Interaction Between N-Methyl-D-Aspartate Recepto'r Antagonists and Imipramine in Shock-Induced Depression
Indian Journal of Experimental Biology Vol. 37, October 1999, pp. 952-958
Interaction between N-methyl-D-aspartate recepto'r antagonists and imipramine in shock-induced depression
H K Chaturvedi*, Dinesh Chandra & J S Bapna** Department of Pharmacology, Maula!1a Azad Medical Co ll ege, New Delhi 110 002. India
Received 24 Febrtw/), 1999; revised 15 July 1999
In the past few years, literature has accumulated describing manifestation of seizures following administration of certain antidepressants. Such reports are of particular importance because depress ion is a freq uent psychiatric prob lcm associatcd with epilepsy. Therefore, in the view of the fact t.hat NMDA receptor ant ago ni sts have been rcportcd to reduce behavioural deficits and have been shown to be antico nvu lsant. it was considered imperative to stud y thcir antidcpressant d lcct lI si ng shock-induced depression mod el in mi ce. Presentation of inescapable foot shock significa nt ly reduced
The possibility th at drugs that block N-methyl Therefore, in view of the fac t that J\MDA receptor D-aspartate (NMDA) receptors have some therapeutic antagonists have been reported to reduce behavioural benefit is being investigated in detail. It has been deficits lO and have been shown to be devo id of shown that over-activation of NMDA receptors may convu I sant actI. v.i ty 11 -1.1. It was consl' de re d'Imp erati. ve l 2 be involved in several human neuropathologies . . to study the ant idepressant effect of NM DA receptor The hi gh affinity of the NMDA receptor antagonists antagonists. for their receptors, rapid CNS penetration, long duration of action and uncompetetive antagonism Materials and Methods makes these compounds attracti ve and potential Animals-Adult alb in o mI ce of eith er sex , candidates for clinical trial s. Of these MK 80 I has weighing 25±5g, rai sed in the Central Animal Facility been widely studied and is a potent anticonvulsant in of Maulana Azad Med ical College. were used in the a range of animal seizure models:1.4. Indeed MK 80 I stud y. They were maintained at a 12 hr day/ni ght has been tested as anticonvulsant in human cli nical cycle, and were acclimatized to the laboratory trials as an add-on drug for patients with refractory conditions 24 hr before testing and had free access ro 5 complex partial seizures . food and water. The animal s were drawn at rand om Literature is avai lable describing manifestation of for test and control groups_ The stud y was conducted seizures following administration of certain between 0800 and 1200 hrs . 6 R antidepressants ,7. Aggarwal et al. compared a few Drugs-The dru gs used in the present study were antidepressants with the epi leptogeni c response in imipramine hydrochloride (Torrent harmaceulicals laboratory situations. Such reports are of particular Ltd.), MK 80 I (Merck Research Laborarories), importance because depression IS a freq uent ketamine hydroc hl oride (Themis Chemica ls Ltd. ), psychiatric problem associated with ep ileps/. prazosin hydrochloride (S igma Chemical Co.), haloperidol (Searle India Ltd.), and kctan serin Present address: tartarate (Janssen Pharmaceutica). All th e drugs were *1. K. Drugs & Pharmaceu ti cals Ltd .. Milap Niketan. 8 Bahadur freshly prepared In saline and we re injected Shah Zafar Marg, New Delhi 110002, Indi a intraperitoneally in a volume of 5mllkg_ Fax: 91-1 1-3350993; Emai l h-chaturvedi @hotmai l.com **I nstitute of Human Behaviour & Allied Sciences, Dilshad Wh ile imipramine, MK 80 J and ketamine were Garden, Delhi 110095, India administered 30 min before; prazosi n, haloperidoi and CHATURVEDI e/ al.: NMDA RECEPTOR ANTAGONISTS & ANTIDEPRESSANT EFFECT 953
ketanserin were administered 60 min before bcrivincr b the last 4 min of the 6 min test period was the shock. Control animals received 0.9% saline. recorded. Shock-induced depressioll-The method was adop Statistical analysis- The results are ex pressed as I4 16 ted as earlier - • mean ± standard error of mean. Statistical an alys is of data was performed usin g Student 's t-test, one way (i) Delivery of Shock: Four mice were pl aced on a analysis of variance (ANOY A) foll owed by either grid floor (26x26 cm) made of stainless steel rods Dunnet's test or Tukey's multi ple range test, wherever (2 mm diameter, pl aced I cm apart) connected in appropriate. series. The animals were prevented from escaping or coming in contact with each other by in verting Results separate glass beakers over all four of them. The Inescapabl e foot shock for hr significan tly grid fl oor was connected to a programmable reduced ambul at ion and rearin g wh en compared to no electri c shock ge nerator (Medicare Research shock control in the OFT and in creased immobility Stimulator SB 44, Recorders and Medi care duration (P ment, whereas the effects of MK 80 J and ketamine (4 mglkg). Though, ~etanserin per se failed to modify remained unaltered. The effect of the combinations of the effect of inescapable foot shock, it antagonised imipramine with either of the NMDA antagonists on the effect of imipramine on immobili ty duration. ambulation was attenuated by prazosi n pretreatment. Ketanserin failed to modify th e effect of either of the Table 5 gives the modification of the effect of NMDA antagonists. The effect of combination of imipramine and NMDA antagonists by ketanserin imipramine with both, MK 80 I and ketamine, on Table 2-Effect of imipramine, MK 80 I and ketamine on shock-induced changes in behaviour in mice Treatment (mg/kg) Off FST Ambulation Rearing Immobilit y (,ee) Control 83.62 ± 4.60 10.25 ± 1.75 152.12 ± 7.D Imi pramine (8) 87.50 ± 4.50 10.25±1.14 150.25 ± 4 .7X Imipramine ( 16) 106.75 ± 5.1 3** 12.25 ± 1.58 129.75 ± 4 .70'" Imipramine (32) 129.12±5.01** 15. 12 ± 1. 66 107. 25 ± 5.46** Control 78.62 ± 4.98 10.25 ± 2. 33 155.00 ± ."45 MK 80 1 (0.05) 94.12 ± 6.46 13.00 ± 1.08 141U)O ± 4. T'o MK 801 (0. 1) 112.62 ± 4.67** 18.25 ± 1.54** 122.25 ± 5. )l)*':' MK 80 1 (0.2) 144.87 ± 6.04** 27.12±1.93** 77.00 ± 4.79"': Control 81.70±5.6 1 10. 10 ±1.75 155.20 ± 5.37 Ketamine (2.5) 86.37±5.15 14.37 ± 1. 52 150.H7 ± 5.22 Ketamine (5) 100.25 ± 4.88** 20.75 ± 2.0 1** 132.62 ± 4 58* Ketamine ( 10) 124.00 ± 6.74** 29.25 ± 2.44** 102.62 ± 4. 16** OFf=open fi eld test, FST=forced swimming test. Resul ts are given as mean ± SE (n=IO). While the Off val ues represenr number of epi sodes in 5 min, th e FST values denote duration of immobility in last 4 min of a 6 min test. *P<0.05 and *·~ P Table 3-Moditicati on of the effect of imipramine, M K 80 I and ketamine by haloperidol on shock-in duced changes In behaviour in mice Treatment (mg/kg) Off FST Ambulation Rearing Immobility (sec) Control 87.87 ± 5.24 12.00 ± 1.32 15H.75 ± 6.54 Haloperidol (0.1) 82.50 ± 6.25 10.00 ± 1. 87 160.75 ± 7.44 Imipramine (16) 11 2.37 ± 5.84** 12.25 ± 1.5X 132.62 ±3XF Haloperidol (0. 1)+ Imipramine (16) 113.37 ± 5.79**" 11.75 ± 1.99 126.75 ± 4.6 1**" MK 801 (0.1) 11 8.38 ± 3.75** 18 .25 ± 1.54* 12 2.25 ± 5.59*':' Haloperidol (0.1 )+M K 80 I (0. I ) 94.37±5.91" 11.75 ± 1. 98" 15 0.00 ± 7.12' Ketamine (5) 108.75 ± 6.07* 20.80 ± 1.39** 123.75 ± 5.27** Haloperidol (0. 1) +Ketamine (5) 9 1.75 ± 5.39" I 1.1 4 ± 1. I 0" 151 .42±7.65" Imipramine ( 16)+MK 80 1 (0. 1) 136.50 ± 3.26**1x: 27. 12± 1.08**1><: 89.75 ± 5.77 **1.... Imipramine ( 16)+Ketamine (5) 136.33 ± 4.4 7 * *Ix: 29.16 ±· 1.52**'" 95.88 ± 5.2X **hc Haloperidol (0.1 )+Imipramin e ( 16 )+M K 801 (0. 1) 115.75 ± 3.92**"" 14.00 ± 2.18.1 126.50 ± 5.49**,,,1 Halo peridol (0.1 )+Imipramine ( 16)+Ketamine (5) 111 .25 ± 5.88**,,1 13.25 ± 1.98 r 121un :± 4.80**"1 OFf=open field test, FST=forced swimming test. Results are given as mean ± SE (n=8- 10). While the Off val ues re present number of episodes in 5 min, the FST values denote duration of immohi lit y in last 4 mi n of a 6 min test. *P I 7 1 immobility duration was attenuated by ketanserin wide variety of experimental situations - '} Similarly, pretreatment. in the present study, inescapable foot shock produced a depression of both ambulation and rearing Discussion behaviour of mice in the OFf and increased the Exposure to uncontrollable stress is well known to duration of immobility in the FST. Though. our cause physiological and behavioural alterations in a findings are in agreement with those of earli er Table 4-Moditication of the effect of imipramine, MK 80 I and ketamine by prazosin on the shock-induced changes in behaviour in mice Treatment OFT FST (mg/kg) Ambul ati on Rearin g Im mobili lY (sec) Co nt rol 88.00 ±7.64 11.50 ± 1.88 153.fi2 ± 6.1 3 Prazosin (3) 89.87 ± 5.05 12.50 ± 1.62 154.62 ± 7.<)() Imipramine (16) 11 5.50 ± 5.67 * 10.3 1 ± 1.48 126.88 ± 4.8 1* Prazosin (3)+Imipramine ( 16) 94.87 ± 6.331> 12.50 ± 2.27 12<).fi2 ± 5.49 "" MK801(0.1) 112.62 ± 4.67* 17.69 ± 1. 20* 124.50 ± 4.44"'* Prazosin (3)+MK 80 1 (0.1) 115.25 ± 5.76*" 18. 12±1 .63 *" I I X.OO ± 5.61"' *·1 Ketamine (5) 11 3.00 ± 4.73** 20.65 ± 1.46 ** 133. 38 ± 5.<):F Prazosin (3)+Ketamine (5) 115.38 ± 5.14**" 18.00 ± 1. 63 *" I n .87 ± 6. 1 1**" Imipramine (l6)+MK 80 I (0.1) 141.87 ± 4.39* *oc 26. 10 ± 1.32 **1>" 83. 50 ± 6.03*"lx· Imipramine (I6)+Ketamine (5) 136.75 ± 5.45**hc 28 .21 ± 1.20**1>.: 8<) .88 ± 7.4 1M ix' Prazosin (3)+Imipramine (16)+M K 80 1 (0. 1) 128 .25 ± 6.34**" 26.62 ± 2.0 1**" 93.25 ± 7.". I **" Prazosin (3)+Imipramine (16)+Ketamine (5) 114.12 ± 4.47**,,1" 27 .75 ± 1.58*"" 100.25 ± 6. 17"00"" OFT=open field test. FST=forced swimming test. Results are given as mean ± SE (n=S- 10) . While the OFT val ues represenl numbcr of episodes in 5 min , the FST values denote durati on of immobility in last 4 min of a 6 min test. *1'<0.05 and ** Pdl.O I vs co ntrol usi ng ANOYA and Dunnett's test. Other comparisons: a vs Prazosin (3); I> vs Imipramine (16);" vs MK XO I (0. 1): d vs Imipraminc (16)+ MK 801 (0.1); C vs Ketamin e (5) and I" vs Imipramine (I6)+Ketamine (5) usin g ANOY A and Tukey's multipl e range res t at 5% level. Control (shocked) animals were treated with saline. Table 5-Modification of th e effec t of imipramin e, MK SOI and ket amine by ketanserin on shock-i ndu ced changes in hehaviour in mi ce Treatment OFT FST (mg/kg) Ambulation Rearin g Iml1lohilit y (sec) Control ')0.12 ± 6.3 8 10.50 ± 2. 17 156.:\7 ± 6.60 Ketanserin (4) 89.22 ± 5.03 10.44± 1.4 1 15 2.77 ± 7.".4 Imipramine (16) 11 8.25 ± 5.53 ** 11.28 ± 1.26 124.87 ± 4.89"* Ketanserin (4)+Imipramine (16) 11 8.50 ± 5.65 **" 12.20 ± 2.0X 15 7.90 ± 6.07" MK 801 (0.1) 119.75 ± 4.S5** 20.81 ± 1.3 2* I 14.87 ± 4.85 ** Ketanserin (4)+MK 801 (0.1 ) 117.88 ± 5.69**" 19.88 ± 2.01 *" 121.77 ± 4.08 **" Ketamine (5) 109.75 ±4.99** 19.X 1 ± 1.67 * 126.50 :t 5.80"" Ket anserin (4)+ Ketamin e (5) 11 2.00 ± 6.44**" IS .87 ± 2.9 3*" 1 19.62 ± 5.55 **" Imipramine ( 16)+MK 80 I (0.1) 140.25 ± 5.49**oc 2S. 26 ± 1.40 **1>0 79 .". 8 ± .+ .4O* *'K Imi pramine ( 16)+Ketamine (5 ) 138.85 ± 5.37**hc 27.50 ± /.39** 1,.- 84.25 ± 6.07 *,,1,' Ket anserin (4)+Imipramin e (16)+M K 80 1 (0.1) 142 .30 ± 4.67 **" 29.00 ± 3.08 **" 127 .X8±5.78**"d Ketanserin (4)+Imipramin e (16)+Ketamine (5) 134.37 ± 4.8 1**" 28.87 ± 1.4 1*" " I 1X.25 ± :'l.4 3'i'*'" OFT=open field test, FST=forced swimmi ng test. Results are given as mean ± SE (n=8- 10 ). Whil e the OFT va lu es represent number of episodes in 5 min. the FST values denOle duration of immobility in last 4 min of a 6 min test. *P<0.05 and ** P ANOY A and Dunnett's test. Other compari so ns: a vs Ketanseri n (4): I> vs Imipramine (16): C vs MK 80 I (0. i 1: d vs Imipramine ( 16)+M K 801 (0.1): C vs Ket amine (5) and I vs Imipramin e (16)+Ketamine (5) usin g ANOY A and Tuk e)L's multiple ran ge les t at 5% level. Control (shocked) animals were treated with saline. INDIAN J EX'p BIOL. OCTOBER 1999 workersI5.20.21, they differed from those of Plaznik et Behavioural depression following an ac ure stressor al. 15, who reported a weaker effect of inescapable foot might result from tryptaminergic mechanisms37 or shoc k on the FST than in the OFT. It has been may be attributed to a motor acti vation deficit demonstrated that the behavioural disturbances stemming from reduction of norepinephrine (NE)3H. induced by inescapable shock not only va ri ed across As imipramine i.s a presy napti c uptake inhibitor of 19 individual mi ce with in a strain, but also varied across 5-HT and NE .40, it is logical that thi s dru g could the strain I6.22 . correct the behavioural depressio n cl ue to acute In the present work, both NMDA receptor inescapable foot shock by increasing th e intrasynaptic antagoni sts , MK 80 I and ketamine antagonised the availability of NE and 5-HT. In th e present work, effect of inescapable foot shock in a dose dependent effect of imipramine on open fi eld behavi our was fas hi on. The increased ambulation and rearing in the antago nised by aI-adrenergic antago nist prazos in and OFT and decreased duration of immobility in th e FST not by haloperid ol or ketan se ri n. whereas it s due to these agents was antagonized by hal operidol immobility reducin g effect was antago ni zed by pretreatment. Prazosin and ketanse rin fai led to ketanserin pretreatinent and not by any oth er modify these effects. These results are in agreement antago ni st used. Our findin gs are in line with the with Meloni et al 2J who ha ve shown that dizocilpine work of Plaznik et at. 15. who demonstrated th at (MK 80 I) diminishes the beha vioural deficit administration of N-c hl oroeth yl-2. 2-d ibrolllobenzy l produced by learned helplessness. An indirect amine hydrochl orid e (DSP-4), a selec ti ve neurotox in dopamine (DA) activation, through blockade · of for noradrenergic neurons, decreased onl y open field NMDA receptors, has been proposed for MK 80 I by behaviour and had no effec t on t e duration of a number of workers24.26 . Recently it has been immobility in the FST. Furthermore, it has been demonstrated that haloperidol acts as a se lective shown that maprotiline, a selecti ve NE reuptake inhibitor of MK 80 I binding to the NMDA inhibitor, prevented the depress ion of th e open fi eld receptors27 . Furthermore, two well-known major behaviour leaving the duration of immobility in the 21 inputs to the striatum are the dopaminergic FST unaltered . nigrostriatal bundle and th e glu tamatergic In our work, imipramine fai led to restore the effect 28 3o corticostriatal projections . . There is considerable of inescapable foot shock on rearing be havi our, It has evidence indicating an interaction between these two been shown that DA plays an important role in 1 1 1? V · 11 pat h ways' .. -. erma and KulkarnI ' reported that rearing activit/ I. As imipramine is a weak uptake various depaminergic blockers including haloperidol inhibitor of DA42, therefore, it fail ed to restore th e antagonized the MK 80 I induced stereotypic effect of shock on rearing behaviour. Similar behaviour in nai've mice. Furthermore, Irifune et al. 34 observation has been made by Pal and Da ndi y}l. have shown that ketamine induced locomotion is The present findings demonstrate the effect of an tagonized by haloperidol, in a dose whi ch does not imipramine in the. OFT is medi at ~ d through the affect spontaneous locomotor activity. Moreover, the noradrenergic and in the FST through tryptaminergic destruction of dopaminergic neurons resulted in the pathway as the immobility redu ing effect of suppression of ketamine-induced locomotor activity, imipramine in th e FST was antagonized by ketan serin suggesting that the presence of intact dopaminergic pretreatment only. neurons was indispensable for the re sponse of Furthermore, in the present study. th e concomitant ketamine. They also demonstrated that a-nora·dr administration of either MK 80 I or ketamine with energic antagonists did not inhibit ketamine-induced imipramine produced a greater reduction in shoc k hyperlocomotion. Our finding that prozosin was not induced behavioural depression than either of the able to antagonize the effect of ketamine also support drugs alone. The effect of concomitant administration the view of the earlier workers. Similarly, the effect of imipramine with either of the NMDA receptor of MK 80 I was not antagonized by prazosin pre antagonists on ambulatory activity of mi ce in the OFT treatment. was attenuated by both haloperid ol and prazosin Acute uncontrollable stressors have been shown to pretreatment. As both endogenous E and DA are increase the utilization of catecholamines and considered to affect the locomotor acti vity these serotonin (5-HT), leading to reduced levels of these findings are not unexpected ~1 . Though. imipramine . . . . f h b . 1516 monoammes m vanous regIons 0 t e ram'· ... treatment did not prevent the suppressant effect of CHATURVEDI et al.: NMDA RECEPTOR ANTAGONISTS & ANTIDEPRESSANT EFFECT 957 inescapable foot shock on rearing activity of mice, its 4 Tricklebank MD, Singh L, Oles RJ. Preston C & In versen combination with MK 80 I or ketamine increased the SD, Ellr.l Pharmacal, 167 (1989) 127. 5 Troupin AS , Mendius JR , Chang F & Ri singer MW . in rearing. This effect of the combination of imipramine Current problems ill epilepsy, edited hy Meldrum BS & with NMDA receptor antagonists was antagonized-by Porter RJ (John Libbey. London ) 1986. 19 I . haloperidol pretreatment. The DA reuptake inhibition 6 Trimble M, Epilepsia, 19 (197)1) 241. by imipramine does not explain this effect fully, as 7 Trimble M, Neuropharmacologr. 19 (1980) 1227. 42 imipramine is a weak DA uptake inhibitor . As both 8 Aggarwal R, Dandi ya PC & Vohora SR. Ill diwl .I the typical and atypical antidepressants have been Pha"llacal, 24 ( 1992) 197. 9 BellS TA, in Epilepsv alld psrchial/T. edited hy Reynold s EH shown to increase DA releasing effect of NMDA 44 & Trimble MR (Churchill Livingstone. New York ) 198 1.60. receptor antagonists , our finding is not surprising, 10 Trullas R & Skolnick P, Ellr.l P//{/m/{/co/. 185 ( 1990) I . and suggests a common effector pathway through II Wong EHF, Kemp JA . Priestl ey T. Knight AR, Woodruff DA. 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Hauptman M. 13idzin ski A & depression model, suggest an antidepressant effect of Kostowski W, Braill Res, 447 ( 1988 ) 122. the NMDA receptor antagonists namely , MK 80 I and 16 Sh ank s N & Anisman H, P.Hchophamlllco/lIgy. 99 ( 1989) 122. ketamine, and a complexity of neurotransmitter 17 Ani sman H & Zacharko RM , Be!wv Bmill Sci. 5 ( 1982) X9. mechanisms which are responsible for the occurrence 18 Maier SF, Prog NellroPsYc!lOphllnllllco/ /Jill/ Ps."chial. 8 of behavioural effects in thi s mode l. The present ( 1984) 435. study demonstrated that brain noradrenergic, 19 Pare WP & Glavin GB , Nelll'Osci Bio/u'/1lI 1' HI' v. 10 ( 1986) dopaminergic and tryptaminergic mechanisms ~re 339. involved in the behavioural suppression observed 20 Edwards E, Johnson J. Anderson D. Turano P & Henn FA . Pha rmacal Biachem Belial!. 25 ( 1986) 415 . after inescapable foot shock. 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