Wical might

&DA-

lateral a?& of

HARMINE, HARMALINE AND RELATED ,bCARBOLINES

oidance

J. A. FUENTES* V. G. LONGO and

Laboratoridi ChimicaTerapeutica, Istituto Superiore &nit& Roma,Itaiy di
(Acccptcd 27 May 1970)

UDLDI,
in Proc. II stimll-

uine on

Summary-The hehaviourai and EEG effects of harmine. hammline and 5 related &ca.rbolines

werestudiedin rats and rabbits bearingchronicallyimplantedelectrodes variouscortical in and subcortical areas. Basedon thensults obtained, the 7 derivatives be divided into 3 can

ILof the
iction in Zisevier, :urarisk. , hybrid memory :haviour
THOMAS,

groups. 7%~ first group includes hennine and harmline, which caused excitation, tmnors. andataxiaboth in the rat andin therabbit. Themodifications thecerebral of electricalactivity duringthetremorsconsisted an increase frequency in voltage,observed in the cortical of in and leads. Harrnol, tetrahydro-harmane and 3-methyl-harmane a different toxic effect, conhad sisting of a depressivesyndrome, which canextendto complete paralysis the rat. Hat-mane in and nor-harmane produced. at low doses.a motor depression having a catatonic component; higher doses led to clonic and tonic-clonic type convulsions; tremors were never observed. In the rabbit, but not in the rat, L-DOPA waseffectivein antagonizing tremorsand the the other toxic symptoms caused by the two drugs. These results suggest that the tremors induced by harmine and harmaline may be caused by an effect on the extrapyramidal dopaminergic system.

THE FIRSTsystematic study of the effects of harmine, harmaiine and of other ,&carbolines on laboratory animals was carried out by GUNNet al. (1930, 1931, 1935). Tremors, con-

ponse by ehaviour ii in cats. nl stimuli

ppharma-

vuisionsand excitation characterizedthe toxic syndromeinduced by harmine and harmaline. This has been confirmed by other investigators (CHEN and CHEN, 1939). Later on, an antimonoamineoxidaseeffect was describedfor both alkaloids (PLETSCHERal., 1959). Other et authors have, in particular, examined the effectsof harmine on the central nervous system.
GER~HON LANG (1962) reported a state of anxiety and excitation in the dog. HIMWZH and ef al. (1959) studied the effect of the alkaloid on the cerebral eiectrical activity of the rabbit,

attention iissimilar iormancz Jstitution .d on four o-lysergic n,D.and e pigeon.

describingEEG activation after 5 mg/kg. The tremorigenic effect of harmine in mice was analyzed by HARA and KAWAMORI (1954). These authors noticed that the tremors disappearedafter ablation of either the cerebral cortex or the striatum. On the basis of these Snciingsthey suggestedthat the drug affected the extrapyramidal system. Recentbiochemicalstudies seemto uphold this theory; according to POIRIER al. (1968), harmaiine et hasa specificeffect on brain dopamine and hinders both its synthesisfrom L-DOPA and its conversioninto homovanillic acid. Therefore, the tremor elicited by thesealkaloids could be deemedanalogous to the syndrome observedin mammals (monkey) and man with lesions of the extrapyramidal system. Xs to the other derivatives with a &carboiine structure, literature dealing with pharmaCo[ogicalfindings is scarce. GUNN and MACKHTH (1931) calls attention to the fact that harmoi causes a paralysis instead of the excitation observed with the methoxylated
Fellow, CentroC&mica dei Recettori.ConsiglioNazionale deUe Ricer&e. Italy. 15

16

J. A.

FUENTES

and V. G.

LONGO

derivatives. The pharmacological properties of harmane were studied by SIGG et al. (1964); they described a convulsant effect. In the present work the effects of harmine, harmaline, and of five other @carbolines (see Table) were studied in animals with chronically implanted electrodes. The scope of $ .: .*- *. ,$r ,

cHoJ3&2 3

cpoJ3yx2
H Harmlne 3 W H Harmaline LHJ

Qqq H Hormone
CH3

QK-p

Nor-Hormone

.x. .. .l. * .:_ z Ai .. --* ..

electrodes formed at animals N -with lone channel fi Beside methods I The prese; cube. In ducing b-i] postures a All the free base. rabbits wf chronicall: drug treat: I.

HoQQQ H Harm01
CH3

Q$JQw
3

Tetrahydro-Hormone

Q)---gCH3
CH3

3-Methyl-Hormone
TABLE. CHEMICAL STRUCTURES OF THE

CXMPOUNDS

STUDIED.

our investigations was that of determining any change of cerebral electrical activity that could he related to the motor alterations and, in particular, to the tremors which seem to be a characteristic effect of some of these compounds. The antagonism of some drugs to the toxic syndrome provoked by harmine and harmaline has also been studied.
METHODS

Rat Harmil capabie dl trials it wq death of tl implanted varied fror noted. Ra latency (5 gait. Trerr mglkg. the movement! cases the a lasted for a described f The mc increase in frequency i

Was clearly
In preliminary experiments, the drugs were administered to rats and rabbits to observe

present in I The effc 20 of harm L-DOPA vi

the toxic effectand determine lethal dose.A total of 40 rats and 22 rabbits wereused the
for this purpose. Other preliminary experiments dealt with the action of the compounds on the cerebral electrical activity of rabbits in which electrodes were acutely implanted under etheranaesthesia. Arterial pressurewas recordedfrom a cannulainserted in the femoral artery and connected to a strain gauge transducer. All the wounds were infiltrated -with procaine. The animals were then immobilized with gallamine (5 mg/kg) and placed

rats. Grou

wasobserv

underartificialrespiration.
Experiments were then performed on rats and rabbits bearing chronically implanted

L-DOPA in (% and 101 Along witi to study th

Harm& et al. (1964); electrodes

and related &carbolines

17

/?-carbolines Yhe scope of

in various cortical and subcortical areas. Histological examinations were performed at the end of the experiments to ascertain the position of the deepelectrodes. These animalswere placed in a shielded box (lmx lm) and were connectedto the EEG apparatus with long wires allowing freedom of movement. To analyse the EEG recordings a twochannelfrequency anaiyser (Faraday Electronic Instruments) wasemployed. Besidesobserving the spontaneously displayed behaviour of the animal, the following methodswere used to evaluate other motor deficits occurring in the course of intoxication. The presence catatonia in the rat was assessed by placing one foreleg oa a 7 cm high wood of cube. In the rabbit, the intensity and frequency of the tremors was measured by introducing bipolar needle-electrodes various muscles(foreleg, hindleg, neck). The abnormal in posturesassumedby the animals under the effect of the drugs wereoften photographed. All the substanceswere dissolved in water; the dosesare expressed the weight of the as free base. Unless otherwise stated, the rats received the drugs intraperitoneally, while the rabbits were injected intravenously. In the experiments carried out in the animals with chronically implanted electrodes,at least 3 days were allowed to elapsebetweensubsequent drug treatment.
RESULTS

i.

Rat

activity that :h seemto be drugs to the

ts to observe ts were used compounds ly implanted jerted in the :re infiltrated ) and placed [y implanted

Harmine, harmaline. Preliminary trials were carried out in rats to determine the dose capable of inducing the typical symptoms of intoxication (tremors, excitations). In these trials it was found that, up to 30 mg/kg, neither harmine nor harmaline provoked the death of the animals. Experimentation was then begun using animals bearing chronically i mpiantedelectrodes. Six rats were used,for a total of 22 experiments;the dose administered varied from 2 to 20 mgjkg. No sign&ant differencesin potency betweenthe two drugs were noted. Rats receiving harmine or harmaline in doses of 5-10 mg/kg, after a short period of latency (5 min) showed an increase in spontaneous activity with tremors and an unsteady gait. Tremors, however, were not evident when the animals were not moving. After IS-20 mg/kg, the tremor appeared almost immediately; it was independent of the spontaneous movements was accompaniedby arching of the back and stiffening of the legs. In some and casesthe animais fell on their sides and had clonic convulsions. The continuous tremors iasted for about 10min and then progressivelydiminished, leading to the lesssevere syndrome describedfor the lower doses. The modifications of the cerebral electrical activity during the tremors consisted of an increasein frequency and voltage, observed in the corticai anterior leads; this increasein frequencyis well evident in the frequency analysisdiagram (Fig. I). This EEG modification wasclearly dissociatedfrom the artifacts due to the increasedmuscular activity, for it was Present the records even during the periods when animals did not have tremors. in The effect of r..-DOPA on the toxic syndrome produced by harmine was studied in 14 rats. Groups of 4 animals were treated respectivelywith 10 and 20 mg/kg of harmine and JOof harmaline; once the tremors were fully developedthey were injected with dosagesof L-DOPA varying from 10 to 50 mg/kg. No appreciable attenuation of the toxic syndrome wasobserved. Two animals treated with 20 mg/kg of either harmine or harmahne received L-DOPA intravenously through a needleinserted into the tail vein; also in this casethe drug (50 and 100 mgjkg) did not modify the tremors and the other symptoms of intoxication. :ilong with the above described experiments, some preliminary trials were undertaken lo study the effect of 5-hydroxytryptophan (5-HTP) on the toxic syndrome produced by

J. A. FUENTES V. G. LQNW and

22

1;

2:

li

22

2;

FIG. 1. Efiects of harmine on the rat EEG. Tracings registered in a rat with chronically implanted electrodes. An increase in frequency and voltage is noticeable, particularly in the

analysis the P-O andTH leadsshowsan increase the of of corticalrecordings.The frequency peaksin the 22-23 C/SC section.
Lends:

F-P: fronto-parietal cortex; P-O: parietc+occipital cortex; F-O: fronto-occipital

cortex; TH: antero-medialthalamus;FA: Frequency analysisof the P-O and TH leads. harmine and harmaline (25 mg!kg). 5-HTP did not antagonize the effects of the two alkaloids
FIG. 2.

in the rat, and wheninjectedin doses 40-50mg/kg caused deathof the animals. of the
Harmol, tetrahydro-harmane, 3-methyl-harmane. These three substances gave rise to a toxic syndrome which was clearly different from that observed with harmine and harmaline. Dosesranging from 2040 mgjkg of harm01 caused a brief period of excitement during which the animals exhibited circling movements, and made attempts to grasp their own tails. This was followed by a depressive phase,which had a peculiar character, i.e. the

For fur:

animalsspontaneously on their bellies,head and tail flat on the floor, remaining in this laid
position for some time (Fig. 2.1. The animals eyes were open and they seemed alert. In

fact, evenslight noises,such as the click of the camera usedfor photography, aroused them, andthe ratsthenappeared go about their activities in a normal manner; after a short time to they again assumed the above describedposition. This feature was so typical and constant that it was named the harm01position. L-DOPA, administeredin dosesof up to 50mg/kg, did not influence the behavioural patterns provoked by harmol. The EEG recordings did not show any changewhich could be consideredcharacteristic the in of the harm01 position. Sometimes tracing was synchronized; this case,the EEG

d+ set loop

.m-

the the .tilI l-H FIG. 2. TypIcal posture (harm01 position) assumedby a rat treated with harm01 CL0 mglkg 1.p.J. For further explanattons seetext. Theanimal is connected to the apparatus for the simultaneous registration of the EEG.

lkaloids
11s.

ise to a :maline. during eir own i.e. the

g in this ert. In d them, xt time 0nstant mg/kg,

Xeristic e EEG
Neuro. f.p. 18

Harmine related and /?carhoiines

19

arousal reaction following external stimulation was always present. At other times, even though the animal was lying flat and motionless, the EEG was completely desynchronized. Tetrahydro-harmane and 3-methyl-harmane, at equivalent dosage levels, caused the samesyndrome as observed for harmol. Harmane and nor-hurmune. Harmane and nor-harmane (10 @kg) produceda motor depressionhaving a catatonic component. Higher doses(20 mg/kg)led to clonic and tonicclonic type convulsions; tremors were neverobserved. After the higher doses, the EEG Tracingdisplayed a typical convulsive pattern, that is, spikes and spikes-and-waves.
!I. Rabbit

On the basisof the results obtained in the rat, the effectsof harmine, harmaline and harm01 werestudied in detail in the rabbit. Previous toxicity tests, performed on animals not bearing electrodes, indicated that the lethal doseof harmaline was 20 mg/kg, while that of harmine was60 mg/kg. The tremorigenieeffect, however, appeared at the same dosagelevel (2-3 mg/kg) with both substances. With higher doses (S-10 mg/kg) the tremor was accompanied by excitation, ataxia and mydriasis. The frequency of the tremor in the EMG record was IO-12 c/s and displayed a waxing and waning pattern. The effect of harmine lasted longer: after a 5 mg/kg dose of harmine, tremor was present for 10-15 min while with ha.rmalineit did not last more than 5 min. The tremor appeared 30-60 set after injection and was independent of the sponianeous motor activity displayed by the animal. Later, the tremor was evident only when the animal moved. The EEG tracings, performed on four animals with chronic electrodes,showedthe same increase frequency and amplitude of the cortical wavesas that observedin the rat. Morein over, the hippocampal theta waves (4-5 C/XC) becameprogressively disorganized and at times were replaced by a low voltage rapid (20 c/set) activity. With higher doses (10-20 mg/kg) of both drugs, an EEG grand mai pattern was occasionally seen. Six experiments were performed on acutely prepared animals. Three of these were

curarized femoralblood pressure measured. EEG findingsin these and was The animalswere similarto those of the chronicallypreparedanimals;particularly,the increase frequency of cmdamplitude of the cortical waves observed in the cumrized preparations led to the conclusion that this is a phenomenonoccurring independentlyof the augmented muscular
activity. Bradycardia and an increase in blood pressurewere the other effectsobserved. In the rabbit, contrary to that observedin the rat, L-DOPA waseffectivein antagonizing

:hetremorsandthe other toxic symptoms cansed the two drugs. The tremorscaused by by
s-10 mglkg of harmine and harmaline were immediately attenuated by the i.v. aclministration of 5 mg/kg of L-DOPA and usually completely disappearedwithin 5 min. In Fig. 3, the EMG registration clearly demonstratesthis effect; interestingly, the simultaneousEEG recording was not altered significantly. The duration of the effect of a 5 mg/kg dose of L-DOPA was transitory; tremors and other toxic symptoms reappeared, they could be but

controlledby additionalinjections. Higher doses L-DOPA (20 mgikg)had a lastingand of

apparently curative effect, in that all toxic signs disappeared and the animal appeared

essentially normal, exceptfor a slight degree excitation. of Atropine, in dosesof up to 5 mgikg, and 5-hydroxytryptophan, to 20 mgjkg, were up
without effect on the toxic syndrome produced by the two alkaloids; on the other hand, Pntobarbitoneabolished tremors only at doses mglkg i.v.) whichcaused profound the (15 a

depression the animal,to the point that theanimallosttherightingreflexandlay on its side. of

J. A. FUENTES V. G. LOWGO and

FR

Control *

The re$

F-PmCLW~vw P-O m moves J-v!

&i;*, *

$5

4 min

after

harmine

5mg/kg,

i.v.

moves

FIG. 3. Antagonistic effect of L-DOPA on harmine tremors in the rabbit. Tracings recorded in an animal bearing chronically implanted electrodes in various cerebral areas, and a bipolar naxlk-clcctrode in the hind leg. Afterjharmine (5 m&kg), the tremor apptxed and was accompanied by an increase in frequency and voltage of the cortical waves; the theta rythm in the hippocampus was partially disrupted. Upon administration of L-DOPA, the tremors disappeared but there were only a few changesin the arebd ekcnical activity. Leodr: FR: anterior sensorimotor cortex ; F-P: anterior-posterior sensorimotor cortex; P-O: anterior sensorimotor-optic cortex; HIP: dorsal hi ppocampus; EMG: ekctromyogram of the hind leg.

Previou that distinc behavioura of the cent: tives can b which caus .,... is in agreen cat, monke I is slightly If and by& describedb: _ in the presf HIMWICHe levelsafter the charactl voltage at t that is, the r The fact tha not be taker ever, some i maline. HA mine-induce The sect drugs induct can extend t attributed th However, tl harmane an{ The positioo and doesnot possessing d the harm01I and the press isms. The ix significantly almedthrou animals (guh

stimulations. animalhigh (
The third hErmanewen -+.

In the rabbit, harmol, in dosesup to 30 mg/kg, did not causeany significant change in behaviour or the EEG; in particular, what has been previously described as the harm01 position in the rat was never observed. Doses of 50 mg/kg brought about a state of excitement followed by convulsions, accompaniedby the appearanceof spikes in the EEG.

the .a& between ..$,.

Harmine related~-carbolines and

DISCUSSION

21

The results obtained in theseexperiments will be discussedfrom two viewpoints. The first concernsthe behavioural effectsof the various compounds, as related to the modifications of the cerebral electrical activity. The second deals with the antagonistic effect of L-DOPA on the tremors caused by ham&e and harmaiine. previous work done with the ,&carboline anaiogues of harmine gave some indications that distinct pharmacoiogical effects exist within this group. This study, combining both behavioural observations and recording of the EEG, allowed a more precise delineation or the central effectsof thesecompounds. Based on the results obtained, the sevendcrivatives can be divided into three groups. The tirst group includes harmine and harmaiine, which causeexcitation, tremors, and ataxia both in the rat and in the rabbit. This syndrome is in agreementwith previously reported data on theseand other laboratory animals (mouse, cat, monkey), (BEER, 1939; CHEN and CHEN, 1939). The frequency of tremors in the rabbit is slightly lessthan that reported for the mouse (15-20 C/XC)by AHMED and TAYLOR (1959) and by HARA and KAWAMORI (1954), but has the same character of waxing and waning describedby theseauthors. In relation to the EEG effectof the two alkaloids, resultsobtained in the present experimentshave confirmed and extended the preliminary observations of HIMWCH et al. (1959), in which a modified activation at the cortical and hippocampal levelsafter harmine administration (5 mg/kg) was described. Basedon the present results, the characteristic EEG effect of these two alkaloids is an increase in both frequency and voltage at the cortical and hippocampal levels. Tracings taken from other cerebral areas, that is, the reticular formation and thecaudate nucleus,did not show any significantchanges.
The fact that a drug causes alterations in electrical activity in a particular cerebral area can

ilot be taken to meanthat the drug possesses specific action in that particular area. Howa ever, some authors have data suggestingthat there is a cortical effect of harmine and harmaline. HARA and KAWAMORI (1954) reported in the mouse the disappearance of the harmine-inducedtremors following decortication. The secondgroup includes harmol, tetrahydro-harmane and 3-methyl-harmane. These drugs induce a completely different toxic effect, consisting of a depressive syndrome, which canextendto completeparalysisin the rat. Gunn describeda similar effectin 1935,and he
attributed the depressive syndrome to the alcoholic hydroxyl group present in the molecule. tiowever, this syndrome was aiso noticed, in the present investigation, with tetrahydro-

harmane 3-methyl-harmane, and which do not possess samechemicalcharacteristics. the

The position assumed by the rat treated with these 3 substances has some unusual features, and does not appear to have any point in common with that observed after othercompounds

Possessing depressive effects,and it is difficult to classify becauseof this. On the one hand the harmoi position indicates a depression of the motor system,but the absence catatonia, of 2nd the presenceof the righting reflex speak for the relative integrity of the postural mechaaisms. The immediate responseto external stimuli suggeststhat the sensorysystemis not rignificantly affected. This is partiy confirmed by the EEG recordings which were not alteredthroughout the toxic period and remained sensitiveto the activating effectof external stimulations. GUNN(1935) reported For harm01 a depressiveaction in other laboratory animals (guinea-pig, rabbit) which were not confirmed in this study in the rabbit. In this nnimal high doses(50 mg/kg) of harmol causedconvulsions and tremors. The third group includes harmane and nor-harmane. The convulsant properties of
llannane were reported bv SIGGer al. (1964) ; this present study made evident aclear difference

betweenthe effectsof these compounds from those of harmine and hanaline, basedon

22

J.A. Fm

and V. G. LINGO

both the toxic syndrome and the EEG alterations. Harmane and nor-harmane cause a catatonic state in rats, and the convulsionsobserved following high doseswere of the cionic type, the corresponding EEG being composed of spikes and spike-and-waves. The finding that L-DOPA antagonizesthe tremors and the other toxic symptomscaused by harm&e and harmaline might have important implications in regard to classifying the central action of thesealkaloids. The effectsof harmine have often beeniinked to an activity on the extrapyramidal system. The rather discouraging clinical application on the therapy of parkinsonism was basedon these theoretical considerations (cf. SOURKES, 1964, for references). On the other hand, the tremorigenic action of harmine has been used as a screeningdevise for drugs possessing antiparkinsonian activity (ZETLER, 1957). With the discovery of the inhibitory effectsof harmine on the monoamine oxidase (PLETSCHER et al.; 1959)it was thought that their central effects were dependent on this action. It should be noted, however, that other substanceshaving a similar anti-monoamine oxidase effects do not provoke the sametoxic syndrome. Therefore, the tremorigenic effect of these alkaloids must be attributed to other actions. Biochemical studies have indicated that ha&e causesa slighht increasein brain dopamine in the rat (HOLZER and HORNYKIEWICZ, 1959). According to POIRIER al. (1958)kveis of dopamine in the cat striatum were not modified et 1 hr after treatment with harmaline (IO-15 mg/kg); on the other hand, if treatment with harmaline was prolonged (5 mg/kg every 3 hr, for 24 hr) the dopamine content markedly diminished and the homovanillic acid wasreduced to very low levels. Theseauthors suggest that harmaline, in adequatedoses,has an effect both on the biosynthesisand destruction of dopamine. In other studies on animals (monkeys and cats) with unilateral lesions in the and (1966) have described a substantia nigra, POIRIER al. (1966) and SOUFKES POIRIER ef significant reduction of the striatum dopamine content, which in the monkey was accompanied by extrapyramidal-type disturbancesin the controlateral limbs. The administration of L-DOPA, although increasing the cerebral dopamine content, did not modify the motor

AJ.IMED,A. am

m,

A. G. (IS Harm BUTCRER, 1 L. decarboxy t2tusmw A.,

dcs ayptoph

350-354.

Qm,A.L.a.n GERSHON,s. U Ph7nQcoc GUNN. A. Cl J.

lwr. 38: !
GUNN,

J. A. a~

33-51. GUNN, J. A.

( uses, the in

Mcchanisr: HIMWICH, E H. In: Neuro.

HOLZJX, ant G.
der Ratte. HORNYKIEWICZ

HARA, S. and 1

syndrome caused thelesion.On the otherhand,in these by animals,harmineandharmaline

causedan intensetremor, appearingin thelimbs with the motor deficit. The effectof L-DOPA on the tremors causedby the two alkaloids wasnot studied by the aforementionedauthors.

329-333. E

Theresultsof this studyon an antagonistic effectof L-DOPA suggest an important that

part of the toxicity of harmine and harmaline is their influence on cerebral dopamine levels. It should benoted that L-DOPA alleviatestremors in the rabbit but not in the rat; preliminary trials carried out in our laboratory demonstrated that the antagonism exists also in the cat. This may be explained by the fact that in the rat much less dopamine is formed upon administrationof L-DOPA (BUTCHER ENGEL,1969). The role of dopamine in the and genesis of the extrapyramidal disturbances in man is well known (cf. HORNYRIEWICZ, 1966). According to this investigator, along with the anatomo-pathological alteration of the substantia nigra and of the striatum found in parkinsonism, there is a reduction in the dopamine content in these areas, which under normal conditions is high. In support of these theories stand the results obtained in clinical use of L-DOPA, which relieves the rigidity and

LEVY. andM J.
souris. In: PAOLm-rt, I ~%HER, A., sung des 2 Harmala-A hruea, L. J., !

mentdtnx bmnat, L. J..SI

and its me
Phmac. 4 B.E.and
X51-360.

-,

on rigidity

however, theataxia(but not thetremors)ofparkinsonianpatients(SOURKES, It seems, 1964).

that there is a certain difkrence between the effects of L-DOPA in human parkinsonism and

sm. E.B.,GYE
T. L. system. In: pJuaf-rI, R -, T. L. a
--,

-,

Archsint. I

the effectsprovoked by brain lesions in the experimental animal, since POUUER al. (1966 ez

report that L-DOPA was inefkctive in antagonizingthe extrapyramidal disturbances in

monkey with lesions of thesubstantia nigra. On the other hand, in laboratory animals it has been demonstrated that L-DOPA antagonizes depressive the effectsand the other symptomsof motor deficitcaused reserpine by (c,4RUSON al., 1957).Roos and !BEG(1964) et

b.med. A G. (195:

Harmine and related &arholines

23

e cause a the clonic 11s caused ifying the u1activity t therapy 1964, for ssed as a With the
mt et,al.,

report that dopamine is also effective on the tremors caused by this alkaloid in the rat. However,L-DOPA is without effect on the tremors causedby tremorine in the mouse (LEVY and MICHEL-BER, 1964). In conclusion, these results suggestthat the tremors induced by harmirie and harmaline may be caused by an effect on the extrapyramidal dopaminergic system.The intimate mechanismof this effect remains to be clarified, hearing in mind that at such a highly integrated level one can not dissociatethe dopaminergic from other interrelated systems,which certainly play a role in the various manifestations of extrapyramidai pathophysiology.
REFERENCES AH,-, A. and TAYLOR,N. R. W. (1959). The analysis of drug-induced tremorin mice. J. Ph4nnac. Br. 14: 350-354. BEER, A. G. (1939). Bertriige zur Pham~&oiogie desextrapyramidalen Systems.I. ~M~I-IXILKJNG: Wiikung Die des Harmins bei Katzen mit intaktem Nervcnsystem. Arch. eq. Path. Pharmak. 193: 377-392. BUTCHER, L. L. and ENGEL, I. (1969). Behavioural and biochemical effects of L-DOPA after peripheral decarboxylase inhibition. Bruin Res. 15: 233-242. CARSSON. A., LINDQVIST,IM. and MAGNUSWN, T. (1957). 3+Dihydroxyphenylalanine and Ehydroxyuyptophan as reserpine antagonists. ~Vu~ure. Land. 180: 1200. CXEN, A. L. and CHEN, K. K. (1939). Harmine. the alkaloid of Caapi. J. Pharm. Pharmnc. 12: 30-38. GERSHON, S. and LANG, W. J. (1962). A psycho-pharmacological study of some indole alkaloids. /frchs inl. Pharmacodyn. Thi. 135: 31-56. GUNN, I. A. (1930). The action of the hat-mine group of alkaloids on the uterus. Archs int. Pharmucodyn.
Thkr. 38: 507-521.

&ould be se effects hese alkat harmine 55, 1959). : modified meritwith markedly rs suggest mction of ms in the
scribed a

esaccom&ration ihemotor mmaline LDOPA LilOrS. nportant he levels. diminary so in the aedupon mein the
KIEWICZ, ration of

J. A. and MACKEITH,R. C. (1931). The pharmacological actions of harmol. J. Phurm. Phurmac. 4: 33-51. GIJNN, J. A. (1935). Relations between chemical constitution, pharmacological actions and therapeutic uses,in the harmine group of alkaloids. Archs int. Pharmacodyn. ThPr. SO: 379-396. HARA, S. and KAWAMORI, K. (1954). Pharmacological studies on the extrapyramidal system. Report N.2. Mechanism of theappearance tremordueto extrapyramidal of poisons. J. Phannac. 149-156. Jq. 3: HIMW~CH, E., VAN M~ER, W. G. and Owen& H. F. (1959). An EEG analysis of psychotomimetic drugs. H. In: Neuro-psychophurmaco/ogy (BRAD-, P. B.. DENIKER, P. and Rwouco-THOMAS, C., Eds.), pp. 329-333. Elsevier,Amsterdam. HOLZER. and HORNYKIFNKKZ G. (1959). ilher denDopamine-(Hydroxytyramine) StoBwechsei Gehim im tier Ratte. Arch. exp. Path. Pharmak. 237: 27-33. HORNYKIEUrICZ. 0. (1966). Dopamine (3-Hydrox~tynum nc) and brain function. Phurmuc. Rev. 18: 925-964.
GUNN.

LEVY. and J.

MICHEL-BER,

E. (1964). iantagonisme De vis+vis dedil%rents effects la trimorinechezles de

PAOLE~. TLETSCHER, A..

Correlation of Cenfral~y Acting Drugs (TRABUCCX& E., R. and CANAL. AN., Eds.),00.109-t 14. Pergamon Prms4z&os~ovalc Medical Press, Pniguc. B-RF. H., BLCHTOU),H. P. and G&, K. F. (1959). vber pharmakologische Bceinflusaus sung des Zentralnervensystems durch KurzwirkendeMonoaminoxydeschcmmer der Gruppe der Harmala-Alkaloide. Helv. physiol. pharmac. Acfa 17: 202-214. jOuriS. In: BiochemicaI and Neuropitys@&al
G., Boucx~~, R. and CARABM, S. (1966). Striatal

POIRER, L. J., SOUFXES, T. L., BOWER,

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