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    6 views4 pages

    Lalonde Joyal Cote Guastavino Botez 1993

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    TaNiTa TiKaRaN

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    © All Rights Reserved
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    Restorative Neurology and Neuroscence, 5 (1993) 367-370 © 1993 Elsevier Seience Publishers B.V, All rights reserved 0922-6028/93)S06.00 367 RESTOR 00191 Short Communications Amantadine and ketamine-induced improvement of motor coordination in lurcher mutant mice Robert Lalonde®, Christian C. Joyal *, Jean-Marie Guastavino?, Chantal Coté* and M.I. Botez* * Hotel Dieu Hospital, Neurology Service, Neurobiology Laboratory, Montreal, Quebec, H2W 178 (Canada) and Unversity of Montreal, Departments Of Medicine and Psychology, Monreal, Quebec (Canada) and.” University of Nancy f, Behavioral Biology and Physiology Laboratory Vandoewsre-es-Nancy (France) (Received $ August 1993) (Revised version oceived 24 February 1993) (Accepted 11 March 1993) Key words: Lurcher mutant; Cerebellum; Ketamine; NMDA antagonist Abstract The effects of amantadine and ketamine were compared to a placebo in a coat-hanger test on lurcher mutant mice. This test ‘measures motor coordination and is dependent on cerebellar functioning. Both drugs improved motor coordination of the cer ebellar mutants in that the time taken to reach the side-bar according to a 2 paw criterion was decreased during the drugged condition in comparison to the non-drugged condition, This result indicates tha NMDA receptor antagonists may improve motor coordination in animals with cerebellar disease. Recent open clinical trial findings [4,5] have indi- cated the prospect of improving the motor deficits in inherited spinodegenerative cerebellar ataxias such as olivopontocerebellar atrophy and Friedreich's ataxia Visual and auditory reaction times and movement times were improved in both patient groups after chronic administration of amantadine [4,5]. Thisis a dopamine- releasing agent [19]. Memantine, an amantadine ana- logue, has N-methyl-D-aspartate antagonist (NMDA) properties [3,11]. Ataxia scores were improved with amantadine in Friedreich’s ataxia patients [16]. The amelioration in reaction and movement times is prob- ably not due strictly to dopamine activation because it ‘was not correlated to initial low levels of the dopamine metabolite, homovanillic acid [5]. In view of these en- couraging results, we have initiated experimental stud- Correspondence: R. Lalonde, HOtel-Dieu Hospital, Neurology Ser= vice, Neurobiology Laboratory, Montreal, Quebec, Canada H2W’ Ts, ies with amantadine and the NMDA antagonist, ket amine [14], in an effort to reverse motor deficits in an animal model of cerebellar disease: lurcher mutant mice, whose main characteristics include degeneration of Purkinje cells, granule cells and inferior olive cells [6,20,21]. Ketamine is not a direct dopamine-releasing agent [1,10]. As a dopamine-reuptake inhibitor, it is 10,000 times less potent than GBR 12909 [10]. How- ever, dopaminergic mechanisms may be activated in an indirect way by this drug because NMDA receptor an- agonists are potent activators of A10 (ventral tegmen- tal) neurons [8]. This interaction may explain the re- semblance between the behavioral effects af NMDA receptor antagonists and dopamine activators. These agents cause similar brain field potentials in the rat [7]. In the ketamine study, ten lurcher mutant mice (7 females, 3 males, age: 2 months) were used, half being randomly assigned either to a placebo group (0.9% saline) or to a ketamine group (10 mgikg, ip, from the base, injection volume=2 cc/kg, Parke-Davis, Mont- 368 real). Animals were injected with ketamine or placebo every day for 10 days and tested in the coat-hanger test [12] 20 min after injection. After this 10 day period, 7 day washout period intervened, followed by a second, 10 day period in which mice receiving placebo were administered ketamine and mice receiving ketamine were administered placebo. The mice were placed in the middle of a thin hori= zontal bar (length = 40 cm, diameter = 2 mm) of a coat- hanger of triangular shape made of steel (length of di agonal side-bars= 19 cm, inclination = 45°) and the time taken to reach ene of the side-bars was deter- mined. The mice began the test upside down and ap- peared motivated to move across the horizontal bar and to attempt to climb one of the side-bars in order to achieve a stable right-side-up position. ta a previous study [12], the coat-hanger was held in place loosely from a vertical pole. In the present study, the coat- hanger was held firmly in place with masking tape. Preliminary studies had indicated that this approach ‘maximized performances: the mice could reach the end of the horizontal bar without having the bar lean down- ward because of their weight. The coat-hanger was placed at a height of 82 cm from a table with a soft blanket spread out for the purpose of cushioning their falls. Four latencies were determined with a stop-watch by an experimenter blind in regard to drug treatment. Latencies 1-3 measured the time elapsed before the mice reached either side-bar (the mice were always po- sitioned toward the right but sometimes turned left) with two (latency 1), three (latency 2), or all four paws (latency 3) touching the diagonal bar. Latency 4 was the time elapsed before a fall. Thus, low values for laten- cies 1-3 indicate superior performance (reaching the side-bar quickly) while low values for latency 4 indicate inferior performance (rapid falls). In addition, the num- ber of successful half-way and complete climbs to the top of the hanger was tabulated. Whenever a mouse reached the top, a value of 60 s (maximal score) was given for latency 4. The cut-off point for any trial was 60 s. There were 2 trials a day, separated by approxi- mately 5 min, an appropriate rest-ime, as we have found no evidence of tiedness on trial 2 with this in- terval In the amantadine study, pretiminary experiments had indicated that this drug seemed suecessful in ame- liorating the mutants with the lowest scores in the test, but not those with the highest scores. This differential effect was not seen with ketamine, Therefore, we se- lected the 11 lowest performing mutants (6 females, 5 males, age:1-5 months) among a group of 22 and as- signed them randomly to a placebo group (0.9% saline) or to an amantadine group (40 mgikg, i.p., 2 co/kg, 60 min post-injection, Du Pont de Nemours, Wilming- ton, DE). Two of these 11 mutants had taken part in the ketamine study but had not taken that drug for over one month. As in the previous experiment, animals were injected with amantadine or placebo every day for 10 days and then after a 7 day washout period, the pharmacological treatments were reversed for 10 addi- tional days. A 7 day washout period seemed appropri- ale in view of evidence that excretion of amantadine is complete within 12 h after oral administration in mice [2]. At these dose levels, neither ketamine nor aman- tadine caused visible side effects and did not decrease body weights. Drug doses were determined following preliminary experimentation and on the basis of previ- ‘ous behavioral tests in normal rodents [13,18]. In neither study did we detect order of presentation (drug first vehicle second or the reverse) or practice (spontaneous improvement over time) effects as deter- mined by the Wilcoxon matched-pairs signed-ranks test (P> 0.05). In the ketamine study, lurcher mutants had lower values for latency 1 under ketamine than under placebo (W+10=11, P=0.05). There were no differences be- tween drug conditions for the other three latencies or for the number of successful climbs (half-way or to the top) (Table I). Latencies and successful climbs in Table reflect the total value per day (maximal score: 120 s for latencies and 2 for successful climbs). Thus, lurcher mutants reached the side-bar more quickly when in- jected with ketamine than placebo according to the 2 paw but not the 3 or 4 paw criteria. The improvement for latency 1 (2 paw criterion) was mild (mean differ- ence: 7.2 s of approximately a 10% improvement), yet important because the majority (7/10) of the mutants had lower latencies with ketamine. ‘Among the 11 lurcher mutants tested, 9 improved and there were 2 ties under amantadine (W + =0; f= 9; P<0.001) for latency 1. The other latencies and the successful climbs measure were not altered by the drug (Table II). There was a 9.5 s or 8.3% decrease in TABLEL Mean (SD) latencies and successful cmb in cot-hanget test for larcher ‘matant mice (n= 10) under 10 mike of Ketamine or placebo Drg Latency Latency Latency Lateney Successfid Sucessfil PoP 4 climbs elms (halway) (to the top) Placebo 754 904 93.7 108.906 686) G41) G27) G3) 8) 07) Ketamine 68.2" 878 919 107.8 0.7 06 G97 34 G39 G1) OS) 7 05. TABLE ML Mean (SD) latencies and successful elms in cont hanger test for archer 1) under 40 mk of amantadine or placebo Drwg Latency Lateney Latency Lateney Suecessfl Successful P23 chinks clomke (halfnay) (10 the top) Placebo 1144 119.7 1200 610 ° 65) G40 © G5 O © Amantadine 1049" 171 18S 1136 01 0 (76) 45) 02) 09) 0) =Pen00l latency 1 during amantadine treatment. Latencies 1-3 are higher in this study than in the previous one because the lurchers were pre-selected on the basis of low ini- tial scores. The results indicate that ketamine and amantadine permitted lurcher mutants to reach the side-bar more quickly than placebo. This was true only for the 2 paw (latency 1) and not the more difficult 3 or 4 paw criteria, In this test, the mice appeared motivated to reach the side-bar in order to attain the right-side-up position. On most occasions, they were unable to achieve a stable (all 4 paws) position on the side-bar, but were never- theless often able to climb the side-bar with their two front paws. Latency 1 is necessarily always shorter (or equal when the mice cannot touch the side-bar) than latencies 2 and 3 because the animals must first reach the side-bar with 2 paws before reaching it with 3 or 4 paws. Latencies 2 and 3 may be described as more

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