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Effect of NE-100, a novel sigma receptor ligand, on phencyclidine-induced delayed cognitive dysfunction in rats
ELSEVIER
Neuroscience Letters 189 (1995) 60-62
1ElTIlS
Effect of NE-100, a novel sigma receptor ligand, on phencyclidine-induced delayed cognitive dysfunction in rats Shigeru Okuyama *, Shin-ichi Ogawa, Atsuro Nakazato, Kazuyuki Tomizawa Ist Laboratory, Medicinal Research Laboratories, Taisho Pharmaceutical Co., Ltd., I-403, Yoshino-Cho, Ohmiya, Saitama 330, Japan Received 31 January 1995; revised version received 27 February 1995; accepted 27 February 1995
Abstract Phencyclidine (PCP), in a dose of 15 mg/kg, produced delayed cognitive dysfunction (at 24 h) in rats subjected to water maze tasks. At 24 h after PCP administration, ataxia, hyperlocomotion and stereotyped behavior were not induced. NE-100, NJ-dipropyl-2-[4methoxy-3-(2-phenylethoxy)phenyl]-ethylamine monohydrochloride, a selective and potent sigma receptor ligand, was administered orally 10 min after PCP administration or 15 min before the first trial (24 h after PCP administration). In both cases, NE-100 dosedependently attenuated the delayed cognitive dysfunction induced by PCP. As these findings show that ingestion of PCP led to delayed
cognitive dysfunction similar to the cognitive signs of psychosis seen in humans, NE-100 is being further studied for possible treatment of subjects with schizophrenia. Keywords:
NE-100; Sigma ligand; Phencyclidine;
Cognition; Psychosis
NE-100, iV,N-dipropyl-2-[4-methoxy-3-(2-phenylethoxy)phenyl]ethylamine monohydrochloride, is a novel compound with high affinity for sigma1 but low affinity for sigma*, dopamine D1, dopamine D,, serotonin 5HT,,, serotonin 5-HT, and phencyclidine (PCP) receptors [1,8]. The head-weaving behavior induced by either (+)N-allylnormetazocine (SKF 10,047) or PCP was dosedependently antagonized by NE-100 [8]. The PCPinduced ataxia in dogs and monkey was to some extent overcome by NE-100 [9]. NE-100 did not affect dopamine agonists-induced stereotyped behavior, or hyperlocomotion [8] nor did it induce catalepsy in rats [8]. All these findings suggest that NE-100 may be an effective antipsychotic agent, without the motor side effects common to most neuroleptics. PCP induces a psychotomimetic state that closely resembles schizophrenia [5]. The administration of PCP to rats leads to a complex syndrome of behavior, i.e. hyperactivity, stereotyped behavior and ataxia [2]. A single dose of PCP produces an initial increase then a prolonged decrease in regional cerebral glucose metabolism lasting longer than 24 h and this effect is prominent in rat limbic structures [4]. Moreover, the psychotomimetic effects of *Corresponding
author, Tel.: +81 48 6631111; Fax: +81 48 6527254.
PCP, particularly of delayed effects may be mediated by limbic glutamatergic synapses selective for N-methyl-Daspartate (NMDA) [3]. This is of interest since the limbic system has long been implicated in psychotic conditions such as schizophrenia [lo]. We previously reported the effects of NE-100 on PCP-induced acute cognitive dysfunction in rats in the water maze task [7]. In the present work, we examined the PCP-induced delayed effect on cognition in rats subjected to the Morris water maze, and the effects of NE-100 (sigma, receptor ligand) on the delayed effect of PCP. Male Wistar rats (Clea Japan, Inc., Tokyo, Japan), weighing about 250 g at the start of experiments, were used. The animals were housed in a temperatureand light-controlled room (a 12 h light cycle starting at 0700 h). The rats had free access to food and water except during the experiment, and were manually handled prior to the experiments. A circular tank (140 cm in diameter and 45 cm high) was used. A transparent platform (10 cm in diameter and 25 cm high) set inside the tank was filled to a height of 27 cm with water at approximately 22°C (the platform’s surface was 2 cm below the surface of the water). The pool was located in a large test room and many external cues within the pool could be used by the rat for spatial
0304-3940/95/$09.50 0 1995 Elsevier Science Ireland Ltd. All rights reserved SSDI 0304-3940(95)1 1440-5
S. Okuyama et al. I Neuroscience
PCP
NE-100 10min
100
-
60
-
I ’
24 h
G LoE g 3
Fig. 1. Effect of NE-100, when given 10 min after PCP administration, on PCP-induced delayed cognitive dysfunction in rats. N, number of animals. Control versus PCP; treatment effects F(l,llO) = 17.43, P < 0.01 by ANOVA, and P < 0.01 by Dunnett’s test; PCP versus NE100 (1 mg/kg); treatment effects F( 1,110) = 6.70, P < 0.05 by ANOVA and P < 0.05 by Dunnett’s test. #P c 0.05 and ##P < 0.01 versus control (Dunnett’s test).
orientation. The position of the cues was unchanged throughout the training. The rats was placed at one of three starting positions for each training session, but the sequence of positions were selected randomly. The platform was located in a constant position in the middle of one quadrant, equidistant from the center and the edge of the pool. In each training session, the time to escape onto the hidden platform was recorded. If the rat found the platform within 100 s, it was allowed to remain there for 30 s then it was returned to its home cage. If the rat was unable to find the platform within 100 s, it was placed on the platform for 30 s and a maximum time of 100 s was assigned. The experimental session consisted of 5 trials at 2 h intervals 24 h after PCP administration. Phencyclidine hydrochloride (PCP) was dissolved in 0.9% saline. NE-100 was dissolved in distilled water. PCP was administered i.p. in a volume of 1 ml/kg of body weight. NE-100 was given orally 10 min after the PCP administration or 15 min before the first trials. The data are expressed in terms of mean latency and were analyzed using two-way analysis of variance (2-way ANOVA) and Dunnett’s test. When 15 mg/kg of PCP was administered, ataxia, hyperlocomotion and stereotyped behavior were absent 24 h later (data not shown). The swimming latencies of PCP-treated rats on the first trial did not differ from findings in the control group. However, throughout the training, PCP-treated rats were slower than the control group to find the platform. PCP did not affect swimming ability, posture or speed but did affect swimming pattern used to find the platform in the water maze task.
61
Letters 189 (1995) 60-62
In case of NE-100 (0.1-l mg/kg p.o.j given 10 min after PCP administration, NE- 100 dose-dependently attenuated the delayed cognitive dysfunction induced by PCP (Fig. 1). Statistical data: control versus PCP; treatment effects F(l,llOj = 17.43, P < 0.01 by ANOVA, and P < 0.01 by Dunnett’s test; PCP versus NE-100 (1 mg/ kg); treatment effects F( 1,110) = 6.70, P < 0.05 by ANOVA, and P < 0.05 by Dunnett’s test. In the case of NE-100 (0.03-0.3 mg/kg p.o.) given 15 min before the first trial, NE-100 also dosedependently attenuated the delayed cognitive dysfunction induced by PCP (Fig. 2). Statistical data: control versus PCP, treatment effects F(1,90) = 23.87, P < 0.01 by ANOVA, and P < 0.01 by Dunnett’s test; PCP versus NE100 (0.3 mg/kgj, treatment effects F( 1,90) = 7.74, P < 0.01 by ANOVA, and P < 0.01 by Dunnett’s test. PCP (15 mg/kgj ingestion by rats led to delayed cognitive dysfunction, without the induction of ataxia, hyperlocomotion and stereotyped behavior. The threshold for effective doses (over 15 mg/kgj of PCP appears critical since lower doses (under 10 mg/kgj had no apparent effects, in pilot experiments. Gao et al. [3,4] reported the 24 h effects of PCP on NMDA sensitive [3H]glutamate binding sites and on the metabolism of cerebral glucose; these was an increase in NMDA binding and a decrease in regional cerebral glucose metabolism in limbic structures, limbic related neocortex and posterior cingulate cortex 24 h after a single dose of PCP. Thus, PCP-induced delayed cognitive dysfunction may possibly be mediated by limbic glutamatergic synapses for NMDA. The effect of NE-100 administration at 10 min after administration of PCP, and NE-100 administration at 15 min before the first trial (24 h after administration of NE-100
PCP
t
tn
24 hr
01 1
+
+ NE-100 (0.3 mgikg, p.0.) (pd3.01 vs. PCP. ANOVA) (~~10)
I
2
3
4
5
Trials Fig. 2. Effect of NE-100, when given 15 min before first trial (24 h after PCP administration), on PCP-induced delayed cognitive dysfunction in rats. N. number of animals. Control versus PCP; treatment effects F(1.90) = 23.87. P < 0.01 by ANOVA, and P < 0.01 by Dunnett’s test; PCP versus NE-100 (0.3 mg/kg); treatment effects F(I .90) = 7.74, P < 0.01 by ANOVA, and P < 0.01 by Dunnett’s test. “P < 0.01 versus control (Dunnett’s test).
62
S. Okuyuma et al. I Neuroscience
PCP), was compared in the improvement of PCP-induced delayed cognitive dysfunction. The purpose of this comparison was to elucidate whether NE-100 is effective through the inhibition of PCP induction of delayed cognitive dysfunction at an early phase of delayed cognitive dysfunction formation, or NE-100 is effective in the improvement of formed delayed cognitive dysfunction at a later phase (24 h after PCP administration). As a result, NE-100 showed efficacy in improving PCP induced delayed cognitive dysfunction by administration at either early (10 min after PCP administration) or late phase (24 h after PCP administration), but showed efficacy from a lower dose in the NE-100 administration at 15 min before the first trial (24 h after PCP administration). Thus, not only the limbic glutamatergic synapse for NMDA [3,4], but also sigma receptor seems to be related to PCPinduced delayed cognitive dysfunction in the early phase of formation as well as after formation, and it is suggested that clinical used of NE-100 which showed efficacy at a lower dose in forming delayed cognitive dysfunction, may have possibly improve cognitive dysfunction in schizophrenia patients. NE-100 has little affinity for the PCP receptor in rat brain membranes [8]. However, Yamamoto et al. [ 11,121 found that several sigma ligands, such as NE-100, haloperidol, (+)pentazocine 1,3-di-o-toly-guanidine (DTG), (+)-SKF10.047, (+)- and (-)-3-(3-hydroxyphenyl)-N-(lpropyl)piperidine (3-PPP), inhibit [3H]-N-[1-(2-thienyl)cyclohexyl-3,4-piperidine (TCP) intact cell binding in primary cultured neuronal cell from the fetal rat telecephalon and that the IC50 values of these sigma ligands for [3H]TCP binding to primary cultured neuronal cell closely correlated with Ki values of the corresponding drugs for sigma, site (formerly DTG site 1) in the guinea pig brain. These findings indicated that the sigma ligands indirectly modulate the NMDA receptor-ion channel in vivo, through the sigma, binding sites. In addition, DTG and 3-PPP enhanced the hyperlocomotion and headweaving behavior induced by MK-801 [6]. The enhancement of MK-801-induced hyperlocomotion and headweaving was blocked by NE-100, while NE-100 had no effect on MK-801-induced behavior [6]. Thus, the mode of action of NE-100 on the delayed effect of PCP may be
Letters 189 (1995) 60-42
related to modification of the interaction between sigma1 binding sites and the NMDA/PCP receptor/ion channel complex. We thank M. Ohara for her helpful comments. VI Chaki, s., Tanaka, M., Muramatsu, M. and Otomo, S., NE-100, a novel potent a-ligand, preferentially binds to c-1 binding sites in guineapig brain, Eur. J. Pharmacol., 251 (1994). Rl-R2. Ul Contreras, P.C., Rice, K.C., Jacobson, A.E. and O’Donohuc, T.L.,
r31
r41
r51
161
[71
181
r91
[lOI
r111
1121
Stereotyped behavior correlates better than ataxia with phencyclidine-receptor interactions, Eur. J. Pharmacol., 121 (1986) 9-18. Gao, X.-M., Kakigi, T. and Tamminga, C.A., Delayed phencyclidine effects on NMDA sensitive ‘H-glutamate binding, Sot. Neurosci. Abstr., 18 (1992) 978. Gao, X.-M., Shirakawa. 0, Du, F. and Tamminga, C.A., Delayed regional metabolic action of phencyclidine, Eur. J. Pharmacol., 241 (1993) 7-15. Javitt, D.C. and Zukin, S.R., Recent advances in the phencyclidin model of schizophrenia, Am. J. Psychiatry, 148 (1991) 13011308. Kitaichi, K., Hasegawa, T., Furukawa, H. and Nabeshima. T., Sigma ligands modulate MK-801-induced hyperlocomotion and head-weaving in rats, Jpn. J. Pharmacol., 64 (Suppl. 1) (1994) 358P. Ogawa, S., Okuyama, S., Araki, H. and Otomo, S., Effect of NE100, a novel u-receptor ligand, on phencyclidine-induced cognitive dysfunction, Eur. J. Pharmacol., 263 (1994) 9-15. Okuyama, S., Imagawa, Y., Ogawa, S., Araki, H., Tanaka, M., Muramatsu. M., Nakazato, A., Yamaguchi, K., Yoshida, M. and Otomo, S., NE-100, a novel sigma receptor ligand: in vivo tests, Life Sci., 53 (1993) PL 285-290. Okuyama. S.. Imagawa, Y., Sakagawa, T., Nakazato, A., Yamagichi, K., Katoh, M., Yamada, S., Araki, H. and Otomo, S., NE-100, a novel sigma receptor ligand: effect on phencyclidineinduced behaviors in rats, dogs and monkeys, Life Sci., 55 (1994) PL 133-138. Tamminga, CA., Thaker, G.K., Buchanan, R., Kirkpatric, B., Alphs, L.D., Chase, T.N. and Carpenter, W.T., Limbic system abnormalities identified in schizophrenia using positron emission tomography with fluorodeoxyglucose and neocortical alterations with deficit syndrome, Arch. Gen. Psychiatry, 49 (1992) 522-530. Yamamoto, H, Yamamoto, T., Sagi, N., Okuyama, S.. Kawai, N., Baba, A. and Moroji, T., NE-100, a novel sigma ligand: effects of [3H]TCP binding to intact primary cultured neuronal cells, Life Sci., 56 (1994) 3943. Yamanoto, H, Yamamoto, T., Sagi, N., Kleneroca, V., Kawai, N., Baba, A., Takamori, E. and Moroji, T., Sigma ligands indirectly modulate the NMDA receptor-ion channel complex on intact cell viao-1 site, J. Neurosci., 15 (1995) 731-736.
Neuroscience Letters 189 (1995) 60-62
1ElTIlS
Effect of NE-100, a novel sigma receptor ligand, on phencyclidine-induced delayed cognitive dysfunction in rats Shigeru Okuyama *, Shin-ichi Ogawa, Atsuro Nakazato, Kazuyuki Tomizawa Ist Laboratory, Medicinal Research Laboratories, Taisho Pharmaceutical Co., Ltd., I-403, Yoshino-Cho, Ohmiya, Saitama 330, Japan Received 31 January 1995; revised version received 27 February 1995; accepted 27 February 1995
Abstract Phencyclidine (PCP), in a dose of 15 mg/kg, produced delayed cognitive dysfunction (at 24 h) in rats subjected to water maze tasks. At 24 h after PCP administration, ataxia, hyperlocomotion and stereotyped behavior were not induced. NE-100, NJ-dipropyl-2-[4methoxy-3-(2-phenylethoxy)phenyl]-ethylamine monohydrochloride, a selective and potent sigma receptor ligand, was administered orally 10 min after PCP administration or 15 min before the first trial (24 h after PCP administration). In both cases, NE-100 dosedependently attenuated the delayed cognitive dysfunction induced by PCP. As these findings show that ingestion of PCP led to delayed
cognitive dysfunction similar to the cognitive signs of psychosis seen in humans, NE-100 is being further studied for possible treatment of subjects with schizophrenia. Keywords:
NE-100; Sigma ligand; Phencyclidine;
Cognition; Psychosis
NE-100, iV,N-dipropyl-2-[4-methoxy-3-(2-phenylethoxy)phenyl]ethylamine monohydrochloride, is a novel compound with high affinity for sigma1 but low affinity for sigma*, dopamine D1, dopamine D,, serotonin 5HT,,, serotonin 5-HT, and phencyclidine (PCP) receptors [1,8]. The head-weaving behavior induced by either (+)N-allylnormetazocine (SKF 10,047) or PCP was dosedependently antagonized by NE-100 [8]. The PCPinduced ataxia in dogs and monkey was to some extent overcome by NE-100 [9]. NE-100 did not affect dopamine agonists-induced stereotyped behavior, or hyperlocomotion [8] nor did it induce catalepsy in rats [8]. All these findings suggest that NE-100 may be an effective antipsychotic agent, without the motor side effects common to most neuroleptics. PCP induces a psychotomimetic state that closely resembles schizophrenia [5]. The administration of PCP to rats leads to a complex syndrome of behavior, i.e. hyperactivity, stereotyped behavior and ataxia [2]. A single dose of PCP produces an initial increase then a prolonged decrease in regional cerebral glucose metabolism lasting longer than 24 h and this effect is prominent in rat limbic structures [4]. Moreover, the psychotomimetic effects of *Corresponding
author, Tel.: +81 48 6631111; Fax: +81 48 6527254.
PCP, particularly of delayed effects may be mediated by limbic glutamatergic synapses selective for N-methyl-Daspartate (NMDA) [3]. This is of interest since the limbic system has long been implicated in psychotic conditions such as schizophrenia [lo]. We previously reported the effects of NE-100 on PCP-induced acute cognitive dysfunction in rats in the water maze task [7]. In the present work, we examined the PCP-induced delayed effect on cognition in rats subjected to the Morris water maze, and the effects of NE-100 (sigma, receptor ligand) on the delayed effect of PCP. Male Wistar rats (Clea Japan, Inc., Tokyo, Japan), weighing about 250 g at the start of experiments, were used. The animals were housed in a temperatureand light-controlled room (a 12 h light cycle starting at 0700 h). The rats had free access to food and water except during the experiment, and were manually handled prior to the experiments. A circular tank (140 cm in diameter and 45 cm high) was used. A transparent platform (10 cm in diameter and 25 cm high) set inside the tank was filled to a height of 27 cm with water at approximately 22°C (the platform’s surface was 2 cm below the surface of the water). The pool was located in a large test room and many external cues within the pool could be used by the rat for spatial
0304-3940/95/$09.50 0 1995 Elsevier Science Ireland Ltd. All rights reserved SSDI 0304-3940(95)1 1440-5
S. Okuyama et al. I Neuroscience
PCP
NE-100 10min
100
-
60
-
I ’
24 h
G LoE g 3
Fig. 1. Effect of NE-100, when given 10 min after PCP administration, on PCP-induced delayed cognitive dysfunction in rats. N, number of animals. Control versus PCP; treatment effects F(l,llO) = 17.43, P < 0.01 by ANOVA, and P < 0.01 by Dunnett’s test; PCP versus NE100 (1 mg/kg); treatment effects F( 1,110) = 6.70, P < 0.05 by ANOVA and P < 0.05 by Dunnett’s test. #P c 0.05 and ##P < 0.01 versus control (Dunnett’s test).
orientation. The position of the cues was unchanged throughout the training. The rats was placed at one of three starting positions for each training session, but the sequence of positions were selected randomly. The platform was located in a constant position in the middle of one quadrant, equidistant from the center and the edge of the pool. In each training session, the time to escape onto the hidden platform was recorded. If the rat found the platform within 100 s, it was allowed to remain there for 30 s then it was returned to its home cage. If the rat was unable to find the platform within 100 s, it was placed on the platform for 30 s and a maximum time of 100 s was assigned. The experimental session consisted of 5 trials at 2 h intervals 24 h after PCP administration. Phencyclidine hydrochloride (PCP) was dissolved in 0.9% saline. NE-100 was dissolved in distilled water. PCP was administered i.p. in a volume of 1 ml/kg of body weight. NE-100 was given orally 10 min after the PCP administration or 15 min before the first trials. The data are expressed in terms of mean latency and were analyzed using two-way analysis of variance (2-way ANOVA) and Dunnett’s test. When 15 mg/kg of PCP was administered, ataxia, hyperlocomotion and stereotyped behavior were absent 24 h later (data not shown). The swimming latencies of PCP-treated rats on the first trial did not differ from findings in the control group. However, throughout the training, PCP-treated rats were slower than the control group to find the platform. PCP did not affect swimming ability, posture or speed but did affect swimming pattern used to find the platform in the water maze task.
61
Letters 189 (1995) 60-62
In case of NE-100 (0.1-l mg/kg p.o.j given 10 min after PCP administration, NE- 100 dose-dependently attenuated the delayed cognitive dysfunction induced by PCP (Fig. 1). Statistical data: control versus PCP; treatment effects F(l,llOj = 17.43, P < 0.01 by ANOVA, and P < 0.01 by Dunnett’s test; PCP versus NE-100 (1 mg/ kg); treatment effects F( 1,110) = 6.70, P < 0.05 by ANOVA, and P < 0.05 by Dunnett’s test. In the case of NE-100 (0.03-0.3 mg/kg p.o.) given 15 min before the first trial, NE-100 also dosedependently attenuated the delayed cognitive dysfunction induced by PCP (Fig. 2). Statistical data: control versus PCP, treatment effects F(1,90) = 23.87, P < 0.01 by ANOVA, and P < 0.01 by Dunnett’s test; PCP versus NE100 (0.3 mg/kgj, treatment effects F( 1,90) = 7.74, P < 0.01 by ANOVA, and P < 0.01 by Dunnett’s test. PCP (15 mg/kgj ingestion by rats led to delayed cognitive dysfunction, without the induction of ataxia, hyperlocomotion and stereotyped behavior. The threshold for effective doses (over 15 mg/kgj of PCP appears critical since lower doses (under 10 mg/kgj had no apparent effects, in pilot experiments. Gao et al. [3,4] reported the 24 h effects of PCP on NMDA sensitive [3H]glutamate binding sites and on the metabolism of cerebral glucose; these was an increase in NMDA binding and a decrease in regional cerebral glucose metabolism in limbic structures, limbic related neocortex and posterior cingulate cortex 24 h after a single dose of PCP. Thus, PCP-induced delayed cognitive dysfunction may possibly be mediated by limbic glutamatergic synapses for NMDA. The effect of NE-100 administration at 10 min after administration of PCP, and NE-100 administration at 15 min before the first trial (24 h after administration of NE-100
PCP
t
tn
24 hr
01 1
+
+ NE-100 (0.3 mgikg, p.0.) (pd3.01 vs. PCP. ANOVA) (~~10)
I
2
3
4
5
Trials Fig. 2. Effect of NE-100, when given 15 min before first trial (24 h after PCP administration), on PCP-induced delayed cognitive dysfunction in rats. N. number of animals. Control versus PCP; treatment effects F(1.90) = 23.87. P < 0.01 by ANOVA, and P < 0.01 by Dunnett’s test; PCP versus NE-100 (0.3 mg/kg); treatment effects F(I .90) = 7.74, P < 0.01 by ANOVA, and P < 0.01 by Dunnett’s test. “P < 0.01 versus control (Dunnett’s test).
62
S. Okuyuma et al. I Neuroscience
PCP), was compared in the improvement of PCP-induced delayed cognitive dysfunction. The purpose of this comparison was to elucidate whether NE-100 is effective through the inhibition of PCP induction of delayed cognitive dysfunction at an early phase of delayed cognitive dysfunction formation, or NE-100 is effective in the improvement of formed delayed cognitive dysfunction at a later phase (24 h after PCP administration). As a result, NE-100 showed efficacy in improving PCP induced delayed cognitive dysfunction by administration at either early (10 min after PCP administration) or late phase (24 h after PCP administration), but showed efficacy from a lower dose in the NE-100 administration at 15 min before the first trial (24 h after PCP administration). Thus, not only the limbic glutamatergic synapse for NMDA [3,4], but also sigma receptor seems to be related to PCPinduced delayed cognitive dysfunction in the early phase of formation as well as after formation, and it is suggested that clinical used of NE-100 which showed efficacy at a lower dose in forming delayed cognitive dysfunction, may have possibly improve cognitive dysfunction in schizophrenia patients. NE-100 has little affinity for the PCP receptor in rat brain membranes [8]. However, Yamamoto et al. [ 11,121 found that several sigma ligands, such as NE-100, haloperidol, (+)pentazocine 1,3-di-o-toly-guanidine (DTG), (+)-SKF10.047, (+)- and (-)-3-(3-hydroxyphenyl)-N-(lpropyl)piperidine (3-PPP), inhibit [3H]-N-[1-(2-thienyl)cyclohexyl-3,4-piperidine (TCP) intact cell binding in primary cultured neuronal cell from the fetal rat telecephalon and that the IC50 values of these sigma ligands for [3H]TCP binding to primary cultured neuronal cell closely correlated with Ki values of the corresponding drugs for sigma, site (formerly DTG site 1) in the guinea pig brain. These findings indicated that the sigma ligands indirectly modulate the NMDA receptor-ion channel in vivo, through the sigma, binding sites. In addition, DTG and 3-PPP enhanced the hyperlocomotion and headweaving behavior induced by MK-801 [6]. The enhancement of MK-801-induced hyperlocomotion and headweaving was blocked by NE-100, while NE-100 had no effect on MK-801-induced behavior [6]. Thus, the mode of action of NE-100 on the delayed effect of PCP may be
Letters 189 (1995) 60-42
related to modification of the interaction between sigma1 binding sites and the NMDA/PCP receptor/ion channel complex. We thank M. Ohara for her helpful comments. VI Chaki, s., Tanaka, M., Muramatsu, M. and Otomo, S., NE-100, a novel potent a-ligand, preferentially binds to c-1 binding sites in guineapig brain, Eur. J. Pharmacol., 251 (1994). Rl-R2. Ul Contreras, P.C., Rice, K.C., Jacobson, A.E. and O’Donohuc, T.L.,
r31
r41
r51
161
[71
181
r91
[lOI
r111
1121
Stereotyped behavior correlates better than ataxia with phencyclidine-receptor interactions, Eur. J. Pharmacol., 121 (1986) 9-18. Gao, X.-M., Kakigi, T. and Tamminga, C.A., Delayed phencyclidine effects on NMDA sensitive ‘H-glutamate binding, Sot. Neurosci. Abstr., 18 (1992) 978. Gao, X.-M., Shirakawa. 0, Du, F. and Tamminga, C.A., Delayed regional metabolic action of phencyclidine, Eur. J. Pharmacol., 241 (1993) 7-15. Javitt, D.C. and Zukin, S.R., Recent advances in the phencyclidin model of schizophrenia, Am. J. Psychiatry, 148 (1991) 13011308. Kitaichi, K., Hasegawa, T., Furukawa, H. and Nabeshima. T., Sigma ligands modulate MK-801-induced hyperlocomotion and head-weaving in rats, Jpn. J. Pharmacol., 64 (Suppl. 1) (1994) 358P. Ogawa, S., Okuyama, S., Araki, H. and Otomo, S., Effect of NE100, a novel u-receptor ligand, on phencyclidine-induced cognitive dysfunction, Eur. J. Pharmacol., 263 (1994) 9-15. Okuyama, S., Imagawa, Y., Ogawa, S., Araki, H., Tanaka, M., Muramatsu. M., Nakazato, A., Yamaguchi, K., Yoshida, M. and Otomo, S., NE-100, a novel sigma receptor ligand: in vivo tests, Life Sci., 53 (1993) PL 285-290. Okuyama. S.. Imagawa, Y., Sakagawa, T., Nakazato, A., Yamagichi, K., Katoh, M., Yamada, S., Araki, H. and Otomo, S., NE-100, a novel sigma receptor ligand: effect on phencyclidineinduced behaviors in rats, dogs and monkeys, Life Sci., 55 (1994) PL 133-138. Tamminga, CA., Thaker, G.K., Buchanan, R., Kirkpatric, B., Alphs, L.D., Chase, T.N. and Carpenter, W.T., Limbic system abnormalities identified in schizophrenia using positron emission tomography with fluorodeoxyglucose and neocortical alterations with deficit syndrome, Arch. Gen. Psychiatry, 49 (1992) 522-530. Yamamoto, H, Yamamoto, T., Sagi, N., Okuyama, S.. Kawai, N., Baba, A. and Moroji, T., NE-100, a novel sigma ligand: effects of [3H]TCP binding to intact primary cultured neuronal cells, Life Sci., 56 (1994) 3943. Yamanoto, H, Yamamoto, T., Sagi, N., Kleneroca, V., Kawai, N., Baba, A., Takamori, E. and Moroji, T., Sigma ligands indirectly modulate the NMDA receptor-ion channel complex on intact cell viao-1 site, J. Neurosci., 15 (1995) 731-736.