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Inhibition by noncompetitive nmda receptor antagonists of apomorphine-induced climbing behavior in mice
ELSEVIER
PII SOO24-3205(96)00109-9
LifeSciences,Vol.58, No. 17,pp. 1397-1402, 1996 Copyright 0 1996Ekvier scienceInc. Printedin the USA. All rightsrcsemd 0024-3205/% $lS.cmt .cm
INHIBITION BY NONCOMPETITIVE NMDA RECEPTOR ANTAGONISTS APOMORPHINE-INDUCED CLIMBING BEHAVIOR IN MICE Hack-Seang
Kim’, Gyu-Seek Rhee’, Joo-Yeon Jung’, Jung-Hwa Lee’, Choon-Gon Woo-Kyu Park’
OF
Jang2 and
‘Department of Pharmacology, College of Pharmacy, Chungbuk National University, Cheongju 360-763 and 2Korea Research Institute of Chemical Technology, Taejon 305-606, Korea (Received in final form February 20, 1996)
Summary The N-methyl-D-aspartate (NMDA) subtype of glutamate receptors is an important mediator of several forms of neural and behavioral plasticity. In the present study, we examined the potential role of NMDA receptors in the glutamatergic modulation of dopaminergic function at the postsynaptic dopamine receptor by determining the effects of NMDA antagonists on apomorphine-induced climbing behavior in mice. The noncompetitive NMDA receptor antagonists, MK-80 1, ketamine, dextrorphan, and dextromethorphan attenuated the apomorphine-induced climbing behavior at doses well below those that produce untoward side effects. These results suggest that the NMDA receptors play important roles in the glutamatergic modulation of dopaminergic function at the postsynaptic dopamine receptors that mediate the apomorphine-induced climbing behavior in mice. Key Words : climbing behavior, apomorphine, MK-801, ketamine, dextrorphan, dextromethorphan It has been demonstrated that MK-801 (1) produces a dose-dependent increase in locomotion in mice and (2) increases the ambulatory activity of cocaine, indicating that m-801 possesses agonistic action on central dopaminergic systems through an acceleration of dopaminergic transmission (2,3). However, MK-801 also caused marked ambulatory stimulation in monoaminedepleted mice and pretreatment with a dopamine (DA) receptor antagonist, haloperidol, did not antagonize the MK-801-induced stimulation of ambulation (4,5), suggesting that the ambulationaccelerating effect of MK-801 is DA-independent. Similar results from studies using other noncompetitive NMDA receptor antagonists such as ketamine (6,7), dextromethorphan (8), phencyclidine (9) and dextrorphan (10) have also been reported. Therefore, interpretations of MK801-induced increases in locomotor activity and of behavioral interactions between MK-801 and other drugs remain controversial since the experimental conditions and methods used have differed among experiments, as were the untoward side effects of the different NMDA receptor antagonists. Climbing behavior has been used as a convenient means of screening DA agonists or antagonists and to assess striatal DA activity. This behavior is reduced after destruction of the striatum and is enhanced by 6-hydroxydopamine-induced lesions of DA input into the striatum (11). In our Correspondence to: Dr. Hack-Seang Kim, Department of Pharmacology, College of Pharmacy, Chungbuk National University, Cheongju 360-763, Korea, [Tel] 431-61-2813, [Fax] 431-68-2732
1398
NMDA
Receptor Antagonists
and Apomorphine
Vol. 58, No. 17, 1996
preliminary study, a single administration of MK-801 showed antidopaminergic action by inhibiting apomorphine-induced climbing behavior. This result indicated that MK-801 could modulate DA activity via an NMDA receptor mechanism. The aim of our present experiments was to determine a property specific to MK-801, and if other non-competitive NMDA receptor antagonists would also produce similar effects. Although MK-801 is a potent and selective NMDA antagonist, there are reports that this drug can produce effects on other systems (1,12) as well as increasing locomotor activity by acting like a DA agonist (2,4,5). It is thus possible that the ability of this drug to inhibit apomorphine-induced climbing behavior may result from actions other than NMDA blockade. In order to definitively establish that the NMDA receptor is involved in the apomorphine-induced dopaminergic action at the postsynaptic DA receptor, it is necessary to demonstrate that noncompetitive NMDA receptor antagonists other than MK-801 would inhibit these phenomena. Therefore, we examined the effect of four different non-competitive NMDA antagonists, MK-801, ketamine, dextrorphan, and dextromethorphan on apomorphine-induced climbing behavior. Each of these drugs inhibited this behavior at low doses, suggesting that this inhibition results from blockade of NMDA receptormediated actions at the NMDA receptor ion channel (13,14), and that this blockade results in the inhibition of apomorphine-induced postsynaptic dopaminergic action ; i.e. it is not a side effect of the drugs. Moreover, a high dose of apomorphine (2 mg/kg) acting as a postsynaptic DA agonist and the very low doses of non-competitive NMDA antagonists were used in the tests of apomorphine-induced climbing behavior. In the present study, we examined the potential role of NMDA receptors in the glutamatergic modulation of dopaminergic function at the postsynaptic DA receptor by determining the effects of NMDA receptor antagonists on apomorphine-induced climbing behavior in mice Methods The animals used were ICR male mice (Samyuk Laboratory Animal Inc., Osan, Korea) weighing 20-25 g in a group of 12- 15. They were housed in an acrylfiber cage in a controlled room (temperature 22 & 3 “C) and were maintained on a 12 hr light/dark cycle. They were given a solid diet and tap water ad libitum. The drugs used were : apomorphine hydrochloride (Sigma Chemical Co., St. Louis, MO), (+) MK-801 maleate (Research Biochemicals International, Natick, MA), ketamine hydrochloride (RBI), dextrorphan tartrate (RBI), and dextromethorphan hydrobromide (RBI). Except for apomorphine, which was dissolved in saline containing 0.1 % ascorbic acid, all drugs were dissolved in physiological saline just before the experiment. Climbing behavior was measured using the 3-point rating scale of Protais et al (11). Immediately after an injection of apomorphine (2 mg/kg,sc), the mice were put into cylindrical cages (diameter, 12 cm ; height, 14 cm) with the floor and wall consisting of metal bars (0.2 cm diameter ; separated by 1 cm gaps) and covered with a lid. After a 5-min period of exploratory activity, climbing behavior was scored by an observer who was blind to the drug treatment at 10, 20 and 30 min after apomorphine administration. Climbing behavior was scored for 1 min during the three time periods of testing, and the highest rating observed during this I-min sample was used in the calculations. The scores of this behavior were evaluated as follows : four paws on the floor (0 point), fore-feet holding the wall (1 point) and four paws holding the wall (2 points). The scores for the period were summed. All drugs were administered (ip) to mice 30 min before the injection of apomorphine.
Vol. 58, No. 17, l!B6
NMDA Receptor Antagonists and Apomorphiie
1399
Results In our preliminary experiment, a single administration of apomotphine (0.5, 1, 2 and 4 mgkg, ip) produced climbing behavior dose dependently, and 2 mg/kg of apomorphine showed the greatest effect of climbing behavior in mice, when compared with the saline group (data not shown). Thus, 2 mg/kg of apomorphine was used to induce climbing behavior in these experiments. MK-801 (0.05, 0.1 and 0.2 mg/kg) attenuated apomorphine-induced climbing behavior by about 28 % (p < 0.02), 53 % @ < 0.002) and 67 % (p < 0.002), respectively, when compared to the apomorphine control group. But the mice injected only with MK-801 (0.2 mg/kg) produced neither climbing behavior nor ataxia, when compared to the saline group (Fig. la). Ketamine (2.5, 5 and 10 mg/kg) prevented apomorphine-induced climbing behavior by about 40 % (p < 0.05), 46 % (p < 0.02) and 52 % (p < 0.002), respectively, when compared to the apomorphine group (Fig. lb). However, the mice treated with ketamine only (10 mgikg) demonstrated neither ataxia nor climbing behavior. Dextrorphan (40 mgkg) inhibited apomorphine-induced climbing behavior by about 42 % (p < 0.002) when compared to the apomorphine group. But lower doses of 10 and 20 mgkg of dextrorphan did not prevent the apomorphine-induced climbing behavior (Fig. lc). Dextromethorphan (10, 20 and 40 mg/kg) prevented apomorphine-induced climbing behavior by about 46 % (p < 0.05), 52 % (p < 0.02) and 78 % (p < 0.002), respectively, when compared to the apomorphine group (Fig. Id). A higher dose of dextromethorphan (80 mgikg) also prevented the apomorphine-induced climbing behavior significantly, but this higher dose of dextromethorphan produced ataxia or depression, when compared to the saline group (data not shown). Discussion The present results demonstrated that the four different noncompetitive NMDA and dextromethorphan markedly antagonists, MK-801, ketamine, dextrorphan, apomorphine induced-climbing behavior at low doses.
receptor blocked
The climbing behavior induced by apomorphine in mice is due to the stimulation of DA receptors (11,15). In the present study, the fact that glutamate antagonists blocked climbing behavior induced by the direct DA receptor agonist, apomorphine, suggests that glutamatergic neurotransmission may modulate DA function at the postsynaptic level. These are the first data suggesting glutamatergic modulation of dopaminergic function at the postsynaptic DA receptor in intact animals. This study raises several issues concerning the synaptic arrangement of the interaction between glutamate and DA. Although the interaction between striatal glutamate and DA has been a focus of research for over a decade, their precise relationship is as yet undefined. Glutamate evokes DA release and, therefore, exerts a presynaptic facilitatory control on DA terminals 16,17,18,19,20). It has been regarded that this effect is primarily mediated by the NMDA receptor (21), although some evidence is provided for the involvement of quisqualate-kainate receptor subtypes (18,22). Based on analyses of ultrastructure, it has been proposed that both dopaminergic and corticostriatal terminals make contact with the dendrites of striatal output cells, and that this arrangement forms the basis of dopaminergic modulation of incoming cortical signals
1400
Nh4DA Receptor Antagonists and Apomorphine
(b) Ketamine
(a) M-801
### T
r
u
Vol. 58, No. 17, 19%
1 0
5.2
SlO
5.05.1.2 --------cAPO2
(d) Dextromethorphan
(c) Dextroxphan
rn5 8
~2.55 lo ---------_ w32
###
5 r
###
l-
I ko4 k t t : i 3 ii
g4 rn
r
E? .li
2 -E! .t-l
1
$1
thEl l-
0
0
I
s 40 __----_--s 102040 -2
s 40 --_-----_s 102040 APO2
Fig. 1
Effects of (a) m-801, (b) ketamine, (c) dextrorphan and (d) dextromethorphan on apomorphine-induced climbing behavior in mice. Each value is expressed as the mean + SEM of at least 12 mice. Statistical analysis was performed with the nonparametric Mann-Whitney U test. * P < 0.05, ** P < 0.02, *** P < 0.002, compared to the apomorphine (APO) control group. ### P < 0.002, compared to the saline (S) group.
Vol. 58, No. 17, 1996
NMDA Receptor Antagonists and Apomorphine
1401
and subsequent of outgoing signals (23,24,25,26,27). Convincing evidence has not been reported yet for an axoaxonic interaction in striatum. However, evidence for an axodendritic interaction has been provided by the finding that intraaccumbens injections of the quisqualate antagonist, Lglutamic acid diethyl ester (GDEE) or a glutamate receptor antagonist, AP-5, reduce cocaine and amphetamine-stimulated motor activity (28,29). Furthermore, AP-5 was shown to block locomotion induced by DA (30). In considering the hypothesis of axodendritic interaction, we presumed a glutamatergic-dopaminergic axodendritic interaction mechanism for the glutamatergic modulation of DA function at postsynaptic DA receptors. Relating this model to the present work, we suggest that apomorphine induces local dopaminergic activation and thus selectively amplifies information from cortico-limbic areas. Blockade of NMDA receptors attenuates activation of the output pathway and thereby lowers the general level of DA-induced activation (29). Therefore, it is likely that the blockade of NMDA receptors results in a selective behavioral effect such as the inhibition of apomorphine-induced climbing behavior or a general increase in locomotor behavior. In addition to the present results, the fact that the intraaccumbens injection of AP-5 or MK-801 (ip) alone generally increases locomotor behavior (29, 30) provides support for this interpretation of the selective behavioral effects of the NMDA receptor antagonists. In support of the present study, there is a report that apomorphine-induced climbing behavior is partially decreased by low doses of GDEE, but is almost completely blocked by high doses of GDEE (3 1). Therefore, it is possible that the actions of NMDA receptor antagonists could involve a variety of EAA (excitatory amino acid) receptor subtypes and that a range of EAA receptor subtypes may mediate glutamate-DA interactions. Therefore, on the basis of our results which demonstrated the inhibitory effects of NMDA antagonists on the apomorphine-induced climbing behavior in mice, we propose that NMDA receptors play important roles in the glutamatergic modulation of dopaminergic function mediated via the glutamatergic-dopaminergic axodendritic interaction at the postsynaptic DA receptor. Thus, climbing behavior in mice may be used as a rapid means to screen or to reveal glutamatergic modulation of dopaminergic function at postsynaptic DA receptors. References 1. B.V. CLINESCHMIDT, G.E. MARTIN, P.R. BUNTING and N.L. PAPP, Drug Dev. Res. 2 135 145 (1982). 2. H. KURIBARA, T. ASAMI, I. IDA and S. TADOKORO, Japan J. Pharmacol. 58 11-18 (1992). 3. W. DIMPFEL and M. SPULER, Psychopharmacology 1013 17-323 (1990). 4. M. CARLSSON and A. CARLSSON, J. Neural Transmission 75 221-226 (1989). 5. R.B. RAFFA, M.E. ORTEGON, D.M. ROBISCH and G.E. MARTIN, Life. Sci. 44 1593-1599 (1989). 6. Y. UCHIHASHI, H. KURIBARA and S. TADOKORO, Japan J. Pharmacol. 60 25-3 1 (1992). 7. B. LANNES, G. MICHELETTI, J.M. WARTER, E. KEMFF and G.D. SCALA, Neurosci, Lett. 128 177-181 (1991). 8. M. BARTOLETTI, M. GAIARDI, C.GUBELLINI and M. BABBINI, Neuropharmacology 22 177-181 (1983). 9. E.D. FRENCH and G. VANTINI, Psychopharmacology 82 83-88 (1984). 10. J.R. MARTIN and A.E. TAKEMORI, Eur. J. Pharmacol. 119 75-84 (1985) 11. P. PROTAIS, J. COSTENTIN and J.C. SCHWARTZ, Psychopharmacology 50 l-6 (1976). 12. A.M. CHILD& R.H. EVANS and J.C. WATKINS, Eur. J. Pharmacol. 145 81-86 (1988).
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13. G.L. COLLINGRIDGE and R.A.J. LESTER, Pharmacol. Rev.a 143-210 (1989). 14. J.C. WATKINS, The NMDA receptor, 2nd Edition, J.C. Watkins and G.L. Collingridge (eds),l-30, Oxford University PresqNew York (1989). 15. J. COSTENTIN, P. PROTAIS and J.C. SCHWARTZ, Nature (London) 257 405-407 (1975). 16. M.F. GIORGUIEFF, M.L. KEMEL and J. GLOWINSKI, Neurosci. Lett. 6 73-77 (1977). 17. L. HEIMER, R.D. SWITZER and G. W. VAN HOESEN, J. Neurochem. 5 83-87 (1982). 18. C.J. CARTER, R. L’HEUREUX and B. SCATTON, J. Neurochem. 2461-468 (1988). 19. B. MOGHADDAM, R.J. GUEN, R.H. ROTH, B.S. BUNNEY and R.N. ADAMS, Brain Res. 518 55-60 (1990). 20. N. SHIMIZU, S. DUAN, T. HORI and Y. OOMURA, Brain Res. Bull. 25 99-102 (1990). 2 1. D. W. CLOW and K. JHMANDAS, J. Pharmacol. Exp. Ther. 248 722-728 (1989). 22. L. BARBEITO, A. CHERAMY, G. GODEHEU, J.M. DESCE and J. GLOWINSKI, Eur. J. Neurosci. 2 304-3 11 (1990). 23. J.J. BOUYER, D.H. PARK, T.H. JOH and V.M. PICKEL, Brain Res. 302 267-276 (1984). 24. T.F. FREUND, J.F. POWELL and A.D. SMITH, Neuroscience 13 1189- 12 16 (1984). 25. P. SOMOGYI, J.P. BOLAM and A.D. SMITH, J. Comp. Neurol. 195 567-584 (1981). 26. S. TOTTERDELL and A.D. SMITH, J. Chem. Neuroanat. 2 285-298 (1989). 27. A.D. SMITH and J.P. BOLAM, Trends Neurosci. 12 259-265 (1990). 28. L. PULVIRENTI, N.R. SWERDLOW and G.F. KOOB, Neurosci. Lett. 103 2 13-218 (1989). 29. A.E. KELLEY and L.C. THRONE, Brain Res. Bull. 29 247-254 (1992). 30. M.H. HAMILTON, J.S. DE BELLEROCHE, I.M. GARDINER and L.J. HERBERG, Pharmacol. Biochem. Behav. 25 943-948 (1986). 3 1. W.J. FREED and H.E. CANNON-SPOOR, Psychopharmacology 101 456-464 (1990).
PII SOO24-3205(96)00109-9
LifeSciences,Vol.58, No. 17,pp. 1397-1402, 1996 Copyright 0 1996Ekvier scienceInc. Printedin the USA. All rightsrcsemd 0024-3205/% $lS.cmt .cm
INHIBITION BY NONCOMPETITIVE NMDA RECEPTOR ANTAGONISTS APOMORPHINE-INDUCED CLIMBING BEHAVIOR IN MICE Hack-Seang
Kim’, Gyu-Seek Rhee’, Joo-Yeon Jung’, Jung-Hwa Lee’, Choon-Gon Woo-Kyu Park’
OF
Jang2 and
‘Department of Pharmacology, College of Pharmacy, Chungbuk National University, Cheongju 360-763 and 2Korea Research Institute of Chemical Technology, Taejon 305-606, Korea (Received in final form February 20, 1996)
Summary The N-methyl-D-aspartate (NMDA) subtype of glutamate receptors is an important mediator of several forms of neural and behavioral plasticity. In the present study, we examined the potential role of NMDA receptors in the glutamatergic modulation of dopaminergic function at the postsynaptic dopamine receptor by determining the effects of NMDA antagonists on apomorphine-induced climbing behavior in mice. The noncompetitive NMDA receptor antagonists, MK-80 1, ketamine, dextrorphan, and dextromethorphan attenuated the apomorphine-induced climbing behavior at doses well below those that produce untoward side effects. These results suggest that the NMDA receptors play important roles in the glutamatergic modulation of dopaminergic function at the postsynaptic dopamine receptors that mediate the apomorphine-induced climbing behavior in mice. Key Words : climbing behavior, apomorphine, MK-801, ketamine, dextrorphan, dextromethorphan It has been demonstrated that MK-801 (1) produces a dose-dependent increase in locomotion in mice and (2) increases the ambulatory activity of cocaine, indicating that m-801 possesses agonistic action on central dopaminergic systems through an acceleration of dopaminergic transmission (2,3). However, MK-801 also caused marked ambulatory stimulation in monoaminedepleted mice and pretreatment with a dopamine (DA) receptor antagonist, haloperidol, did not antagonize the MK-801-induced stimulation of ambulation (4,5), suggesting that the ambulationaccelerating effect of MK-801 is DA-independent. Similar results from studies using other noncompetitive NMDA receptor antagonists such as ketamine (6,7), dextromethorphan (8), phencyclidine (9) and dextrorphan (10) have also been reported. Therefore, interpretations of MK801-induced increases in locomotor activity and of behavioral interactions between MK-801 and other drugs remain controversial since the experimental conditions and methods used have differed among experiments, as were the untoward side effects of the different NMDA receptor antagonists. Climbing behavior has been used as a convenient means of screening DA agonists or antagonists and to assess striatal DA activity. This behavior is reduced after destruction of the striatum and is enhanced by 6-hydroxydopamine-induced lesions of DA input into the striatum (11). In our Correspondence to: Dr. Hack-Seang Kim, Department of Pharmacology, College of Pharmacy, Chungbuk National University, Cheongju 360-763, Korea, [Tel] 431-61-2813, [Fax] 431-68-2732
1398
NMDA
Receptor Antagonists
and Apomorphine
Vol. 58, No. 17, 1996
preliminary study, a single administration of MK-801 showed antidopaminergic action by inhibiting apomorphine-induced climbing behavior. This result indicated that MK-801 could modulate DA activity via an NMDA receptor mechanism. The aim of our present experiments was to determine a property specific to MK-801, and if other non-competitive NMDA receptor antagonists would also produce similar effects. Although MK-801 is a potent and selective NMDA antagonist, there are reports that this drug can produce effects on other systems (1,12) as well as increasing locomotor activity by acting like a DA agonist (2,4,5). It is thus possible that the ability of this drug to inhibit apomorphine-induced climbing behavior may result from actions other than NMDA blockade. In order to definitively establish that the NMDA receptor is involved in the apomorphine-induced dopaminergic action at the postsynaptic DA receptor, it is necessary to demonstrate that noncompetitive NMDA receptor antagonists other than MK-801 would inhibit these phenomena. Therefore, we examined the effect of four different non-competitive NMDA antagonists, MK-801, ketamine, dextrorphan, and dextromethorphan on apomorphine-induced climbing behavior. Each of these drugs inhibited this behavior at low doses, suggesting that this inhibition results from blockade of NMDA receptormediated actions at the NMDA receptor ion channel (13,14), and that this blockade results in the inhibition of apomorphine-induced postsynaptic dopaminergic action ; i.e. it is not a side effect of the drugs. Moreover, a high dose of apomorphine (2 mg/kg) acting as a postsynaptic DA agonist and the very low doses of non-competitive NMDA antagonists were used in the tests of apomorphine-induced climbing behavior. In the present study, we examined the potential role of NMDA receptors in the glutamatergic modulation of dopaminergic function at the postsynaptic DA receptor by determining the effects of NMDA receptor antagonists on apomorphine-induced climbing behavior in mice Methods The animals used were ICR male mice (Samyuk Laboratory Animal Inc., Osan, Korea) weighing 20-25 g in a group of 12- 15. They were housed in an acrylfiber cage in a controlled room (temperature 22 & 3 “C) and were maintained on a 12 hr light/dark cycle. They were given a solid diet and tap water ad libitum. The drugs used were : apomorphine hydrochloride (Sigma Chemical Co., St. Louis, MO), (+) MK-801 maleate (Research Biochemicals International, Natick, MA), ketamine hydrochloride (RBI), dextrorphan tartrate (RBI), and dextromethorphan hydrobromide (RBI). Except for apomorphine, which was dissolved in saline containing 0.1 % ascorbic acid, all drugs were dissolved in physiological saline just before the experiment. Climbing behavior was measured using the 3-point rating scale of Protais et al (11). Immediately after an injection of apomorphine (2 mg/kg,sc), the mice were put into cylindrical cages (diameter, 12 cm ; height, 14 cm) with the floor and wall consisting of metal bars (0.2 cm diameter ; separated by 1 cm gaps) and covered with a lid. After a 5-min period of exploratory activity, climbing behavior was scored by an observer who was blind to the drug treatment at 10, 20 and 30 min after apomorphine administration. Climbing behavior was scored for 1 min during the three time periods of testing, and the highest rating observed during this I-min sample was used in the calculations. The scores of this behavior were evaluated as follows : four paws on the floor (0 point), fore-feet holding the wall (1 point) and four paws holding the wall (2 points). The scores for the period were summed. All drugs were administered (ip) to mice 30 min before the injection of apomorphine.
Vol. 58, No. 17, l!B6
NMDA Receptor Antagonists and Apomorphiie
1399
Results In our preliminary experiment, a single administration of apomotphine (0.5, 1, 2 and 4 mgkg, ip) produced climbing behavior dose dependently, and 2 mg/kg of apomorphine showed the greatest effect of climbing behavior in mice, when compared with the saline group (data not shown). Thus, 2 mg/kg of apomorphine was used to induce climbing behavior in these experiments. MK-801 (0.05, 0.1 and 0.2 mg/kg) attenuated apomorphine-induced climbing behavior by about 28 % (p < 0.02), 53 % @ < 0.002) and 67 % (p < 0.002), respectively, when compared to the apomorphine control group. But the mice injected only with MK-801 (0.2 mg/kg) produced neither climbing behavior nor ataxia, when compared to the saline group (Fig. la). Ketamine (2.5, 5 and 10 mg/kg) prevented apomorphine-induced climbing behavior by about 40 % (p < 0.05), 46 % (p < 0.02) and 52 % (p < 0.002), respectively, when compared to the apomorphine group (Fig. lb). However, the mice treated with ketamine only (10 mgikg) demonstrated neither ataxia nor climbing behavior. Dextrorphan (40 mgkg) inhibited apomorphine-induced climbing behavior by about 42 % (p < 0.002) when compared to the apomorphine group. But lower doses of 10 and 20 mgkg of dextrorphan did not prevent the apomorphine-induced climbing behavior (Fig. lc). Dextromethorphan (10, 20 and 40 mg/kg) prevented apomorphine-induced climbing behavior by about 46 % (p < 0.05), 52 % (p < 0.02) and 78 % (p < 0.002), respectively, when compared to the apomorphine group (Fig. Id). A higher dose of dextromethorphan (80 mgikg) also prevented the apomorphine-induced climbing behavior significantly, but this higher dose of dextromethorphan produced ataxia or depression, when compared to the saline group (data not shown). Discussion The present results demonstrated that the four different noncompetitive NMDA and dextromethorphan markedly antagonists, MK-801, ketamine, dextrorphan, apomorphine induced-climbing behavior at low doses.
receptor blocked
The climbing behavior induced by apomorphine in mice is due to the stimulation of DA receptors (11,15). In the present study, the fact that glutamate antagonists blocked climbing behavior induced by the direct DA receptor agonist, apomorphine, suggests that glutamatergic neurotransmission may modulate DA function at the postsynaptic level. These are the first data suggesting glutamatergic modulation of dopaminergic function at the postsynaptic DA receptor in intact animals. This study raises several issues concerning the synaptic arrangement of the interaction between glutamate and DA. Although the interaction between striatal glutamate and DA has been a focus of research for over a decade, their precise relationship is as yet undefined. Glutamate evokes DA release and, therefore, exerts a presynaptic facilitatory control on DA terminals 16,17,18,19,20). It has been regarded that this effect is primarily mediated by the NMDA receptor (21), although some evidence is provided for the involvement of quisqualate-kainate receptor subtypes (18,22). Based on analyses of ultrastructure, it has been proposed that both dopaminergic and corticostriatal terminals make contact with the dendrites of striatal output cells, and that this arrangement forms the basis of dopaminergic modulation of incoming cortical signals
1400
Nh4DA Receptor Antagonists and Apomorphine
(b) Ketamine
(a) M-801
### T
r
u
Vol. 58, No. 17, 19%
1 0
5.2
SlO
5.05.1.2 --------cAPO2
(d) Dextromethorphan
(c) Dextroxphan
rn5 8
~2.55 lo ---------_ w32
###
5 r
###
l-
I ko4 k t t : i 3 ii
g4 rn
r
E? .li
2 -E! .t-l
1
$1
thEl l-
0
0
I
s 40 __----_--s 102040 -2
s 40 --_-----_s 102040 APO2
Fig. 1
Effects of (a) m-801, (b) ketamine, (c) dextrorphan and (d) dextromethorphan on apomorphine-induced climbing behavior in mice. Each value is expressed as the mean + SEM of at least 12 mice. Statistical analysis was performed with the nonparametric Mann-Whitney U test. * P < 0.05, ** P < 0.02, *** P < 0.002, compared to the apomorphine (APO) control group. ### P < 0.002, compared to the saline (S) group.
Vol. 58, No. 17, 1996
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and subsequent of outgoing signals (23,24,25,26,27). Convincing evidence has not been reported yet for an axoaxonic interaction in striatum. However, evidence for an axodendritic interaction has been provided by the finding that intraaccumbens injections of the quisqualate antagonist, Lglutamic acid diethyl ester (GDEE) or a glutamate receptor antagonist, AP-5, reduce cocaine and amphetamine-stimulated motor activity (28,29). Furthermore, AP-5 was shown to block locomotion induced by DA (30). In considering the hypothesis of axodendritic interaction, we presumed a glutamatergic-dopaminergic axodendritic interaction mechanism for the glutamatergic modulation of DA function at postsynaptic DA receptors. Relating this model to the present work, we suggest that apomorphine induces local dopaminergic activation and thus selectively amplifies information from cortico-limbic areas. Blockade of NMDA receptors attenuates activation of the output pathway and thereby lowers the general level of DA-induced activation (29). Therefore, it is likely that the blockade of NMDA receptors results in a selective behavioral effect such as the inhibition of apomorphine-induced climbing behavior or a general increase in locomotor behavior. In addition to the present results, the fact that the intraaccumbens injection of AP-5 or MK-801 (ip) alone generally increases locomotor behavior (29, 30) provides support for this interpretation of the selective behavioral effects of the NMDA receptor antagonists. In support of the present study, there is a report that apomorphine-induced climbing behavior is partially decreased by low doses of GDEE, but is almost completely blocked by high doses of GDEE (3 1). Therefore, it is possible that the actions of NMDA receptor antagonists could involve a variety of EAA (excitatory amino acid) receptor subtypes and that a range of EAA receptor subtypes may mediate glutamate-DA interactions. Therefore, on the basis of our results which demonstrated the inhibitory effects of NMDA antagonists on the apomorphine-induced climbing behavior in mice, we propose that NMDA receptors play important roles in the glutamatergic modulation of dopaminergic function mediated via the glutamatergic-dopaminergic axodendritic interaction at the postsynaptic DA receptor. Thus, climbing behavior in mice may be used as a rapid means to screen or to reveal glutamatergic modulation of dopaminergic function at postsynaptic DA receptors. References 1. B.V. CLINESCHMIDT, G.E. MARTIN, P.R. BUNTING and N.L. PAPP, Drug Dev. Res. 2 135 145 (1982). 2. H. KURIBARA, T. ASAMI, I. IDA and S. TADOKORO, Japan J. Pharmacol. 58 11-18 (1992). 3. W. DIMPFEL and M. SPULER, Psychopharmacology 1013 17-323 (1990). 4. M. CARLSSON and A. CARLSSON, J. Neural Transmission 75 221-226 (1989). 5. R.B. RAFFA, M.E. ORTEGON, D.M. ROBISCH and G.E. MARTIN, Life. Sci. 44 1593-1599 (1989). 6. Y. UCHIHASHI, H. KURIBARA and S. TADOKORO, Japan J. Pharmacol. 60 25-3 1 (1992). 7. B. LANNES, G. MICHELETTI, J.M. WARTER, E. KEMFF and G.D. SCALA, Neurosci, Lett. 128 177-181 (1991). 8. M. BARTOLETTI, M. GAIARDI, C.GUBELLINI and M. BABBINI, Neuropharmacology 22 177-181 (1983). 9. E.D. FRENCH and G. VANTINI, Psychopharmacology 82 83-88 (1984). 10. J.R. MARTIN and A.E. TAKEMORI, Eur. J. Pharmacol. 119 75-84 (1985) 11. P. PROTAIS, J. COSTENTIN and J.C. SCHWARTZ, Psychopharmacology 50 l-6 (1976). 12. A.M. CHILD& R.H. EVANS and J.C. WATKINS, Eur. J. Pharmacol. 145 81-86 (1988).
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