EXPERIMENTAL EVALUATION OF THE ANTIDEPRESSANT ANDNEUROLEPTIC ACTIVITY OF MAPROTILINE

J. J. BALSARA. N. V. NANDAL, V. R. MANE AND A. G. CHANDORKAR

Departmen t of Pharmacology.V.M. Medical College. Solapur- 413 003

(Received on April 14.1982)

Summary: Maprotiline. a tetracyclic antidepressant drug, was evaluated for antidepressant and neuro­

leptic activity. In antidepressant tests. maprotiline antagonized reserpine-induced ptosis in rats but,

unlike the tricyclic antidepressants. was found to antagonize methamphetamine stereotypy in rats,

to decrease the intensity of L-dopa induced behavioural syndrome in pargyline-pretreated mice and

to be ineffective in int~nsifying the 5-HTP induced behavioural 3yndrome. In neuroleptic tests. maproti­line was found to. antagonize apomorphine-induced cage climbing behaviour. induce catalepsy, inhibit

the CAR and traction respons". decrease the spontaneous motor activity and exploratory behaviour,

and to potentiate the hypnotic ~ffect of pentobarbitone. Our resu Its indicate that maprotiline exhibits

a profile of activity which resembles the neuroleptics and most probably exerts post-synaptic striatal DA

rec~ptor blocking activity.

Key words: maprotilinll antidepressant activitytraction response mllthamphetaminll st~reotypyapomorphine climbing behaviour

INTRODUCTION

neuroleptic activityreserpine-induced ptosis

conditioned avoidance response

Maprotiline hydrochloride (LUDIOMIL) is a new tetracyclic antidepressantdrug which exerts antidepressant activity by blocking the neuronal reuptake of nor­adrenaline (19, 20. 24). Recently Delini-Stula and Vassout (10), on the basis of theirobservation that maprotilfne antagonises apomorphine-induced contralateral turning in ratswith unifatE;ral 6-hydroxydopamine lesions of the substantia nigra. have suggested thatmaprotiline possesses postsynaptic dopamine (DA) receptor blocking activity. Wetherefore. decided to re-evnluate the antidepressant and neuroleptic activity of maprotiline.

MATERIALS AND METHODS

Male albino rats and mice. weighing between 100 to 200 g and 20 to 30 grespectively, were used for the study. They ware allowed food and water ad libitumupto the time of experimentation. Each animal was used once only. All observationswere made between 10.00 and 17.00 hr at 27 to 30°C in a noiseless, diffusely illumir,atedroom.

81, Batsara IIf at. July-September 1982Ind. J. Physiol. Pharmao.

The drugs used were maprotiLlle HCI (CiiJa-Gelgy). d!')s;rramine HCI (Ciba­3eigy). Imipram;~e HC! (Ciba-Geigy). clomipramine HCI (Ciba-G,cigy). chlorpromaz;ne,CI (May and Baker). oel tobarbitone Na (Abbott). pargyline HC! (Abbott), apomorphine-lCI (Sigma). l-dihydroxyphen';13Ianine (Roche), 5-hydroxytryptophan (Sigma), haloperi­:fol ('Serenace' injection, Searle). reserpine ('Serpasil' injection. Ciba) and methamphetamine-lCI ('M8thedrine' inject/en. Burroughs Wellcome) Maprotil'ine (MAP). desipramine:OMI). imipramine (IMI). clomipramine (CIMI), chlorpromazine (CPZ), pentobarbitone:PEN) an,j l1argylme (PAR) wem dissolved in distilled water while apomorphine (APO)/lias dissolved in distilled water containing 0.2 mg/rnl ascorbic acid Haloperidol (HAL).~serpine (RES) and methamphetamine (MAMP) injection solutions were diluted toequired strength with distilled water. L-dihydroxyphenylal8iline (L-DOPA) was dissolvedn minimal quantity of 0.5 N HCI, neutralised to pH 5 with sodium bicarbonate and

Hluted to required strength with distilled water while 5-hydroxytryptophan (5-HTP) waslissolved in physiological salin€. The doses refer to the forms mentioned. All drugs.lxcept 5- HTP, were administered intraperitoneally while 5-HTP was injected intravenouslyhrough the tail vein. In rats. all drugs except MAP. were injected in a volume of 0.2

711/100 9 aody weight While MAP was injected in a volume of 0.5 ml/l00 g body weightn mice, ail drugs were Injected in a volume of 0.1 ml/l0 g body weight. Control animalseceived requisite volume of vehicle intraperitoneally Unless otherwise stated groups)"f 10 animals per dose level of the drug were used.

The significance of differences between means was assessed by the Student'smpaired t-test while the EDso was computed by the method of Miller and Tainter

:21).

reserpine-induced ptosis in rats :

The animals received either MAP, OM!, IMI or distilled water (control group)oJjowed 1 hr later by RES. They were te~ted for ptosis 3 hr after RES injection. Ptosisn each eye was graded according to the method of Lapin (18) as follows: complete)tosis =4 points; more than half closed =3 points: half closed =2 points; less than half:Iosed =1 point; absence of ptosis =0 point. The mean response of both eyes was noted

rhe maximal mean response for ptosis was 4 points.

'v1ethamphetamine-induced stereotyped behaviour (58) in rats.-

The effect of MAP pretreatment on MAMP induced SB was studiea n'l'he method of Costall and Naylor (6). The animals received either MAP, IMI, DM!. HAL)r distilled IN'lt-3r (control group) followed 30 min later by MAMP. For observation

Antidepressant and Neuroleptic Activity of Maprot;line 186volume 26Number 3

the animals were placed In individual cages made of wire netting. measuring 30 em x 20 emand 20 em high. They were placed in the observation c2ges 30 min before drug treatmentto allow adaptation to the environment. The intensity of SB was assessed overa 30 sec observation period at 10 min intervals for 4 hr according to the follo­wing scoring system: 0: short lasting period of locomotor activity but no SB;1 : discontinuous sniffing. constant exploratory activity, 2 : continuous sniffing andsmall head movements, periodic exploratory activity; 3: continuous sniffing and small

head movements. discontinuous gnawing, biting or licking and very brief periods oflocomotor activity and 4 : continuous gnawing, biting or licking, flO exploratory acti·.lity

and occasional backward locomotion.

L-DOPA induced behavioural syndrome in mice

The method similar to that of Ross et al. (28) was followed. The animals receivedPAR (20 mg/kg) followed 4 hr later by either MAP, DMI. IMI or distilled water (controlgroup) and followed 1 hr later by L-DOPA injection. Following the injection of L-DOPAthe animals were observed for 1 hr for the presence of following signs: 1) piloerection.2) salivation. 3) exophthalmos, 4) Straub tail. 5) tremors, 6):lxcitation and increased

motor activity and 7) abduction and extension of the hind limbs. The scoring methodfollowed was similar to that of Rubin et al. (29). Each mouse was given one point foreach sign and the maximum score for a mouse was 7 points.

5- HTP- induced behavioural syndrome in mice:

The method similar to that of Hyttel and Fjalland (16) was followed. The animalsreceived either MAP. CIMI or distilled water (control group) followed 30 min later by5-HTP. In the consecutive 15 min the animals were observed for the presence of thefollowing signs: 1) head twitches, 2) excitation, 3) tremor and 4) abduction andextension of the hind limbs. Each animal was given one point for each sign and themaximum score for a mouse was 4 points.

Apomorphine-induced cage climbing behaviour in miee:

Effect of MAP pretreatment on APO-induced climbing behaviour was studied bythe method of Costa II et al. (7). The animals received either MAP, HAL or distilled water(control group) followed 30 min later by APO. For observation the animals were placedin individual Perspex cages measuring 27 em x 20 em and 15 em high. One of the verticalfaces was wire netted with 1 em'l wire mesh. made of wire 2 mm in diameter. for ventila-

186 Balsara 81 8/. July-September 1982Ind. J. Physiol. Pharmac.

tion and to allow climbing. M ice were placed in the observation cages 30 min before drugtreatment to allow adaptation to the environment. The animals were individually testedfor climbing bahaviour taking 'the percentage of time spent climbing during the 30 minperiod after the first climb' as a measure of climbing ('climbing index'). Further. themaximum time (in min) spent in a single climb throughout the duration of the apomor­phine effect was also recorded.

Conditioned avoidance response (CAR) in rats:

The effect on CAR was studied in trained rats by the technique of Cook and Weidley(4). Both control and drug-treated groups were tested for CAR 30 min after the injec­tion. The drug effect on CAR was expressed as the percentage of animals which failed

to climb the pole on hearing the buzzer but did climb the pole in response to the electricshock.

Traction response in mice :

The control and drug-treated groups were tested for the traction response by themethod of Courvoisier et al. (8) at 60 mrn time interval after the injection. The responsewas said to be inhibited when the animal was unable to draw itself up to touch the wirewithin 5 sec of placement.

Induction of catalepsy in mice:

The animals were tested for catalepsy 60 min after drug injection by placing bothfront paws on a wooden block 4 cm high and were considered cataleptic if they maintainedthis posture for atleast 30 sec (1).

Spontaneous motor activity (SMA) in rats:

The technique described by Vad et al. (32) was used for recording SMA. Onlyone animal was placed in the activity cage at a time. After waiting for 10 min to allowthe initial excitement to pass away, the vertical movements of the animal were recordedby the lever of the Marey's tambour on a moving kymograph for the next 30 min. Theanimal was then injected drug or distilled water and was kept aside for 20 min. It wasthen placed in the activity cage and after 10 min interval. the record was again made for30 min.

lume 26Number 3

Exploratory behaviour of mice :

Antidepressant a"a Neuroleptic Activity of Ivlaprutiline 187

Effect 011 exploratory beha'Jiour was studied by the method of Shi!lito (30). One,:ontrol group was always used simultaneously with groups to which various doses ofdrugs had been admi~·ljsered. Mice were placed one at a time on the left hand corneruf a wooden board measuring 61 x 61cm onto which 12 tunnels 7.5 cm long and 4 cm indiameter were fixed arranged in a symmetrical pattern. The tunnels were numbered.Drugs were given 30 min bEfore the observations, while the control group received distilledwater. Each mouse was watched for 5 min after it was placed on the board. The numberof different tunnels entered in the first minute. the total number of tunnels entered a~

well as the total number of different tunnels entered during the 5 min observation periodby the animal was noted. The experiments were conducted at the same time each after­noon.

Pentobarbitone induced sleep in mice:

The animals received the hypnotic (40 mg/kg) or subhypnotic (20 mg/kg) doseof PEN 30 min after receiving distilled water (control group) or MAP. The time of lossand recovery of righting reflex was used to determine the duration of sleep. The meapsleeping time with standard error. was determined for each group.

RESULTS

The doses of antidepressants and neuroleptics used in the present study had noeffect on the motor co-ordination. muscle tone or righting reflex of the animals.

i. Effect on reserpine-induced ptosis in rats :

MAP, OMI and IMI significantly (P<0.001) anagonized reserpine-induced ptOSIS(Table I). While OMI and IMI were equally effective. MAP was significantly (P<0.01)ress effective than either OMlor IMI in antagonizing reserpine-induced potosis (Table I).

2. Effect on methamphetamine-induced S8 in rats :

Pretreatment with 10 mg/kg dose of IMI and OMI significantly increased heintenSIty of MAMP stereotypy while MAP (10 and 20 mg/kg) like HAL (0.25 mg/kg) -;g­nifica tly decreased the intensity of MAMP stereotypy (Table II).

rABLF

"up Trearmemct se mg/kg

1. Vehicle +RES (30)

2. MAP 20 +RES I, (101

3. DMI 20 +RES (, (10)

4. IMI 20 +RES 5 (10)

'P<O.001; "P<O 01. "'P>O.O"

Effect of maprotillne. desipramine and ,mipramine 0'1

"('serpine-induced Ptosis; 11 rills,

ProSIS scoreMean±S.E.M

3. 72±0.()<i

2., 12.±O 24

1.10±012

July·-September 1982indo J. Physiol Phllrmac.

S rarisrica/ly comparedgroup,

2 vS. l'

2 vs. 3"

3 vs. l'

3 V5. 4···4 V'S. 1­

4 VS. 2"

Numerals follO\'ving the drugs indiC',L> ltle" rioSe,S (mg/kg).

=i\lures in pareC1theslo jndjr~l', ilL number of animo!.,.

E';wet. of mJprotiline. imipramine. deslpramlfle a;;j h310pendQI ()methamplw'arr,ine-induced stereot\'ped bEfhaviour In rats.

..iUjdy Tr-98trnenl.' (Jose mg/kg

'l. MAMP 4

2. IMI 10 + MAMP 4

3. OMI 10 + MAMP 4

4, MAP 10 + MAMP 4

5. MAP 20 + MAMP 4

6. HAL 0.25 + MAMP 4

,. 1- MAMP 6"2. MAP 10 + IViAMP 6

3. MAP 20 + MAMP 6

4. HAL 0.25 + MA'~1P l:'

IntenSity scorelVIean±S.E.M.

2.4±O 16

3.4±O.16'

3.2±013'

1.5±O.16'

o 7±O.15"

°3.6±O.162.7±O.15·

1.6±O.15"

0.7±0.15"

F<O.01 ", <0.001 . i'.;umerals follO",,'ing the drugs indic~t" til,,,, doses (my/kg).

3. Effect on L-·DOPA-Induced behavioural sync/rome 1/1 mice

IMi c;i1d OMI, in doses of 10 and 20 mg/kg, were equallv effective ill IntensifYlllq.hG L-DOPA Induced behavioural syrxirome while MAP i;, closes of 10 and 20 mg/kg:ecreasod tho intenSity of L-DOPA inducod behavioural ;;vndrorne iii a dosEJ-daperJdentnanner (Table III),

V:llume 2~

Number 3AntidepressaN and r'!"uroleptic Activity ')f Mepr<>lili'1c 189

TABLE III Effect of maprotiline. imipramine and desipramine on L-DOPi'.induced behavioural syndrome in mice.

Study Treatment dose mq/kg

1. L-DOPA 100

2. IvIAP 10 + L-DOPA 100

3. MAP 20 + L-DOPA 100

II 1. L-DOPA 100

2. IMI 10 + L-DOPA 100

3. livil 20 + L-DOPA 100

IntensIty scoreMean ±SEM

4.6±0.16

3 O±O.OO·

2 7±0.15·

4.5±0.16

6.0±O.00·

7. O±O. 00·

III L-DOPA 100

2. D~!i1 10 + L-DOPi' 100

3. DMI 20 + L·DOPA 100

47±0.15

6.2±O.13·

7.0±0 00·--_._---_..._-------- ----

·P<O.OOl. Numerills following the drugs indicate their doses (mg/kg)

'+ Eflecl on 5-HTP inducec! behavioural syndrome in mice .

MAP (5-20 mg/kg) was Iileffectlve in ifltellslfyi"\l t;,e 5-HTP induc;~d Oell.l'vIOL/rd '

sy::drume while elMI (5-20 mg/kg) did intensify it (Table IV)

TABLE IV : Effcct of maprotiline and clomipramine on 5-HTP induced behavioural syndrome ,n mice.

Study Treatment dose mg/kg

5-HTP 100

2. MAP 5 + 5-HTP 100

3. MAP :0 + 5-HTP 100

'.~ MAP 20 + 5-HTP 100

II 1. 5-HTP 100

2. CIMI 5 + 5·HTP 100

3. CIMI 10 -+- 5-HTP 100

4. eiMI 20 + 5-HTP 100

·P<O.Ol; ··P<O.OO1.

Intensity scoreMean ± S.E.M.

1.5±0.16

1.6±Ol

.7±O 15

4±O 10

,.±O I"

2 7±O.15·

3. 7±0. 15··

4.0±0.00··

Numerals following the drugs indicate their doses (mg/kg).

5 Effect Of} apomorphine-induced climbmg behaviour //I mice.

Pretreatment with MAP (2.5-10 rng/kg) and HAL (0.05 and 0.1 mg/kg) IIrtl~u-

nized APO (1 mg/kg)-induced climhing behaviour Crable 'J).

190 Balsars et &1. J uty-SepttllTlber 1982Od. J. Physio!. Pharmac.

TABLE V : Effect of ma~ro\l"ne ~nd haloperid lOr, apomorphlne-Ir,duted caQe climbing behavioClr in mice.

Study Trearment dose mg/kg Climbing index ('Jb) Maximum rime (min)Mean±SEM. Mean ± S.E.M.

APO 1 744±2.2 12.2*0.9

2. MAP 1 .25 + APO 1 n.7±29 11.9±07

3 MAP 2.50 + APO ! 44.2±2. r 6.4*0.6'

4. MAP 5.00 + APO 1 20.4±3 2" 2.7:i:1.1"

MAP 10.0 + APO O.O±OO 0.0*0.0

I; i. APO 1 n.9±2.7 12.1:i:07

~ HAL 0 05 + APO 1 7.5±3.2*' 1.1*0.9"

2- HAL 0.10 + APO i O.O±OO 0.0:i:01O--_.

·P<O.Ol. "p< 0.00". Numorals following the drugs indicate their doses (mg/kg).

t; Effect on CAR in Iii I.':

The EO,o of MAP for inhibiting the CAR was 14.13 mg ± 0.44 whilE; thoseof CPZ and HAL were 4.07 mg ± 0.14 and 0.38 mg ± 0.02 respectively. OM I upto40 mg/kg body weight was inactive in inhibiting thE- CAR.

Influence on traction response /{i mice

The EO,o of MAP for inhibiting the traction response was 18.75 mg ± 0.64 whilet ose of CPZ and HAL were 5.62 mg ± 0.31 and 0.69 mg ± 0.04 respectively. OM Iarid IMI upto 40 mg/kg body weight were inactive in inhibiting the traction response.

f Induction of catalepsy in mice :

MAP at 2.5 mg/kg dose did not induce catalepsy while at doses of 5 and 10 mg/kgit induced catalepsy in 50% and 100% of the animals respectively. OMI and IMI upto20 mg/kg dose did !lot induce catalepsy while HAL (0.25 mg/kg) induced catalepsy in100% of the animals tested.

!1. Effect on spontaneous motor activity (SMA) in rats

MAP at a dose of 2.5 mg/kg did not affect the SMA. However. an increase indose to 5 mg/kg slightlY. reduced the SMA and fI further increase in do e to 10 mg/kg

Volume 20Number 3

Antidepressant and Neuroleptic Activity of Meprotiline 191

reduced the SMA markedly. DMI had no effect on SMA in the dose range (2.5-10mg/kg) studied. CPZ at a dose of 2 mg/kg reduced the SMA markedly.

10. Effect on exploratory behaviuur of mice:

MAP (2.5 mg/kg) and DM I (2.5- 10 mg/kg) did not significantly affect theexploratory behaviour. However, MAP (5 and 10 mg/kg) and CPZ (2 mg/kg) did sig­nificantly decrease the exploratory behaviour of mice. The number of different tunnelsentered during the first min and during the 5 min of observation period and the totalnumber of tunnels entered during the 5 min period was significantly lower than that oftheir respective control group (Table VI).

TI\BLE VI : Effect of m"protiline, cesipremine and chlorpromazine on the exploratory behaviour of mice.

Study Treatment Total number of Toeal number of Toeal number ofdose mg/kg different eunnels different tunnels tunnels entered

entered during ehe entered during ehe during ehe 5 minfirst min 5 min pef/od period (mean±S.E.M.)

(mean±S.E.M.) (mean±S.E.M.)

1. Control 2.1±0.10 7.2±0.44 16.2±0.89

2. MAP 2.5 2.0±0.00 7.1±0.39 15.9±0.97

1. Control 22±0.13 7 .O±O. 28 16.1±0.77

2. OMI 2.5 2.2±0.13 7.2±0.42 16.0±0.74

" 1. Control 21±0.10 7.4±0.37 15.9±0.92

2. MAP 5 1.2±0.13· 5.7±0.29· 12.4±O.n'1. Control 2.2±0.13 7.3±0.41 15.7±0.64

2. OMI5 2.0±0.OO 71 ±O 37 15.8±0.75

1:1 1. Control 2.1±0.10 7.4±0.42 16.4±0.77

2. MAP 10 0.9±0.10· 4.2±024· 10.7±O.69·

1. Control 2.0±O.OO 7. 2±O. 36 162±O.75

2. OMI 10 1.8±0.13 7.3±0.38 i 6.1±0. 64

tV 1. Control 2.2±0 13 7.2±O43 16. 2±O. 77

2. CPZ 2 o 7±O 15' 37±O22' I02±065'

·Sigr.ifk~ant in relation to corresponding controls (p<O.05 or less).

Numerdls following the drugs indicate their dos~s (mg/kg).

j 97 BalSbra et al.

11. Effect on pentobarbitone sleep in mice :

July-September 1982Ind. J. Physiol Pharmac.

Pretreatment with MAP (10 and 20 mgHg) not only significantly prolonged pen­tobarbitone (40 mg/kg) sleeping time but also induced sleep in mice treated with a sub-

hypnotic (20 mg/kg) dose of pentobarbitor,e (Table VII).

TABLE VII : Effed oi maprotiiine pretreatment ,n mice treated with a hypnotic and subhypnotic dose of pentobarbitone.

Group Dose and roure n Number of animals Sleeping time in min(mgikg, ip) which slept Mean±S.E.M.

PE~J 40 ZO ZO 47.4±Z.79

II MAP 10+ PEN 40 10 10 74. 9±3. 2Z·

MAP 20+PEN 40 10 10 92.4±3.4Z·

III PEN 20 40 0 0

IV MAP lO~-PEN 20 20 18·· 9. Z±0.74

MAP 20+PEN 20 ZO ZO·· 12 7±0 52

n= Number of animals used. Numerals following the drugs indicate their doses (mg/kg).

·The statistical significance of differences between means was calculated by Student's unpaired t-test. Group II iscompared 'Nith Group /: P<O.001.

··R~ults andlvseri hy Fisher's ex?ct ~;t. Group IV is compered with Group III; P<O.OO1.

DISCUSSION

Tile antidepressar.t activity of a drug is convefltiona Ily evaluated by testing itsability to ant3gonize or reverse reserpine- induced behavioural and autonomic effects.

potemiate amphetamine responses, or the signs of excitation induced byL- DOPA in mice pretreated with a MAO inhibitor or the 5-HTP induced behaviouralsyndrome. A drug is evaluated for neuroleptic activity by testing its ability to antagonizemethamphetamine or apomorphine stereotypy, inhibit the CAR and traction response.decrease the SMA and exploratory behaviour. induce the catalepsy and potentiate.

the hypnotic effect of barbiturates (9. 14).

Our observation that maprotiline, though effective in anatagonlzlng reserpine­induced ptosis, was however, less effective than imipramine and desipramine. concurswith the findings reported by Baltzer et al. (2) and Benesova et al. (3).

Methamphetamine-induced SB results from activation of postsynaptic striatal andmesolimbic DA receptors by the released DA and is antagonized by postsynaptic DA recep­

tor blockers like haloperidol (27, 33). Our observation that maprotiline. unlike imipramine

--

Volume 26Number 3

Antidepressant and Neuroleptic Activity of Meprot'lin~ 193

and desipramine but like haloperidol. decreased the intensity of methamphetamine stereo­typy can be readily explained on the basis of the recent report of Delini-StuJa and Vassout(10) that maprotiJine possesses postsynaptic striatal DA receptor blocking activity. Furthermore, our observation that maprotiline like haloperidol antagonized apomorphine-inducedclimbing behaviour which occurs as a result of direct stimulation of postsynaptic striatalDA receptors by apomorphine and is antagonized by DA receptor blockers like haloperidol(7,25), supports the contention of Delini-Stula and Vassout (10), that maprotiline posses­ses postsynaptic striata I DA receptor blocl<ing activity, and helps to explain the anatagonismof methamphetamine stereotypy by maprotiline. Our finding that maprotiline antagonizesapomorphine-induced stereotyped climbing behaviour in mice confirms the observationof Olpe (23) Similarly our observation that imipramine and desipramine increase theintensity of methamphetamine stereotypy concurs with that of Simon and Lwoff (31).

In the past. potentiation of the L-dopa induced behavioural syndrome by thetricyclic antidepressants was related to their ability to block the neurona I reuptake of nor­adrenaline (11). However, recently it has been reported that administration of L-dopapredominantly increases the brain DA levels (13) and the potentiation of L-dopa inducedbehavioura I syndrome by the anti-depressants is now co-related with their ability to inhibitthe neuronal reuptGke of DA (9, 22, 26). Though maprotiline in high doses inhibits theneuronal reuptake of DA (26), it is likely that at the doses used in the present study itspostsynaptic DA receptor blocking activity might have manifested with resultant antago­nism of the L-dopa-·induced behavioural syndrome.

The potentiation of 5-HTP induced behavioural syndrome by clomipramine isattributed to its ability to inhibit the neuronal reuptake of 5-HT (16. 28). As reported(16. 28), clomipramine did poter,tiate the 5-HTP induced behavioural syndrome whilemaprotiline proved ineffective. Our finding with maprotifine confirms the report of Maitreet al. (20) that maprotiline is practically ineffective in inhibiting the neuronal reupiake

of 5-HT.CAR is a DA-mediated response (5) and the inhibition of CAR by neuroleptics

like haloperidol. has been attributed to blockade of post-synaptic striatal DA receptors(17). Catalepsy is attributed to a lack of DA at postsynaptic striatal DA receptors andneuroleptics induce catalepsy by blocking postsynaptic striatal DA receptors (15). Ourfindings. on maprotiline antagonizing methamphetamine stereotypy and apomorphine­induced climbing behaviour, taken together with those of Olpe (23) and Delini-Stulaand Vassout (10). suggest that maprotiline exerts postsynaptic DA receptor blocking acti­vity. Thus it was expected to. and indeed was found to inhibit CAR in rats and to inducecatalepsy in mice. Further, the traction response in mice and the SMA and exploratorybehaviour of rodents. which is selectively inhibited by the DA receptor blocker~ (8, 14).was also inhibited by maprotiline.

194 Bals~rE' et al. July-September 1982Ind. J. Physiol. Pharmac.

The prolongation of pentobarbitone sleeping time by maorotiline is probably notmec'jated through interference with th9 metabolism of barbiturate as it W2~ elso found toinduce sleep in mice treated with a subhypnotic dose of pentobarbitone. We suggestthat maprotiline, by blocking the postsynaptic DA receptors (10), decreases the activityof the nigrostriatal and mesolimbic DA- ergic systems involved in cortical activationand behavioural arousal (12) and thus sensitizes the CNS to the depressant action ofpentobarbitone with resultant potentiation of pentobarbitone hypnosis.

In conclusion, on the basis of our results, we suggest that maprotiline possesses

postsynaptic striatal DA receptor blocking activity and exhibits activity profile resembling

the neuroleptics.

ACKNOWLEDGEMENTS

We are grateful to Ciba-Geigy Ltd (Switzerland), May and Baker (India), Abbott(USA) and Roche (India) for their generous gift of the drugs used in the present study,

to Mr. S.S. Chavan and Mrs. S.G. Moholkar for technical assistance and to the Dean,V.M. Medicai College, Solapul', for providing facilities.

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