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 <l mbulati on and rearing in the open field arena and increased immobility duration in the FST. Pretreatment with imipramine. M K 80 I ;1I1U ketamine sign ificantly prevented the effect of shock. Also. the combin ation of imipramine with ei th er of th e NMDA antagonists antagonised the effect of shock. Halo peridol , prazosin and ketanserin pretreatment mod i lied the effec t of th ese agents. These find ings suggest an antidepressant elTect of th e NMDA receptor antagoni sts. and a complexi lY of neurotransmitter mechanisms. which are responsible for the occurrence of behav iou ral effects in shock-induced dep ression model. 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<O.OO I) in the FST (Table I). Systems, India). The stimulator was programmed Pretreatment with imipramine (8-32 mg/kg) . MK to deliver 360 foot shocks (300 ~A ) of 2 sec 80 1 (0.05-2 mg/kg) and ketamine C2 ..'i- IO mg/kg) duration at intervals of 9 sec. The animals were significantl y reversed th e cffect of shock on shocked for a total of I hr. Spec ial attenti on was behaviour. The onl y difference betwee n imiprami ne paid to keep the grid clean from faeca l matter to and oth er agents was that i mi prami ne fai led to avoid short circuits terminating the shock ant agonise the effect of foot ,hock on rearing delivery. Control animal s Were merely pl aced on behav iour. These observations are shown in Table 2. the grid under in verted beakers for I hI' but were Table 3 gives th e modificati on of the effect of not shocked. imipramine, MK 80 I and ketamine by hal operidol (ii ) Behavioura l Testing: Twent y-four hours after the (0.1 mg/kg). Haloperidol per .1'(' did not modify the shock admin istration, beha vioural depression was effect of inescapable foot shock. Though. th e effect of measured by an open fi eld test (OFT) foll owed by Imipramine remain ed un altered in presence of a forced swimming test (FST). The OFT was haloperidol, the effect of both MK 801 and ketal1lin ' carri ed out in a circular wooden arena (84 cm was ant ago ni sed. The effect of imipramin e wi th el lilC' di ameter, 30 cm hi gh) with a white sun mi ca base, of the NMDA antagonist on ambuiati on and with three concentri c circles di vided in to immobili ty durati on were att enu ated by hal operi dol. segments by rad ial lin es ori ginating from the whereas th e effect of th e combinat ions on reari ng \ a:-­ centre. Each animal wa s tested for 5 min . also an tago ni sed by hal operi dol pretreatment. Ambul at ion (locomotor behav iour) was measured The modifi cati on of th e effect of imipramin e. MK as number of lines crossed by an an imal , and 80 I and ketami ne by prazosin (3 mg/kg) i · give n in reari ng (ex pl oratory activity) was measured as Tabl e 4. Prazos in per se di d not mod ify th e effe ct of number of times th e an imal stood on its hind inescapab le foot shock. The effect of imipramine on limbs with or wi th out th e support of circul ar wall. ambul ati on was an.tagoni sed by prazosin pretreat- The count in g of ambu iati on and rearin g responses Table I-En'cci ofi nescapa blc 1001 , hock Oil hc hav ill ur III mi ce was done using a hand operated counter. OFT FST Immediately after th e behaviour testing procedu re Ambul ali on Rearing Imlllohi lit y the animals were subj ected to FST. The ani mal s were forced to swi m individually, fo r 6 min, in a Co nl ro l I 59.50±5.42 22. IO±2.1' X2.20± .. 5 1 glass beaker ( I I cm diameter, 15 cm hi gh) Shocked SO.50±4.6 1** 11.3 0±1.. Y " 15X.,)()±4J11 "* containing fresh water upt o a height of 6 cm and maintained at a temperature of 22°± 1°C. Each OF r=open licld tes!. FST=fo rced swimming lesl. Results arc give n as mean ± SE (n=I O) . Wh il e Ih e OFl' valu es re prcsent animal made vigorous attempts to get out of glass numbe r of episodes in 5 min , the FST values dellot c the durali oll beaker during the first few minutes and thereafter of imillobil ity in iast 4 min or a 6 min test.