administration of tolazoline, phentolamine and yohimbine, but not by phenoxybenzamine. Pretreatment with cc-methyl-p-tyrosine was only partially effective in preventing the EEG synchronization due to clonidine. Reserpine was without effect. Amphetamine proved able to reverse the effects of clonidine and furthermore, clonidine attenuated the behavioural and EEG changes due to amphetamine. These data suggest that clonidine and naphazoline induce through stimulation of the central cc-adrenergic receptors.

sedation

and EEG synchronization

Clonidine was initially tested, like other imidazoline derivatives possessing a peripheral a-sympathomimetic action, as a nasal decongestant (GRAUBNER and WOLF, 1966). It was later used as an antihypertensive agent, since it was found that it lowered blood pressure through a mechanism as yet unidentified. Furthermore, the drug proved to possess sedative effects both in man (BRUNER and KLEIN, 1968) and in animals. In animals, clonidine reduces the spontaneous motor behaviour, enhances chloral hydrate narcosis, antagonizes amphetamine, induces sleep in young chickens and in rats (HOLMAN, SHILLIT~and VOGT, 1971; SCHMITT, 1971). In the rabbit, the drug elicits synchronization of the EEG and inhibition of the EEG arousal to reticular stimulation (GOGOLAK and STUMPF, 1966). These and other effects, such as analgesia, anorexia, adypsia, and hypothermia, have been correlated to the central a-sympathomimetic action of clonidine. Some experiments performed with r-adrenolytic compounds have demonstrated that these drugs are able to prevent or antagonize, in whole or in part, some of the central effects of clonidine (HOLMAN et al., 1971; AND~N, CORRODI, FUXE, H&FELT, H&WELT, RYDIN and SVENSSON, 1970; FEIGNER,1971; BROEKKAMP and VAN ROSSUM,1972). In the present experiments, we studied the effects of clonidine on the EEG and on behaviour in the rat, rabbit and cat, and the modification of these effects by cc-adrenolytic drugs and other compounds acting on the sympathetic system. In addition to clonidine, naphazoline, a parent compound, for which sedative effects have also been described (FRIEDMANN,195.5; GOGOL~K and STUMPF,1966), was considered. METHODS

All experiments were performed in animals bearing chronically implanted electrodes. The implantation procedure was carried out under pentobarbital anaesthesia and at least one week was allowed to pass between surgery and the initiation of EEG and behavioural observations. Eighteen male albino rats, ranging in weight from 220_3OOg, were each implanted with four cortical electrodes, which were fixed to the skull with dental cement. The rats were permanently housed in plexiglass cylinders, 50 cm in diameter, with food and *Present

address:

Cattedra

di Fisiologia

Applicata,

II Facolti 707

di Medicina,

Universiti

di Napoli,

Italy.

V. FLOKIO,L.

70X

BIANCHIand

V. G.

LINGO

water ad l~~it~~}~. The EEG was always recorded at the same period of the day (3 p.m.7p.m.) without removing the animals from their cages. The electrodes were connected to the EEG apparatus by long wires which passed through a hole on the top of the cage. Eight rabbits, ranging in weight from 2.5-3 kg, were implanted with cortical and subcortical (periaqueductal grey matter at the mesencephalic level or dorsal hippocampus) electrodes. The recording sessions were p~rforlned with the animals in a shielded cage, 1 x 1 x 2 m in size. In the control recordings, the thresholds of reticular electrical (2%.300Hz; 0.1 msec) stimulation for EEG arousal and for the spasm of the neck muscles (the tegmental reaction) were determined (see FLORIO and LONGO. 1971 for details). Three cats, ranging in weight from 3.2-4.3 kg, were chronically implanted with six vitalliLlm cortical electrodes (motor, association and visual cortex) which were connected to a socket and fixed to the skufl with dental cement. The cats were housed in cages le.5 x 15 x 2m in size, which allowed free movement. The EEG was recorded without removing the animal from its cage, by inserting a miniaturized 3-channel telemetering apparatus into the socket. The tracings were registered by means of a radio FM receiver connected to an EEG machine. Drugs were administered intraperitoneally in the rat and cat and intravenously via an ear vein in the rabbit. All doses refer to the weight of base of the drug. Only one drug experiment per week was performed in the same animal. RESULTS

Rat. Qonidine was adlninistered in dosages ranging from 0.0~0.2 mg/kg. Each dose was administered to at Least three animals. The dose of 0.05 mg/kg did not exert any appreciable influence on the EEG and behaviour. Within S-10 min after the

Vohimbinr

0.5 + Clan. 0.1 mglkg

i-l L-- .w&.“wee

Fig. 1. Antagonistic effect of yohimbine towards the EEG synchroni~~t~otl induced by clonidine in the rat. Sample of controi EEG patterns (upper tracing). compared with that observed 10 min after intraperitoneal injection of Cl.1mg!kg clonidine (middle tracing). Notice the scarce effect of the noise on the trains of spindles present in the record. The Iower tracing was recorded five days later in the same animal: the same dose of clonidine. administered 40 min after yohimbine (0.5 mg/kg. i.p.) did not induce sign~~~ant alterations of the EEG. Leads. LF-LP: anterior sensorimotor cortex: LF-LO: posterior s~ns~~rimotor cortex; LP-LO: optic cortex; RF: reticular formation.

Central

effects of sympathomimetic

drugs

709

administration of @1 mg/kg, the rats appeared to be sedated, crouched in a corner of the cage. and walked ataxically when handled. Concomitant with these behavioural changes, synchronization of the EEG occurred. Acoustic or photic stimuli were unable to induce an EEG and behavioural arousal (Fig. 1). When painful stimuli (pinching the tail) were applied, it was possible to obtain an EEG desynchronization and this was accompanied by struggling and biting. The effects of the drug lasted for about 60min. A dose of 0.2 mg/kg clonidine had the same effects, which lasted for about 90min. A slight catatonia and exophthalmus also occurred with this dose. Rabbit. Clonidine was administered in dosages ranging from 0.02550.4mg/kg. Each dose was given to at least three animals. No appreciable alteration of the EEG or of gross behaviour was observed after 0025 mg/kg. Administration of 0.05 mg/kg clonidine elicited synchronization of the EEG with the appearance of high voltage slow waves and of spindles. The arousal reaction to external stimuli was blocked and the reticular tllresholds for the arousal and for the spasm of the neck muscles were increased. The animals exhibited a sedated appearance and eventually a sleep-like state, with the head on the floor between the anterior limbs. The effects of the drug lasted for about 60 min. Higher doses (O-2-0.4 mg/kg) affected behaviour more drastically. Mydriasis and polypnea appeared. the cornea1 reflex was sluggish. and ataxia and motor inco-ordination were also present. With these doses. the duration of the drug effects was only slightly prolonged, i.e. 7c-90 min. Cat. Only two dosages of clonidine (0+025 and 0.05 mg/kg) were used and each dose was administered to at least two animals. The same EEG and behavioural symptoms described for the rabbit, appeared in the cat treated with O.O25mg/kg clonidine (Fig. 2). However, in the cat, the sedation and the sleep-like state were preceded by a brief period of excitation, retching and vomiting. The drug effect lasted for one hour. The higher dose induced the same symptoms, but the period of sedation lasted for two hours. EJfkcts qf r-udr_etmlJTic ugetlts on the EEG and b~~~a~~ou~alsyrldrorw irlduced by clouidb~e

Before testing the effects of the various a-adrenolytics on the syndrome induced by clonidine, a series of experiments were carried out in order to ascertain the influence of these drugs on the EEG and behaviour. The drugs studied were phentolamine, tolazoline, phenoxybenzamine and yohimbine. At least two animals were treated with the various doses of the drugs. Rat. Phentolamine or tolazoline, at doses of 2 and 10 mg/kg, did not have any appreciable effect on the behaviour and EEG of the rat. These drugs, when injected at the dose of 10 mg/kg 30 min before clonidine (0.1 mg/kg), were able to attenuate the behavioural and EEG effects caused by clonidine. The animals appeared calm, but were easily aroused by means of sound or photic stimuli. The EEG record showed periods of des~l~chronization alternating with the slow waves. Phentolamine and tolazoline, at the dose of 2 mg/kg, were ineffective. Yohimbine (0.5 mg/kg) did not alter the EEG and the gross behaviour of the animals, while 1 mg/kg induced a desynchronization of the record and a slight degree of excitation. The effect of yohimbine pretreatment on the behavioural and EEG action of clonidine (0.1 mg/kg) was quite dramatic. In rats treated 30 min in advance with 1 mg/kg yohimbine, clonidine did not induce any of the symptoms observed in control animals. A marked attenuation of the sedative effects and of the EEG synchronization caused by clonidine was also observed after pretreatment with 0.5 mg/kg of yohimbine (Fig. I). Phenoxybenzamine (2 and lOmg/kg) exhibited a tranquillizing action in rats. Spontaneous movements decreased, long periods of sy~lchronization appeared in the EEG, but the arousal reaction to external stimuli was preserved. With the higher dose, these effects lasted for 3-4 hours. Pheno~y~nzamine, injected four hours in advance in doses of 2 and lOmg/kg, did not affect the EEG and behavioural action of 0.1 mg/kg of clonidine. An outline of the results obtained in the rat using the various adrenolytics is presented graphically in Figure 3.

0

P

F

Fig. 2. Effects of clonidine on the EEG of the cat. Top record: electrocorticogram on the normal animal. At the arrow, an acoustic stimulus evokes an EEG and behavioural arousal. Bottam record: 20min after drug injection, the animal is asleep, the EEG is synchronized and the acoustic stimulus is without effect on the EEG. The animal bears chronically implanted electrodes and a telemetry system. Leads. F: anterior suprasylvian gyrus; P: association cortex; 0: visual cortex.

Lonwoi

Central

EEG

PATTERNS

CONTROL

CLON

IN

0.1

THE

effects of sympathomimetic

drugs

711

RAT

YOHIM CLON

0.5 0.1

TOLAZ CLON

m

DESVNCHR.

m

MIXED

0

SYNCHR.

10 0.1

PHENT CLON

10 0.1

PHENOXV 10 CLON 0.1

a-MPT CLON

MO 0.1

RESERP 2 CLON 0.1

Fig. 3. In the graph are charted, in percentages (f SE.) of the time of total recording (80 min), the EEG patterns of the rat classified as desynchronized. mixed, or synchronized. Under control conditions, there was a prevalence of desynchronization. In animals treated with clonidine the synchronization prevailed. Of the sc-adrenolytics, yohimbine, tolazoline and phentolamine antagonized the synchronizing effect of clonidine, while phenoxybenzamine was ineffective. Reserpine had no effect, while c+MPT was only partially active. The figures in parentheses indicate the number of experiments.

Rabbit. Phentolamine and tolazoline, in doses of 2 and 10 mg/kg, yohimbine (0.5 mg/ kg) and phenoxybenzamine (2mg/kg) did not alter the gross behaviour or the EEG of the animals. Phenoxybenzamine, at doses of lOmg/kg, induced sedation and synchronization of the EEG. Experiments on antagonism with clonidine were carried out in at least two animals for each dose. Injected 30 min before clonidine, phentolamine (10 mg/kg), tolazoline (10 mg/kg), or yohimbine (05 mg/kg), prevented the appearance of the signs of sedation and of the EEG synchronization observed in control animals. Phenoxybenzamine (2 and lOmg/kg) was devoid of any antagonistic effect against clonidine. Cat. Using three animals, only yohimbine (0.5 mg/kg) was tested. It was administered 30 min before 0.05 mg/kg clonidine. The animals pretreated with yohimbine did not show behavioural depression and acted and walked quite normally in the cage. The EEG record was predominantly activated and the arousal reaction was preserved. In two animals, yohimbine pretreatment reduced the early phase of excitation and vomiting caused by clonidine. Effects of rx-methyl-p-tyrosine, syndrome induced by clonidine

reserpine arzd amphetamine in the rat.

on the EEG

and behavioural

In addition to the cc-adrenolytics, some other drugs which interfere with the adrenergic system were studied. Three rats were treated for three days with 100 mg/kg per day of c+methyl-p-tyrosine methylester. Twenty four hours after the last dose, the animals appeared sedated but did not exhibit any significant modification of the EEG. When clonidine (0.1 mg/kg) was administered at this time, a more severe behavioural depression ensued, which, however, was not accompanied by the EEG synchronization usually induced by clonidine. Reserpine (2 mg/kg) was administered to three animals. Twenty four hours later the rats showed piloerection, hunched back, palpebral ptosis, and reduced motor activity. The EEG did not differ significantly from the normal. When clonidine (0.1 mg/kg) was injected at this time, the animals showed further sedation and EEG synchronization (see Fig. 3). Amphetamine (1 or 2 mg/kg) was given to three rats 15 min prior to the administration of 0.2 mg/kg clonidine. Amphetamine induced in the rat increased alertness, some exciClonidine, tation, pupillary dilatation, exophtalmus and EEG desynchronization.

712

V. FLOKIO,

L. B~ANCHI

and V. G. Lorvco

administered 15 min later, markedly attenuated the behavioural and EEG actions of amphetamine. In three other rats amphetamine was given after clonidine and in this case arnphet~l~il~e reversed the depression and the EEG syll~l~roni~dtion induced by clonidine. In these animals a certain degree of motor impairment was still present and only a few breakthroughs of excitatory signs due to amphetamine were observed.

The study of the effects of naphazoline, in dosages varying from O-025 to I mgj’kg, was carried out in rabbits and cats. At least two animals were treated with each dose of the drug.

Fig. 4. Antagonistic effect of toiazoline towards the EEG synchronization caused by naphazoiine in the rabbit. Upper tracing: control resting patterns as well as EEG arousal patterns upon electrical stimulation of the reticular formation (at the bar). Middle tracings: 30 min after naphazoline (0.05 n&kg. iv.) there is a partial inhibition of the EEG arousal. The lower tracing was recorded one week later in the same animal: the same dose of napha7oline. administered 3Omin after tolazoline (IOmg:kg. i.v.) did not affect the EEG arousal. Leads: see Fig. 2.

Rabbit. The administration of 0.025 mg/kg of naphazolinc was not followed by any observable modification of the EEG or of behaviour. The dose of 0.05 mg/kg induced a syn~hronizatioI1 of the EEG, which peaked within the first 1Omin and gradually subsided over the following hour. The arousal reaction was always preserved. ~~ltllougll significantly shortened with reference to the control. Accompanying these EEG alterations were a number of grossly observable signs, such as motor depression, ataxia. muscular relaxation. Higher doses of naphazoline (up to 0.5 mg/kg) induced the same EEG and behavioural effects. Even with the highest dose. a block of the arousal EEG reaction to external stimuli or to reticular electrical stimulatio~l was never obtained. The appearance of the EEG and behavioural effects of naphazoline (0.05 mgjkg) could be prevented by either yohimbine (0.5 mg/kg), phentolamine (lOmg/kg) or tolazoline (10 mg/kg), administered 30 min previously (Fig. 4). Phenoxybenzamine (10 mgjkg). administered 4 hr before 0.05 mg/kg of naphazoline, did not modify the EEG and behavioural effects of the drug. Cnt. The administration of doses up to O.:!mg/kg of l~apliazoline did not induce any observable modification. A few minutes after administr~~tion of 0.5 or I mgikg,

Central

effects of sympathomimetic

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713

retching and vomiting appeared, concomitant with piloere~tion and nasal mucous secretion. The animal appeared anxious and miaowed but later quietened down. The EEG showed, after an initial activation, a mixed pattern as in the control period. A synchronization was never observed and the acoustic stimuli continued to induce a normal arousal reaction.

DISCUSSION

the present experiments some aspects of the central effects of clonidine and naphazoline were investigated in several animal species. Our results confirm the data in the literature (see Introduction), which describes the induction of behavioural depression and EEG sy~~chro~~i~~tio~~ by these drugs. There dre several indications that these effects are common to a group of drugs. in~Iudin~ clonidine, naphazoline, xylazine and 2-(2,6dimethylph~nylamino)-1,3-oxazol-A’-ine (LD 2855) which have been classified by SC~IMITT 1971) as ~.sympathomimetic amines with central effects”. These drugs have peripheral sympathomimetic properties and, because of their chemical characteristics. penetrate easily into the brain, exerting at that level effects allegedly due to the stimulation of x-adrenergic receptors. These effects, however, are mainly depressant and are in contrast with the widely accepted concept that the central adrenergic system is connected with behavioural and EEG arousal. Therefore, the effects of clonidine must be discussed within the framework of a more generalized problem, namely, the central effects of the sympathomimetic drugs. The study of this problem is hindered by the fact that the various cdtecholamines. injected parenterally, hardly cross the blood---brain barrier. In fact, behavioural and EEG arousal is obtained only with sympathomimetic drugs of the ~~mphetamine type or with c~~tliecolamine precursors such as L-DOPA. On the other hand, behavioural effects similar to those observed with centrat depressants are obtained when norepinephrine or ~pinephrine are adnlinistered by intraventricular or intracisternal injection (GRUKDEN, 1969). In some investigations, the central effects of clonidine have been compared with that of norepinephrine. According to HOLMAN& al. (1971), clonidine administered intravenously to chickens, elicits a syndrome (sleep and relaxation) very similar in appearance to that seen after doses 25-50 times higher of norepinephrine or epinephrine. In chickens pretreated with phentolamine, clonidine or norepinephrine fail to cause complete relaxation. FCJGNERand HOEFKE (1971) described an antagonism on the part of phentolamine and tolazoline of the depressant effects of clonidine and norepinephrine in the young chick. Adrenolytic drugs are therefore able to prevent the behavioural and EEG effects of clonidine and of the sympathetic neurotransmitters. This is another argument in favour of the hypothesis that drugs such as clonidine or naphazoline induce sedation and EEG synchronization through stimL]lation of the central r-adrenergic receptors. In our experiments, as well as in those of other investigators, plle~loxybenzamine showed depressant and synchronizing properties and was devoid of any antagonistic effect towards clonidine. According to the results of AUTR~T. SCHMITT.FEKAIXI> and PETILLOT(1971), of all the adrenolytics tested. phenoxybenzamine was the only drug which showed a non-competitive antagonism towards the haemodynamic effects of various cc-sympathomimetic drugs. If phenoxybenzamine has antagonistic properties distinct from those of the other adrenolytics at the periphery, it is conceivable that it also has different effects at the central level. In our experiments, the synchronizing and calming effects of clonidine were still present in spite of depletion of norepinephrine stores by reserpine or after blockade of norepinephrine synthesis by x-methyl-p-tyrosine. These data would indicate that the drug directly stimulates central norepinephrine receptors which are responsible for the aforemelitioned effects. Similar evidence of central norepinephrine receptor stimulation was obtained by AND~N et al. (1970) in spinalized rats treated with reserpine and with cc-methyl-p-tyrosine: clonidine was still able to enhance the tlexor hind-limb reflex, which is known to be dependent upon the activity of norepinephrine receptors. In

V.

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FL.ORIO. L.

BIANCHIand V. G.

L~NCKI

Amphetamine proved able to reverse the effects of clonidine and, conversely, clonidine attenuated the behavioural and EEG changes due to amphetamine. While in the case of the cc-adrenolytics, an antagonism with clonidine at the receptor level can be postulated, in the case of amphetamine a different mechanism should be sought. Several hypotheses have been advanced to explain the central excitant effect of amphetamine. The view that catecholamine liberation mediates the excitatory effect of amphetamine (RANDRUP and ~UNKVAD, 1966) is not supported by the above discussed results, which indicate a depressant action of the catecholaminergic neurotransmitters. DEWHURST and MARLEY (1965) have reported an excitant effect of amphetamine in the young chick, while norepinephrine and dopamine exhibited depressant effects. These workers have attributed this action of amphetamine to a stimulation of the tryptaminergic receptors. According to COSTA, GROPPETTI and NAIMZADA (1972), acceleration of striatal dopamine turnover

is associated

with the enhancing

in rats. One must consider

the possibility

effects of amphetamine that modification

on motor

activity

of biosynthesis

may be

per se instrumental

in determining changes in behaviour. The results of DEWHURST and MARLEY (1965), which showed excitatory

L-DOPA

administered

to young chickens, can be attributed

effects of

to the dynamics

of conversion, rather than to an effect of the metabolites dopamine and norepinephrine, for which depressant effects have been shown. The antagonism exerted by amphetamine against clonidine depression could therefore depend on the behavioural stimulation due to the increase in monoamine turnover, rather than on an interference at the receptor level. In conclusion, the fact that sympathomimetic drugs such as clonidine induce sedation which is antagonized by adrenolytic compounds, would suggest that the action of adrenergic drugs on discrete sites of the cerebrum is of depressant rather than excitatory nature. On the @her hand, there are several indications that the excitatory effects of amphetamine and of L-DOPA are due to the activation of the biosynthetic routes of the neurotransmitters rather than to the liberation or production of the neurotransmitters. REFERENCES N-E., CORRODE, H., FUXE,K., H&FELT,B., HGKFELT. T., RYIXN,C. and SVENSSON,T. (1970). Evidence for a central noradrenaline receptor stimulation by clonidine. Life Sci. 9: 513423. AUTRET,A.-M., SCHMITT, H., FENARD,S. and PET~LLOT, N. (1971).Comparison of haemodynamic effects of r-sympathomimetic drugs. Eur. J. Pharmnc. 13: 208-217. BROEKKAMP, C. and VAN ROSSUM,J. M. (1972). Cionidine-induced intrahypothalamic stimulation of eating in rats. P~ych~~~~~~c~~ugi~ (Berl.) 25: 162-168. BR~:NER, H. and KLEIN.K. E. (1968). Experimentelle ~ntersuchungen iiber die VerLnderungen der psychomorischen Leistungsbereitschaft unter dem Einfluss eines Antihypertonikums. In Hochdrucktherapir (HEILMEYER, L., HOLTMEIER, H. J. and PFEIFFER,E. F., Eds.) pp. 180-184, G. Thieme, Stuttgart. COSTA, E., GROPPETTI, A. and NAIMZADA,M. K. (1972) Effects of amphetamine on the turnover rate of brain catecholamines and motor activity. Br. J. Pharmac. 44: 742-751. DEWHURST, W. G. and MARLEY,E. (1965).Action of sympathomimetic and allied amines on the central nervous system of the chicken. Br. J. Pharmac. Chemuther. 25: 705-727. FLORIO, V. and Louco, V. G. (1971). Neuroleptic drugs and the central dopaminergic system. .~F~~Q~~u~~~c~togp 10: 45-54. FRIEDMANN. H. T. (1955).Reactions following use of nasal decongestant. J. Am. Med. Ass. 157: 1158. FikNER. A. (1971). Antagonism of the drug induced behavioural sleep in chicks. Arzneimittel-Forsch. 21: ANDkN,

I is0 1352.

WGNER.A. and HOEFKE,W. (1971). A sleep-like state in chicks caused by biogenic amines and other compounds; quantitative evaluation. Ar~/lzitMiitrl-Forsch. 21 : 1243-1247. GCBCOLAK, G. and STIJMPF, C. (1966).Wirkung von 2-(2,-Dichlorophenylamino)-2-imidazolinehydroc~lorid auf die E.E.G.-Weckreaktion beim Kaninchen. Arzneimittef-Forsch. 16: 1050-1052. GRAUBNER, S. and WOLF,M. (1966). Kritische Betrachtungen zum Wirkungsmechanismus des 2-(2,6-Dichlorphenylamino)-~-imi~zolin-hydrochloride. Arzneirnittel-Borsch. 16: 1055. GRUNDEN,L. R. (1969). Action of intraventricular epinephrine on gross behavior, locomotor activity and hexobarbital sleeping times in rats. Int. J. Neuropharmac. 8: 573-586. HOI-MAN,R. B., SHILLITO, E. E. and VOGT,M. (1971):Sleep produced by clonidine (2-(2,6-dichlorophenylamino)2-imidazoline hydrochloride). Br. J. Pharmac. 43: 685-605. RANDRUP, A. and MUNKVAD,I. (1966). Role of cathecolamines in the amphetamine excitatory response. Nature, l&d. 211: 540. SCHMITT, H. (1971). Actions des alpha-sympathomim~tjques sur les structures nerveuses. Act&. P~~~~~c. 24: 93-133.