![[Feedback]](/icons/banner/feedbackACT.gif){kind=icon}
![[For Subscribers]](/icons/banner/subscriberACT.gif){kind=icon}
![[Archive]](/icons/banner/archiveACT.gif){kind=icon}
![[Search]](/icons/banner/searchACT.gif){kind=icon}
![[Contents]](/icons/banner/tocACT.gif){kind=icon}
|
|
|
|
|
||
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
NEUROPHARMACOLOGY
Laboratory of Neuropsychopharmacology, Division of Life Sciences, Graduate School of Natural Science and Technology, Kanazawa University, Kanazawa, Japan
Received September 15, 2006; accepted November 6, 2006.
 |
Abstract |
|---|
 Top Abstract Materials and MethodsResultsDiscussionReferences |
|---|
-[amino-(4-aminophenylthio)methylene]-2-(trifluoromethyl)phenylacetonitrile). Furthermore, the dopamine D1 receptor antagonist, SCH23390 [R-(+)-7-chloro-8-hydroxy-3-methyl-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine], and N-methyl-D-aspartate (NMDA) receptor antagonist, MK-801 [5H-dibenzo[a,d]cyclohepten-5,10-imine (dizocilpine maleate)], blocked the ameliorating effect of ZSET1446 on METH-induced memory impairment, whereas the D2 receptor antagonist, raclopride, had no effect. These results suggest that the ameliorative effect of ZSET1446 on METH-induced memory impairment is associated with indirect activation of ERK1/2 following stimulation with dopamine D1 and NMDA receptors of the PFC. ZSET1446 would be a potential candidate for further preclinical study aimed at the treatment of cognitive deficits in Alzheimer's disease and schizophrenia, as well as METH psychosis.
). ZSET1446 increases extracellular acetylcholine (ACh) levels in the cortex and hippocampus (Yamaguchi et al., 2002, 2003) and enhances nicotine-stimulated ACh release in the hippocampus in normal rats (Y. Yamaguchi et al., unpublished data). In addition, ZSET1446 shows ameliorating effects on the impairment of performance in a passive avoidance task caused by a single intracerebroventricular injection of amyloid 
peptide (A) fragment, A25–35, or by lesions of the nucleus basalis magnocellularis by ibotenic acid (Yamaguchi et al., 2003). Furthermore, the compound ameliorates learning and memory impairment in rats with continuous intracerebroventricular infusion of A1–40 in Y-maze, water maze, and passive avoidance tasks. The ameliorating effects of ZSET1446 are associated with reversal of the decrease in choline acetyltransferase activity in the medial septum and hippocampus, glutathione S-transferase-like immunoreactivity in the cortex and nicotine-stimulated ACh release in A1–40-infused rats to the levels of vehicle-infused control rats (Yamaguchi et al., 2006). Thus, ZSET1446 is a potential novel therapeutic agent for cognitive impairment associated with conditions such as Alzheimer's disease, although the mechanism of action remains to be determined.
Cognitive deficits are also a core feature in patients with schizophrenia. Furthermore, recent studies have demonstrated that chronic use of methamphetamine (METH) causes long-term cognitive deficits (Simon et al., 2000; Kalechstein et al., 2003; Nordahl et al., 2003), in addition to psychiatric signs such as hallucinations and delusions, which are indistinguishable from paranoid schizophrenia (Yui et al., 2002; Srisurapanont et al., 2003). In a previous study, we demonstrated that repeated METH treatment in mice impairs long-term recognition memory after withdrawal and that METH-induced cognitive impairment is reversed by an atypical antipsychotic, clozapine, but not haloperidol (Kamei et al., 2006). Thus, METH-induced cognitive impairment in mice may be a useful animal model for cognitive deficits in METH abusers and schizophrenic patients. In this study, to assess the effects of ZSET1446 on cognitive deficits in schizophrenia, we investigated the effects of ZSET1446 on the impairment of recognition memory in METH-treated mice in a novel-object recognition test (NORT).
|
Materials and Methods |
|---|
|
TopAbstractMaterials and MethodsResultsDiscussionReferences |
|---|
Drugs. Methamphetamine hydrochloride (Dainippon Sumitomo Pharma Co Ltd, Osaka, Japan), S(–)-raclopride (+)-tartrate salt (Sigma-Aldrich, St. Louis, MO), R(+)-7-chloro-8-hydroxy-3-methyl-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine hydrochloride (SCH23390; Tocris Biosciences, Ellisville, MO) and dizocilpine hydrogen maleate (MK-801; Sigma-Aldrich) were dissolved in saline. ZSET1446 was kindly provided by Zenyaku Kogyo Co. Ltd. (Tokyo, Japan) and was suspended in 1% carboxymethyl cellulose (CMC). -[Amino-(4-aminophenylthio)methylene]-2-(trifluoromethyl)phenylacetonitrile (SL327; Sigma) was dissolved in 100% dimethyl sulfoxide and injected at a volume of 0.02 ml/10 g. All drugs except SL327 were administered at a volume of 0.1 ml/10 g b.wt.
Novel-Object Recognition Test. The NORT was carried out as described previously (Nagai et al., 2003; Kamei et al., 2006). The experimental apparatus consisted of a Plexiglas open-field box (30 cm x 30 cm x 35 cm high), with a sawdust-covered floor. The apparatus was located in a sound-attenuated room and was illuminated with a 20-W bulb.
The NORT procedure consisted of three sessions: habituation, training, and retention. Each mouse was individually habituated to the box, with 10 min of exploration in the absence of objects for 3 consecutive days (habituation session, days 1–3). During the training session, two novel objects were symmetrically fixed to the floor of the box, 8 cm from the walls, and each animal was allowed to explore in the box for 10 min (day 4). The objects were constructed from a golf ball, wooden column, and wall socket, which were different in shape and color but similar in size. The animals were considered to be exploring the object when the head of the animal was facing the object or when the animal was touching or sniffing the object. The time spent exploring each object was recorded. After training, mice were immediately returned to their home cages. During the retention sessions, the animals were placed back into the same box 24 h (day 5) after the training session, in which one of the familiar objects used during training was replaced by a novel object. The animals were then allowed to explore freely for 5 min, and the time spent exploring each object was recorded. Throughout the experiments, the objects were used in a counterbalanced manner in terms of their physical complexity and emotional neutrality. A preference index in the retention session, a ratio of the amount of time spent exploring the novel object over the total time spent exploring both objects, was used to measure cognitive function. In the training session, the preference index was calculated as a ratio of the time spent exploring the object that was replaced by the novel object in the retention session over the total exploring time.
Experimental Schedule. In typical experimental conditions, mice were given METH (1 mg/kg s.c.) once daily for 7 days. One day after the last treatment of METH, the NORT commenced, including habituation, training, and retention sessions. To examine the reversibility of METH-induced memory impairment, the NORT was also performed at 3 weeks after the last administration of METH. ZSET1446 or vehicle (1% CMC solution) was administered p.o. 1 h before the training session of the NORT. To test whether activation of the extracellular signal-regulated kinase 1/2 (ERK1/2) pathway was necessary for the ameliorating effects of ZSET1446 in the NORT, SL327 (50 mg/kg), a selective mitogen-activated protein kinase/extracellular signal-regulated kinase kinase (MEK) inhibitor, was administered i.p. 1 h before the training session. SCH23390, raclopride, and MK-801 were administered i.p. 30 min before the training session.
Western Blotting. Phosphorylation of ERK1/2 was examined by Western blotting as described previously (Mizoguchi et al., 2004; Kamei et al., 2006). The protein concentration was determined using a Protein Assay Rapid Kit (Wako Pure Chemicals, Osaka, Japan). Tissue samples from prefrontal cortex (PFC) were homogenized at 4°C in a lysis buffer composed of 20 mM Tris-HCl, 150 mM NaCl, 50 mM NaF, 1 mM EDTA, 1 mM EGTA, 1% Triton X-100, 1 mM sodium orthovanadate, 0.1% SDS, 1% sodium deoxycholate, 0.5 mM dithiothreitol, 10 mM sodium pyrophosphate decahydrate, 1 mM phenylmethylsulfonyl fluoride, 10 µg/ml aprotinin, 10 µg/ml leupeptin, and 10 µg/ml pepstatin (pH 7.4). For the analysis of phosphorylated ERK, 20 µg of protein was boiled in a sample buffer [0.125 M Tris-HCl (pH 6.8), 2% SDS, 5% glycerol, 0.002% bromphenol blue, and 5% 2-mercaptoethanol], applied onto a 10% polyacrylamide gel, subsequently transferred to a polyvinylidene difluoride membrane (Millipore Corporation, Billerica, MA) or a nitrocellurose membrane (GE Healthcare Biosciences, Piscataway, NJ), and blocked with a Detector Block Kit (Kirkegaard and Perry Laboratories, Gaithersburg, MD). Membranes were incubated with anti-phospho-ERK1/2 [phospho-p44/42 mitogen-activated protein kinase (Thr202/Tyr204) (E10) monoclonal antibody] (1:2000 dilution; Cell Signaling Technology Inc., Beverly, MA) and washed with Tris-buffered saline-Tween 20 [10 mM Tris-HCl (pH 7.5), 100 mM NaCl, and 1% Tween 20] three times for 10 min each. After incubation with a 1:5000 dilution of horseradish peroxidase-conjugated anti-mouse IgG for 1 h, membranes were washed with PBS-Tween 20 three times for 10 min each. The immune complex was detected using ECL Western blotting detection reagents (GE Healthcare Biosciences). The same membranes were stripped with a stripping buffer (137 mM NaCl, 2.7 mM KCl, 8.1 mM disodium hydrogen phosphate, 12-water, 1.5 mM potassium dihydrogen phosphate, and 0.2% 2-mercaptoethanol) at 55°C for 30 min, incubated with anti-ERK1/2 (1:5000 dilution, anti-mitogen-activated protein kinase 1/2; Upstate Biotechnology, Lake Placid, NY), and treated as described above.
As there was no change in the level of total ERK1/2, values of phosphorylated ERK1/2 were normalized to the values of total ERK1/2. All data from Western blotting are expressed as a percentage of the control.
Statistical Analysis. All data were expressed as means ± S.E. Statistical significance was determined using one-way analysis of variance (ANOVA), followed by the Student-Newman-Keuls test for multigroup comparisons. P values < 0.05 were taken to indicate statistically significant differences.
|
Results |
|---|
|
TopAbstractMaterials and MethodsResultsDiscussionReferences |
|---|
|
We have previously demonstrated that repeated METH treatment caused an enduring memory deficit, so that METH-treated mice showed recognition memory impairment even 3 weeks after the withdrawal of METH (Kamei et al., 2006). Figure 2 shows the effect of ZSET1446 on METH-induced impairment of recognition memory after the withdrawal of METH for 3 weeks. ZSET1446 (1 µg/kg) significantly improved the cognitive impairment in METH-treated mice [F(2,21) = 12.905, p < 0.05 by one-way ANOVA and p < 0.01 by post hoc test] (Fig. 2A). Treatment with ZSET1446 affected neither the level of exploratory preference for the novel object in the training session [F(2,21) = 2.199, p = 0.1358 by one-way ANOVA] (Fig. 2A) nor the total exploration time in either the training [F(2,21) = 0.520, p = 0.6018 by one-way ANOVA] or retention sessions [F(2,21) = 0.304, p = 0.7409 by one-way ANOVA] in METH-treated mice (Fig. 2B).
|
). To examine the mechanism by which ZSET1446 ameliorates the impairment of recognition memory in METH-treated mice, we examined the effect of ZSET1446 on ERK1/2 phosphorylation in the PFC of METH-treated mice when they were exposed to novel objects. Accordingly, the animals were killed immediately after the exposure to novel objects in the training session, and phosphorylated ERK1/2 levels in the PFC were determined by Western blotting. In agreement with the previous study, a significant increase in the phosphorylation of ERK1/2 levels was observed in the PFC of saline-treated mice immediately after a 10-min exposure to novel objects, and repeated METH treatment abolished novelty-induced ERK1/2 activation in the PFC [F(5,22) = 6.842, p < 0.01 by one-way ANOVA and p<0.05 by post hoc test] (Fig. 3). ZSET1446 (1 µg/kg) significantly recovered the defect of novelty-induced activation of ERK1/2 in the PFC of METH-treated mice (p < 0.05 by post hoc test) (Fig. 3). The levels of total ERK1/2 did not differ among the groups examined.
|
|
Influence of a MEK Inhibitor on the Ameliorating Effect of ZSET1446 against METH-Induced Cognitive Impairment. We have already found that treatment with SL327 (30 and 50 mg/kg i.p.), a selective MEK inhibitor, 1 h before the training session dose dependently impairs long-term recognition memory in naive mice (unpublished data). Then, we examined the effect of SL327 (50 mg/kg) administered before the training session on the improvement of METH-induced impairment of recognition memory by ZSET1446 to determine the involvement of ERK1/2 activation in the effect of ZSET1446. In the training session, treatment with SL327 alone did not affect the exploratory preference for the objects [F(4,26) = 0.432, p = 0.7840 by one-way ANOVA] (Fig. 5A. In the retention test, SL327 completely blocked the ameliorating effect of ZSET1446 on the impairment of exploratory preference for a novel object in METH-treated mice [F(4,26) = 18.738, p < 0.05 by one-way ANOVA and p < 0.01 by post hoc test] (Fig. 5A), although it had no effect on METH-induced impairment of memory retention. The antagonistic effect of SL327 on ZSET1446-induced improvement of exploratory preference in METH-treated mice was not associated with changes in the total exploration time [training: F(4,26) = 0.375, p = 0.8244; retention: F(4,26) = 1.642, p = 0.1938 by one-way ANOVA] (Fig. 5B).
|
; Zanassi et al., 2001) is involved in METH-associated contextual memory in rats (Mizoguchi et al., 2004). Moreover, we have demonstrated that repeated METH treatment in mice induces cognitive impairment in the NORT, which is accompanied by dysfunction of the dopamine D1 receptor-ERK1/2 pathway in the PFC (Kamei et al., 2006). Therefore, we investigated whether activation of dopamine receptors was involved in the ameliorating effect of ZSET1446 on memory impairment in METH-treated mice. We have already found that the dopamine D1 receptor antagonist SCH23390 (0.03 and 0.05 mg/kg i.p.) impaired long-term recognition memory, whereas the D2 receptor antagonist raclopride (0.1 and 0.3 mg/kg i.p.) had no effect in naive mice without affecting locomotor activity or total exploration time of novel objects in the training session (unpublished data). Accordingly, SCH23390 (0.05 mg/kg i.p.) or raclopride (0.3 mg/kg i.p.) was administered before the training session. In the training session, treatment with SCH23390 alone did not affect the exploratory preference for the objects [F(6,49) = 0.459, p = 0.8352 by one-way ANOVA] (Fig. 6A). In the retention test, SCH23390 significantly blocked the ameliorating effect of ZSET1446 on the impairment of exploratory preference for a novel object in METH-treated mice [F(6,49) = 18.539, p < 0.05 by one-way ANOVA and p < 0.01 by post hoc test] (Fig. 6A), although it had no effect on METH-induced impairment of memory retention. In contrast, treatment with raclopride had no effect on exploratory preference in the training and retention sessions (Fig. 6A). Treatment with antagonists did not affect the total exploration time in either the training [F(6,49) = 1.007, p = 0.4319 by one-way ANOVA] (Fig. 6B) or retention sessions [F(6,49) = 0.738, p = 0.6218 by one-way ANOVA] (Fig. 6B).
|
Effect of NMDA Receptor Antagonist on the Ameliorative Effect of ZSET1446 against METH-Induced Cognitive Impairment. Several lines of evidence have demonstrated the interaction between NMDA and dopamine D1 receptors (Wang and O'Donnell, 2001; Lee et al., 2002). The dopamine D1 receptor plays a key role in NMDA receptor-dependent long-term potentiation (LTP) in hippocampal-PFC circuits (Gurden et al., 2000). In addition, repeated METH administration impairs LTP in hippocampal-PFC (Ishikawa et al., 2005). Moreover, both protein synthesis and NMDA receptors are required for the consolidation of recognition memory in the PFC (Akirav and Maroun, 2006). Therefore, we examined whether NMDA receptors were involved in the ameliorative effect of ZSET1446 on memory impairment in METH-treated mice. A NMDA receptor blocker MK-801 was reported to impair object recognition memory in naive rats (de Lima et al., 2005). We also found that MK-801 (0.1 mg/kg i.p.) impaired long-term recognition memory 24 h after the training session in naive mice (data not shown). Therefore, MK-801 (0.1 mg/kg i.p.) was administered before the training session. In the training session, treatment with MK-801 alone did not affect the exploratory preference for the objects [F(4,39) = 0.582, p = 0.6775 by one-way ANOVA] (Fig. 7A). In the retention test, MK-801 blocked the ameliorating effect of ZSET1446 on the impairment of exploratory preference for a novel object in METH-treated mice [F(4,39) = 9.940, p < 0.05 by one-way ANOVA and p < 0.01 by post hoc test] (Fig. 7A), although it had no effect on METH-induced impairment of memory retention. The antagonistic effect of MK-801 on ZSET1446-induced improvement of exploratory preference in METH-treated mice was not associated with changes in total exploration time [training: F(4,39) = 0.622, p = 0.6497; retention: F(4,39) = 0.537, p = 0.7092 by one-way ANOVA] (Fig. 7B).
|
|
Discussion |
|---|
|
TopAbstractMaterials and MethodsResultsDiscussionReferences |
|---|
). These observations in METH-treated mice are consistent with recent studies in human subjects demonstrating that long-term METH use is associated with cognitive deficits (Simon et al., 2000; Volkow et al., 2001). Alternatively, the fact that METH significantly reduced the exploratory preference for novel objects in the retention session could be interpreted as a neophobia. However, a possible involvement of neophobia can be excluded because METH treatment had no effect on total exploration time of novel objects during the training session. Furthermore, it is unlikely that the deficit of recognition memory in repeated METH-treated mice is due to the changes in attention, curiosity, or locomotor activity because repeated METH treatment had no effect on total exploratory time or locomotor activity during training and retention sessions (Kamei et al., 2006).
Accumulating evidence suggests that the dopaminergic system in the PFC is involved in cognitive function. For instance, disruption of dopamine transmission in the PFC by infusions of dopamine D1 receptor antagonists or by excitotoxic lesions impairs the performance of object retrieval-detour tasks, as well as delayed response tasks in nonhuman primates (Sawaguchi and Goldman-Rakic 1991; Dias et al., 1996a,b). A recent study with functional magnetic resonance imaging showed that dysfunction in the PFC of METH abusers is related to cognitive impairment (Paulus et al., 2002). Accordingly, cognitive impairment in METH abusers may be associated with deficits in dopamine transmission in the PFC.
Clozapine, but not haloperidol, completely restored the cognitive impairment induced by METH treatment when repeatedly administered for 7 days after withdrawal from METH, although acute treatment with these antipsychotics had no effect (Kamei et al., 2006). The data are consistent with clinical evidence that clozapine is superior to typical neuroleptics in improving cognitive deficits in schizophrenic patients (Lee et al., 1999). Thus, we propose that cognitive impairment induced by repeated METH treatment in mice is a useful model to study cognitive deficits in schizophrenia and METH psychosis.
In this study, acute treatment with ZSET1446 significantly improved cognitive impairment without affecting motor function in METH-treated mice. These results suggest that ZSET1446 is effective for the treatment of cognitive deficits in patients with schizophrenia and METH psychosis. Furthermore, the effect of ZSET1446 may be superior to clozapine and other antipsychotics because acute treatment with ZSET1446 showed an improving effect whereas repeated treatment was necessary for the effect of clozapine.
Recent studies have demonstrated that the ERK1/2 signaling pathway linked to dopamine D1 receptors (Valjent et al., 2000; Zanassi et al., 2001) is involved in the rewarding effects induced by METH (Mizoguchi et al., 2004) and the behavioral sensitization and rewarding effects induced by cocaine (Valjent et al., 2000). Regarding the mechanism underlying the repeated METH-induced memory impairment, we have already demonstrated dysfunction of the ERK1/2 pathway in the PFC. Hyperphosphorylation of ERK1/2 was found in the PFC when control mice were exposed to novel objects whereas this activation was abolished in repeated METH-treated mice. Inhibition of ERK1/2 by the microinjection of PD98059, a selective MEK inhibitor, into the PFC resulted in cognitive impairment (Kamei et al., 2006). We also found that SL327 (30 and 50 mg/kg i.p.) significantly impaired long-term recognition memory 24 h after the training session in naive mice (unpublished data). In this study, ZSET1446 ameliorated the METH-induced defect of ERK1/2 hyperphosphorylation in the PFC of mice exposed to novel objects. In addition, the ameliorating effect of ZSET1446 on METH-induced object-recognition impairment was completely blocked by pretreatment with the MEK inhibitor SL327. Accordingly, these results suggest that the ameliorating effect of ZSET1446 on METH-induced cognitive impairment is related to the activation of ERK1/2 in the PFC.
In this study, we demonstrated that ZSET1446 increased phosphorylated ERK1/2 levels in the hippocampus, but not the PFC, of naive mice. It is not clear whether this phenomenon is related to the ameliorating effect of ZSET1446 on METH-induced memory impairment, but ZSET1446 significantly increased the exploratory preference for novel objects in normal mice in the NORT (data not shown). As ZSET1446 (10–5 M) has no effect on kinase activity, including ERK1/2 (unpublished data), the data suggest that ZSET1446 indirectly activates ERK1/2 in the brain. Accordingly, it is likely that ERK1/2 in the PFC of repeated METH-treated mice may be activated indirectly by acute ZSET1446 treatment.
It is known that ERK1/2 is critically linked to dopamine D1 receptors coupled with Gs protein (Valjent et al., 2000; Zanassi et al., 2001). Several second messengers could be responsible for the link between dopamine D1 receptors and ERK1/2. Namely, cAMP, the first second messenger to be recognized as a modulator of ERK1/2 phosphorylation, induces the phosphorylation of ERK1/2 via the small Ras-related G protein Rap1, which is activated by protein kinase A and interacts with the B Raf isoform (Vossler et al., 1997; Zanassi et al., 2001; Belcheva and Coscia, 2002). Dopamine plays a critical role in cognitive function; for instance, the dopamine D1 receptor antagonist SCH23390 selectively blocks the maintenance but not the induction of LTP in the PFC. Conversely, activation of dopamine D1 receptors facilitates LTP, and this effect is impaired in heterozygous dopamine D1 receptor knockout mice (Huang et al., 2004). Infusions of the dopamine D1 receptor antagonist SCH23390 or SCH39166 into the PFC of monkeys (Sawaguchi and Goldman-Rakic, 1991, 1994) or rats (Seamans et al., 1995) produce delay-related impairment in spatial working memory performance, whereas comparable infusions of dopamine D2 receptor antagonists show no effect. Moreover, it has been proposed that dopaminergic hypofunction in the PFC is related to the cognitive dysfunction of schizophrenia (Okubo et al., 1997) and that the improving effect of clozapine is related to the enhancement of dopamine transmission in the PFC (Kuroki et al., 1999; Youngren et al., 1999). In this study, we demonstrated that coadministration of a dopamine D1 receptor antagonist blocked the ameliorating effect of ZSET1446 on METH-induced memory impairment, whereas a D2 receptor antagonist had no effect. Therefore, it is suggested that activation of dopamine D1 receptors in the PFC is necessary for the ameliorating effect of ZSET1446.
Interest in the role of NMDA receptors in learning and memory originates primarily from extensive evidence that these receptors are essential for the induction of LTP. Several lines of evidence have demonstrated an interaction between NMDA and dopamine D1 receptors (Wang and O'Donnell, 2001; Lee et al., 2002). D1 receptor-stimulated activation of protein kinase A induces phosphorylation of the NR1 subunit of the NMDA receptor, which is involved in D1 receptor-mediated phosphorylation of cAMP response element-binding protein (Dudman et al., 2003). These signaling pathways play a key role in NMDA-dependent LTP in hippocampal-PFC circuits (Gurden et al., 2000). Considering the interaction between D1 and NMDA receptors, it is possible that the ameliorating effect of ZSET1446 is also associated with the activation of NMDA receptors. In fact, we found that MK-801 significantly attenuated the effect of ZSET1446 on METH-induced memory impairment.
As discussed above, our findings suggest that dopamine D1-ERK1/2 and NMDA receptor systems are required for the effects of ZSET1446. However, because dopamine D1-ERK1/2 and NMDA receptor systems are critical in recognition memory, one might expect that the effects of ZSET1446 would be reversed by these antagonists regardless of the mechanisms of ZSET1446 to attenuate the cognitive impairment in METH-treated mice. However, if the action site of ZSET1446 is downstream of dopamine D1-ERK1/2 and NMDA receptor systems, the receptor antagonists or the MEK inhibitor would fail to reverse the effect of ZSET1446. Accordingly, our data suggest that ZSET1446 acts upstream of dopamine D1-ERK1/2 and NMDA receptor systems.
It has been reported that ZSET1446 increases extracellular ACh levels in the cortex and hippocampus (Yamaguchi et al., 2002, 2003) and extracellular dopamine levels in the hippocampus in normal rats (Y. Yamaguchi et al., unpublished data) although ZSET1446 (10–5 M) does not act on any receptor system (Y. Yamaguchi et al., unpublished data). These findings suggest that the cholinergic system, in addition to the dopaminergic system, may be involved in the pharmacological effect of ZSET1446. As shown in this study, the dopamine D1 receptor antagonist and NMDA receptor antagonist completely blocked the ameliorating effect of ZSET1446 in METH-treated mice. Therefore, it is likely that ZSET1446 attenuates impairment of recognition memory in METH-treated mice by stimulating neurotransmitter release such as dopamine and glutamate, which results in indirect activation of the ERK1/2 pathway in the PFC via dopamine D1 and NMDA receptors. Further studies are necessary to clarify the molecular mechanism of action of this compound.
In conclusion, the ameliorating effect of ZSET1446 on METH-induced memory impairment is associated with indirect activation of the ERK1/2 pathway after stimulation of dopamine D1 and NMDA receptors in the PFC. ZSET1446 is a potential candidate for further preclinical study aimed at the treatment of cognitive deficits in Alzheimer's disease and schizophrenia as well as METH psychosis.
|
Acknowledgements |
|---|
|
Footnotes |
|---|
Y.I. and K.T. contributed equally to this work.
Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.
ABBREVIATIONS: ZSET1446, spiro[imidazo[1,2-a]pyridine-3,2-indan]-2(3H)-one; ACh, acetylcholine; A, amyloid-; METH, methamphetamine; NORT, novel-object recognition test; SCH23390, R-(+)-7-chloro-8-hydroxy-3-methyl-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine; MK-801, 5H-dibenzo[a,d]cyclohepten-5,10-imine (dizocilpine maleate); CMC, carboxymethyl cellulose; SL327, -[amino-(4-aminophenylthio)methylene]-2-(trifluoromethyl)phenylacetonitrile; ERK1/2, extracellular signal-regulated kinase 1/2; MEK, mitogen-activated protein kinase/extracellular signal-regulated kinase kinase; PFC, prefrontal cortex; ANOVA, analysis of variance; NMDA, N-methyl-D-aspartate; LTP, long-term potentiation; PD98059, 2'-amino-3'-methoxyflavone; SCH 39166, (–)-trans-6,7,7,8,9,13-hexahydro-3-chloro-2-hydroxy-N-methyl-5H-benzo[d]naphtho[2,1-b]azepine.
Address correspondence to: Dr. Kiyofumi Yamada, Laboratory of Neuropsychopharmacology, Division of Life Sciences, Graduate School of Natural Science and Technology, Kanazawa University, Kanazawa 920-1192, Japan. E-mail: kyamada{at}p.kanazawa-u.ac.jp
|
References |
|---|
|
TopAbstractMaterials and MethodsResultsDiscussionReferences |
|---|
Akirav I and Maroun M (2006) Ventromedial prefrontal cortex is obligatory for consolidation and reconsolidation of object recognition memory. Cereb Cortex 16: 1759–1765.
Belcheva MM and Coscia CJ (2002) Diversity of G protein-coupled receptor signaling pathways to ERK/MAP kinase. Neurosignals 11: 34–44.[Medline]
de Lima MN, Laranja DC, Bromberg E, Roesler R, and Schroder N (2005) Pre- or post-training administration of the NMDA receptor blocker MK-801 impairs object recognition memory in rats. Behav Brain Res 156: 139–143.[CrossRef][Medline]
Dias R, Robbins TW, and Roberts AC (1996a) Dissociation in prefrontal cortex of affective and attentional shifts. Nature (Lond) 380: 69–72.[CrossRef][Medline]
Dias R, Robbins TW, and Roberts AC (1996b) Primate analogue of the Wisconsin Card Sorting Test: effects of excitotoxic lesions of the prefrontal cortex in the marmoset. Behav Neurosci 110: 872–886.[CrossRef][Medline]
Dudman JT, Eaton ME, Rajadhyaksha A, Macias W, Taher M, Barczak A, Kameyama K, Huganir R, and Konradi C (2003) Dopamine D1 receptors mediate CREB phosphorylation via phosphorylation of the NMDA receptor at Ser897-NR1. J Neurochem 87: 922–934.[CrossRef][Medline]
Gurden H, Takita M, and Jay TM (2000) Essential role of D1 but not D2 receptors in the NMDA receptor-dependent long-term potentiation at hippocampal-prefrontal cortex synapses in vivo. J Neurosci 20: RC106.
Huang YY, Simpson E, Kellendonk C, and Kandel ER (2004) Genetic evidence for the bidirectional modulation of synaptic plasticity in the prefrontal cortex by D1 receptors. Proc Natl Acad Sci USA 101: 3236–3241.
Ishikawa A, Kadota T, Kadota K, Matsumura H, and Nakamura S (2005) Essential role of D1 but not D2 receptors in methamphetamine-induced impairment of long-term potentiation in hippocampal-prefrontal cortex pathway. Eur J Neurosci 22: 1713–1719.[CrossRef][Medline]
Kalechstein AD, Newton TF, and Green M (2003) Methamphetamine dependence is associated with neurocognitive impairment in the initial phases of abstinence. J Neuropsychiatry Clin Neurosci 15: 215–220.
Kamei H, Nagai T, Nakano H, Togan Y, Takayanagi M, Takahashi K, Kobayashi K, Yoshida S, Maeda K, Takuma K, Nabeshima T, and Yamada K (2006) Repeated methamphetamine treatment impairs recognition memory through a failure of novelty-induced ERK 1/2 activation in the prefrontal cortex of mice. Biol Psychiatry 59: 75–84.[CrossRef][Medline]
Kuroki T, Meltzer HY, and Ichikawa J (1999) Effects of antipsychotic drugs on extracellular dopamine levels in rat medial prefrontal cortex and nucleus accumbens. J Pharmacol Exp Ther 288: 774–781.
Lee FJ, Xue S, Pei L, Vukusic B, Chery N, Wang Y, Wang YT, Niznik HB, Yu XM, and Liu F (2002) Dual regulation of NMDA receptor functions by direct protein-protein interactions with the dopamine D1 receptor. Cell 111: 219–230.[CrossRef][Medline]
Lee MA, Jayathilake K, and Meltzer HY (1999) A comparison of the effect of clozapine with typical neuroleptics on cognitive function in neuroleptic-responsive schizophrenia. Schizophr Res 37: 1–11.[Medline]
Mizoguchi H, Yamada K, Mizuno M, Mizuno T, Nitta A, Noda Y, and Nabeshima T (2004) Regulations of methamphetamine reward by extracellular signal-regulated kinase 1/2/ets-like gene-1 signaling pathway via the activation of dopamine receptors. Mol Pharmacol 65: 1293–1301.
Nagai T, Yamada K, Kim HC, Kim YS, Noda Y, Imura A, Nabeshima Y, and Nabeshima T (2003) Cognition impairment in the genetic model of aging klotho gene mutant mice: a role of oxidative stress. FASEB J 17: 50–52.
Nordahl TE, Salo R, and Leamon M (2003) Neuropsychological effects of chronic methamphetamine use on neurotransmitters and cognition: a review. J Neuropsychiatry Clin Neurosci 15: 317–325.
Okubo Y, Suhara T, Suzuki K, Kobayashi K, Inoue O, Terasaki O, Someya Y, Sassa T, Sudo Y, Matsushima E, Iyo M, Tateno Y, and Toru M (1997) Decreased prefrontal dopamine D1 receptors in schizophrenia revealed by PET. Nature (Lond) 385: 634–636.[CrossRef][Medline]
Paulus MP, Hozack NE, Zauscher BE, Frank L, Brown GG, Braff DL, and Schuckit MA (2002) Behavioral and functional neuroimaging evidence for prefrontal dysfunction in methamphetamine-dependent subjects. Neuropsychopharmacology 26: 53–63.[CrossRef][Medline]
Sawaguchi T and Goldman-Rakic PS (1991) D1 dopamine receptors in prefrontal cortex: involvement in working memory. Science (Wash DC) 251: 947–950.
Sawaguchi T and Goldman-Rakic PS (1994) The role of D1-dopamine receptor in working memory: local injections of dopamine antagonists into the prefrontal cortex of rhesus monkeys performing an oculomotor delayed-response task. J Neurophysiol 71: 515–528.
Seamans JK, Floresco SB, and Phillips AG (1995) Selective impairment on a delayed radial arm task following local administration of selective D1, but not a D2, antagonist into the prefrontal cortex. Soc Neurosci Abstr 21: 1942.
Simon SL, Domier C, Carnell J, Brethen P, Rawson R, and Ling W (2000) Cognitive impairment in individuals currently using methamphetamine. Am J Addict 9: 222–231.[CrossRef][Medline]
Srisurapanont M, Ali R, Marsden J, Sunga A, Wada K, and Monteiro M (2003) Psychotic symptoms in methamphetamine psychotic in-patients. Int J Neuropsychopharmacol 6: 347–352.[CrossRef][Medline]
Valjent E, Corvol JC, Pages C, Besson MJ, Maldonado R, and Caboche J (2000) Involvement of the extracellular signal-regulated kinase cascade for cocaine-rewarding properties. J Neurosci 20: 8701–8709.
Volkow ND, Chang L, Wang GJ, Fowler JS, Leonido-Yee M, Franceschi D, Sedler MJ, Gatley SJ, Hitzemann R, Ding YS, Logan J, Wong C, and Miller EN (2001) Association of dopamine transporter reduction with psychomotor impairment in methamphetamine abusers. Am J Psychiatry 158: 377–382.
Vossler MR, Yao H, York RD, Pan MG, Rim CS, and Stork PJ (1997) cAMP activates MAP kinase and Elk-1 through a B-Raf- and Rap1-dependent pathway. Cell 89: 73–82.[CrossRef][Medline]
Wang J and O'Donnell P (2001) D1 dopamine receptors potentiate NMDA-mediated excitability increase in layer V prefrontal cortical pyramidal neurons. Cereb Cortex 11: 452–462.
Yamaguchi Y, Takano M, Saito K, Matsuno T, and Kawashima S (2002) Enhancement of acetylcholine release by ZSET845 and ZSET1446 in the rat hippocampus. Neurosci Res 26 (Suppl): S131.
Yamaguchi Y, Takano M, Saito K, Matsuno T, and Kawashima S (2003) Effects of ZSET845 and ZSET1446 on acetylcholine release in the cortex and learning impairments in the rat, in New Trends in Alzheimer and Parkinson Related Disorders (Hanin I, Fisher A, and Cacabelos R eds) pp 145–148, Monduzzi Editore, Bolonga, Italy.
Yamaguchi Y, Miyashita H, Tsunekawa H, Mouri A, Kim HC, Saito K, Matsuno T, Kawashima S, and Nabeshima T (2006) Effects of a novel cognitive enhancer, spiro[imidazo[1,2-a]pyridine-3,2-indan]-2(3H)-one (ZSET1446), on learning impairments induced by amyloid-1–40 in the rat. J Pharmacol Exp Ther 317: 1079–1087.
Youngren KD, Inglis FM, Pivirotto PJ, Jedema HP, Bradberry CW, Goldman-Rakic PS, Roth RH, and Moghaddam B (1999) Clozapine preferentially increases dopamine release in the rhesus monkey prefrontal cortex compared with the caudate nucleus. Neuropsychopharmacology 20: 403–412.[CrossRef][Medline]
Yui K, Ikemoto S, Goto K, Nishijima K, Yoshino T, and Ishiguro T (2002) Spontaneous recurrence of methamphetamine-induced paranoid-hallucinatory states in female subjects: susceptibility to psychotic states and implications for relapse of schizophrenia. Pharmacopsychiatry 35: 62–71.[CrossRef][Medline]
Zanassi P, Paolillo M, Feliciello A, Avvedimento EV, Gallo V, and Schinelli S (2001) cAMP-dependent protein kinase induces cAMP-response element-binding protein phosphorylation via an intracellular calcium release/ERK-dependent pathway in striatal neurons. J Biol Chem 276: 11487–11495.
This article has been cited by other articles:
|
|
 |
|
  F. Han, N. Shioda, S. Moriguchi, Y. Yamamoto, A. Y. A. Raie, Y. Yamaguchi, M. Hino, and K. Fukunaga Spiro[imidazo[1,2-a]pyridine-3,2-indan]-2(3H)-one (ZSET1446/ST101) Treatment Rescues Olfactory Bulbectomy-Induced Memory Impairment by Activating Ca2+/Calmodulin Kinase II and Protein Kinase C in Mouse Hippocampus J. Pharmacol. Exp. Ther., July 1, 2008; 326(1): 127 - 134. [Abstract] [Full Text] [PDF]
|
|
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
 |
 |
 |
|
 |
 |
 |
, p < 0.05 compared with METH + vehicle group (exposure).
