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Nefiracetam induces a long-lasting facilitation of hippocampal postsynaptic responses in mice lacking the NMDA receptor ϵ1 subunit
Brain Research 956 (2002) 178–181 www.elsevier.com / locate / brainres
Short communication
Nefiracetam induces a long-lasting facilitation of hippocampal postsynaptic responses in mice lacking the NMDA receptor e1 subunit Shinji Matsumoto a,b , Takeshi Kanno a , Tamotsu Nomura a , Tadashi Shiotani c , Sigeo Watabe c , Toshitaka Nabeshima d , Tomoyuki Nishizaki a , * a
Department of Physiology, Hyogo College of Medicine, 1 -1 Mukogawa-cho, Nishinomiya 663 -8501, Japan Department of Neurosurgery, Kobe University School of Medicine, 7 -5 -1 Kusunoki-cho, Chuo-ku, Kobe 650 -0017, Japan c Tokyo R& D Center, Daiichi Pharmaceutical Co. Ltd., Kitakasai, Edogawa-ku, Tokyo 134 -8630, Japan d Department of Neuropsychopharmacology, and Hospital Pharmacy, Nagoya University Graduate School of Medicine, Showa-ku, Nagoya 466 -8560, Japan b
Accepted 28 August 2002
Abstract The present study was designed to assess whether the facilitatory action of nefiracetam, a pyrrolidone derivative, on hippocampal postsynaptic responses is dependent upon N-methyl-D-aspartate (NMDA) receptors or not, by monitoring population spikes (PSs) in the dentate gyrus of hippocampal slices from mice lacking the NMDA receptor e1 subunit. Nefiracetam (1 mM) induced a sustained facilitation of postsynaptic responses in the dentate gyrus of hippocampal slices from wild-type mice. The facilitation occluded the potentiation induced by high-frequency stimulation at the perforant path, and vice versa, suggesting a common mechanism between them. The perforant path long-term potentiation (LTP) was not induced in e1 subunit knock-out mice, but nefiracetam (1 mM) persistently potentiated PS amplitude, reaching 280% of basal levels 50 min after 10-min treatment, similar to the potentiation achieved with wild-type mice. The results of the present study, thus, suggest that nefiracetam exerts its facilitatory action on hippocampal postsynaptic responses in an NMDA receptor-independent manner. 2002 Elsevier Science B.V. All rights reserved. Theme: Excitable membranes and synaptic transmission Topic: Long-term potentiation: pharmacology Keywords: Nefiracetam; Nootropic agent; NMDA receptor; Knock-out mouse; Hippocampal postsynaptic response; Sustained facilitation
Studies have shown that nefiracetam ameliorates impairments of learning and memory in the animal models of aging [13], amyloid-b 1 – 42 neurotoxicity [14], and head trauma [1]. In explanation of the underlying mechanism, we earlier found that nefiracetam persistently potentiated responses of presynaptic nicotinic acetylcholine (ACh) receptors via a PKC pathway, thereby increasing release of the excitatory neurotransmitter glutamate, and then leading to a long-lasting facilitation of hippocampal synaptic transmission [3,4,6,10]. Interestingly, the facilitation occluded long-term potentiation (LTP), a cellular model of learning and memory, and vice versa [3], suggesting that *Corresponding author. Tel.: 181-798-45-6397; fax: 181-798-456649. E-mail address: [email protected] (T. Nishizaki).
nefiracetam facilitated hippocampal synaptic transmission by a mechanism shared with LTP. The LTP is wellrecognized to depend upon N-methyl-D-aspartate (NMDA) receptors. The facilitatory action of nefiracetam, however, was not inhibited in the presence of APV, a selective inhibitor of NMDA receptors [3]. This prompted the present study to assess whether nefiracetam facilitates hippocampal postsynaptic responses, independently of NMDA receptors, using mice lacking the NMDA receptor e1 subunit. The results of the present study demonstrate that nefiracetam still induced an ‘LTP-like’ long-lasting facilitation of hippocampal postsynaptic responses in NMDA receptor e1 subunit knock-out mice. Mice lacking the NMDA receptor e1 subunit were prepared as previously described [11]. Genotype of mice was determined by PCR analysis applied to genomic DNA
0006-8993 / 02 / $ – see front matter 2002 Elsevier Science B.V. All rights reserved. PII: S0006-8993( 02 )03556-4
S. Matsumoto et al. / Brain Research 956 (2002) 178–181
isolated from tails. Population spikes (PSs) were recorded in the granular cell layer by stimulating the perforant path (0.05 Hz, 0.1 ms in duration) of hippocampal slices from wild-type and e1 subunit knock-out mice, both of which were littermates of the transgenic mice, in a standard artificial cerebrospinal fluid (ACSF) (in mM: 125 NaCl, 5 KCl, 1.24 KH 2 PO 4 , 1.3 MgSO 4 , 2 CaCl 2 , 26 NaHCO 3 , 10 glucose) oxygenated with 95% O 2 and 5% CO 2 at 34 8C. The strength of the stimulus was adjusted to elicit a PS with an amplitude approximately 50% of the maximum. Slices were allowed to stabilize for at least 30 min prior to baseline recording. To induce perforant path LTP, highfrequency stimulation (100 Hz for 1 s, three trains with an inter-train interval of 15 s) was applied to slices. We initially examined whether nefiracetam exerts its facilitatory action on hippocampal postsynaptic responses in wild-type mice. As is the case in rats [3,6], nefiracetam (1 mM) induced a gradually-developing and sustained enhancement in the PS amplitude, reaching 281618% of basal levels 50 min after 10-min treatment (Fig. 1A). No further increase in the PS amplitude was obtained with the ensuing high-frequency stimulation (Fig. 1B). High-frequency stimulation at the perforant path induced LTP (total average6S.E.M., 28161% of basal levels), and the LTP occluded the potentiation induced by nefiracetam (Fig. 1B). These results suggest that nefiracetam facilitates hippocampal postsynaptic responses by a mechanism sharing with the LTP. If this is true, one would think that the facilitatory action of nefiracetam is not obtained with mice lacking the NMDA receptor e1 subunit. Nefiracetam (1 mM), however, persistently facilitated hippocampal postsynaptic responses to an extent similar to that achieved in wild-type mice (284624% of basal levels 50 min after 10-min treatment) (Fig. 2A), indicating that nefiracetam is still capable of facilitating hippocampal postsynaptic responses in e1 subunit knock-out mice. In contrast, high-frequency stimulation did not generate the initial phase of the LTP, but an increase in the PS amplitude, with much lesser extent as compared with the increase in wild-type mice, was obtained in the late phase (140620% of basal levels 60 min after high-frequency stimulation) (Fig. 2B). This may imply that expression of perforant path LTP is mainly dependent upon e1 NMDA receptors but that other types of NMDA receptors, other receptors, or ion channels are employed in the expression. These results, taken together with the fact that the nefiracetam action on hippocampal synaptic transmission is not inhibited by a selective inhibitor of NMDA receptors [3], suggest that nefiracetam induces an ‘LTP-like’ facilitation, regardless of activation of NMDA receptors. The question to address is as to why the nefiracetam action, in spite of a common mechanism with LTP, is independent of NMDA receptors. With respect to the NMDA receptor-dependent LTPs, perforant path LTP and Schaffer collateral-CA1 LTP, we have shown that those
179
Fig. 1. Effects of nefiracetam on hippocampal postsynaptic responses and perforant path LTP in normal mice. (A) PSs were recorded in the granular cell layer by stimulating the perforant path, slices were treated with nefiracetam (1 mM) for 10 min. In the graph, each point represents the mean (6S.E.M.) percentage of basal PS amplitude (0 min) (n56). Inset, PSs recorded at 0 and 60 min. (B) High frequency stimulation was applied to slices before (open circle) and after 10-min treatment with nefiracetam (1 mM) (closed circle). In the graph, each point represents the mean (6S.E.M.) percentage of basal PS amplitude (0 min) (n 5 5). Inset, PSs recorded at 0, 60, and 120 min. HS, high frequency stimulation.
LTPs are induced by activating presynaptic nicotinic ACh receptors in the presence of APV [7]. Arachidonic acid, that is a potential retrograde messenger for the expression of LTP, is produced via NMDA receptors [12], and the free fatty acid is released following a huge increase in the glutamate release after tetanic stimulation [9]. Arachidonic acid induced a sustained enhancement in the activity of
180
S. Matsumoto et al. / Brain Research 956 (2002) 178–181
receptors, therefore, could facilitate hippocampal postsynaptic responses, independently of NMDA receptors. In conclusion, the results of the present study suggest that nefiracetam induces a long-lasting facilitation of hippocampal postsynaptic responses in an NMDA receptor-independent manner.
Acknowledgements We are grateful to Prof. M. Mishina (University of Tokyo) for providing us with mice lacking the NMDA receptor e1 subunit.
References
Fig. 2. Effects of nefiracetam on hippocampal postsynaptic responses in mice lacking the NMDA receptor e1 subunit. (A) PSs were recorded in the granular cell layer by stimulating the perforant path, slices were treated with nefiracetam (1 mM) for 10 min. In the graph, each point represents the mean (6S.E.M.) percentage of basal PS amplitude (0 min) (n55). Inset, PSs recorded at 0 and 60 min. (B) High frequency stimulation was applied to slices in the absence of nefiracetam. In the graph, each point represents the mean (6S.E.M.) percentage of basal PS amplitude (0 min) (n 5 5). Inset, PSs recorded at 0 and 60 min. HS, high frequency stimulation.
nicotinic ACh receptors, thereby increasing glutamate release from presynaptic terminals, and then leading to a long-lasting facilitation of CA1 hippocampal synaptic transmission, that occludes tetanic LTP [2,5,8]. Presynaptic nicotinic ACh receptors, thus, would serve as a downstream target of NMDA receptor signal in the LTP pathway. Nefiracetam functionally targeting nicotinic ACh
[1] S.M. Deford, M.S. Wilson, C.J. Gibson, A. Baranova, R.J. Hamm, Nefiracetam improves Morris water maze performance following traumatic brain injury in rats, Pharmacol. Biochem. Behav. 69 (2001) 611–616. [2] Y. Ikeuchi, T. Nishizaki, T. Matsuoka, K. Sumikawa, Arachidonic acid potentiates ACh receptor currents by protein kinase C activation but not by receptor phosphorylation, Biochem. Biophys. Res. Commun. 221 (1996) 716–721. [3] T. Nishizaki, T. Matsuoka, T. Nomura, S. Matsuyama, S. Watabe, T. Shiotani, M. Yoshii, A ‘long-term-potentiation-like’ facilitation of hippocampal synaptic transmission induced by the nootropic nefiracetam, Brain Res. 826 (1999) 281–288. [4] T. Nishizaki, T. Matsuoka, T. Nomura, K. Sumikawa, T. Shiotani, S. Watabe, M. Yoshii, Nefiracetam modulates acetylcholine receptor currents via two different signal transduction pathways, Mol. Pharmacol. 53 (1998) 1–5. [5] T. Nishizaki, T. Nomura, T. Matsuoka, G. Enikolopov, K. Sumikawa, Arachidonic acid induces a long-lasting facilitation of hippocampal synaptic transmission by modulating PKC activity and nicotinic ACh receptors, Mol. Brain Res. 69 (1999) 263–272. [6] T. Nishizaki, T. Nomura, T. Matsuoka, T. Kondoh, G. Enikolopov, K. Sumikawa, S. Watabe, T. Shiotani, M. Yoshii, The anti-dementia drug nefiracetam facilitates hippocampal synaptic transmission by functionally targeting presynaptic nicotinic ACh receptors, Mol. Brain Res. 80 (2000) 53–62. [7] T. Nishizaki, T. Nomura, S. Matsuyama, T. Kondoh, E. Fujimoto, M. Yoshii, Critical role of presynaptic nicotinic ACh receptors in the formation of long-term potentiation: implication for development of anti-dementia drugs, Psychogeriatrics 1 (2001) 209–217. [8] T. Nishizaki, T. Matsuoka, T. Nomura, K. Sumikawa, Modulation of ACh receptor currents by arachidonic acid, Mol. Brain Res. 57 (1998) 173–179. [9] T. Nishizaki, T. Nomura, T. Matsuoka, Y. Tsujishita, Arachidonic acid as a messenger for the expression of long-term potentiation, Biochem. Biophys. Res. Commun. 254 (1999) 446–449. [10] T. Nomura, T. Nishizaki, Nefiracetam facilitates hippocampal neurotransmission by a mechanism independent of the piracetam and aniracetam action, Brain Res. 870 (2000) 157–162. [11] K. Sakimura, T. Kutsuwada, I. Ito, T. Manabe, C. Takayama, E. Kushiya, T. Yagi, S. Aizawa, Y. Inoue, H. Sugiyama, M. Mishina, Reduced hippocampal LTP and spatial learning in mice lacking NMDA receptor e1 subunit, Nature 373 (1995) 151–155. [12] N. Stella, L. Pellerin, P.J. Magistretti, Modulation of the glutamateevoked release of arachidonic acid from mouse cortical neurons: involvement of a pH-sensitive membrane phospholipase A 2 , J. Neurosci. 15 (1995) 3307–3317.
S. Matsumoto et al. / Brain Research 956 (2002) 178–181 [13] D.S. Woodruff-Pak, Y.T. Li, R.M. Hinchliffe, R.L. Port, Hippocampus in delay eyeblink classical conditioning: essential for nefiracetam amelioration of learning in older rabbits, Brain Res. 747 (1997) 207–218.
181
[14] K. Yamada, T. Tanaka, T. Mamiya, T. Shiotani, T. Kameyama, T. Nabeshima, Improvement by nefiracetam of b-amyloid 1 – 42 -induced learning and memory impairments in rats, Br. J. Pharmacol. 126 (1999) 235–244.
Short communication
Nefiracetam induces a long-lasting facilitation of hippocampal postsynaptic responses in mice lacking the NMDA receptor e1 subunit Shinji Matsumoto a,b , Takeshi Kanno a , Tamotsu Nomura a , Tadashi Shiotani c , Sigeo Watabe c , Toshitaka Nabeshima d , Tomoyuki Nishizaki a , * a
Department of Physiology, Hyogo College of Medicine, 1 -1 Mukogawa-cho, Nishinomiya 663 -8501, Japan Department of Neurosurgery, Kobe University School of Medicine, 7 -5 -1 Kusunoki-cho, Chuo-ku, Kobe 650 -0017, Japan c Tokyo R& D Center, Daiichi Pharmaceutical Co. Ltd., Kitakasai, Edogawa-ku, Tokyo 134 -8630, Japan d Department of Neuropsychopharmacology, and Hospital Pharmacy, Nagoya University Graduate School of Medicine, Showa-ku, Nagoya 466 -8560, Japan b
Accepted 28 August 2002
Abstract The present study was designed to assess whether the facilitatory action of nefiracetam, a pyrrolidone derivative, on hippocampal postsynaptic responses is dependent upon N-methyl-D-aspartate (NMDA) receptors or not, by monitoring population spikes (PSs) in the dentate gyrus of hippocampal slices from mice lacking the NMDA receptor e1 subunit. Nefiracetam (1 mM) induced a sustained facilitation of postsynaptic responses in the dentate gyrus of hippocampal slices from wild-type mice. The facilitation occluded the potentiation induced by high-frequency stimulation at the perforant path, and vice versa, suggesting a common mechanism between them. The perforant path long-term potentiation (LTP) was not induced in e1 subunit knock-out mice, but nefiracetam (1 mM) persistently potentiated PS amplitude, reaching 280% of basal levels 50 min after 10-min treatment, similar to the potentiation achieved with wild-type mice. The results of the present study, thus, suggest that nefiracetam exerts its facilitatory action on hippocampal postsynaptic responses in an NMDA receptor-independent manner. 2002 Elsevier Science B.V. All rights reserved. Theme: Excitable membranes and synaptic transmission Topic: Long-term potentiation: pharmacology Keywords: Nefiracetam; Nootropic agent; NMDA receptor; Knock-out mouse; Hippocampal postsynaptic response; Sustained facilitation
Studies have shown that nefiracetam ameliorates impairments of learning and memory in the animal models of aging [13], amyloid-b 1 – 42 neurotoxicity [14], and head trauma [1]. In explanation of the underlying mechanism, we earlier found that nefiracetam persistently potentiated responses of presynaptic nicotinic acetylcholine (ACh) receptors via a PKC pathway, thereby increasing release of the excitatory neurotransmitter glutamate, and then leading to a long-lasting facilitation of hippocampal synaptic transmission [3,4,6,10]. Interestingly, the facilitation occluded long-term potentiation (LTP), a cellular model of learning and memory, and vice versa [3], suggesting that *Corresponding author. Tel.: 181-798-45-6397; fax: 181-798-456649. E-mail address: [email protected] (T. Nishizaki).
nefiracetam facilitated hippocampal synaptic transmission by a mechanism shared with LTP. The LTP is wellrecognized to depend upon N-methyl-D-aspartate (NMDA) receptors. The facilitatory action of nefiracetam, however, was not inhibited in the presence of APV, a selective inhibitor of NMDA receptors [3]. This prompted the present study to assess whether nefiracetam facilitates hippocampal postsynaptic responses, independently of NMDA receptors, using mice lacking the NMDA receptor e1 subunit. The results of the present study demonstrate that nefiracetam still induced an ‘LTP-like’ long-lasting facilitation of hippocampal postsynaptic responses in NMDA receptor e1 subunit knock-out mice. Mice lacking the NMDA receptor e1 subunit were prepared as previously described [11]. Genotype of mice was determined by PCR analysis applied to genomic DNA
0006-8993 / 02 / $ – see front matter 2002 Elsevier Science B.V. All rights reserved. PII: S0006-8993( 02 )03556-4
S. Matsumoto et al. / Brain Research 956 (2002) 178–181
isolated from tails. Population spikes (PSs) were recorded in the granular cell layer by stimulating the perforant path (0.05 Hz, 0.1 ms in duration) of hippocampal slices from wild-type and e1 subunit knock-out mice, both of which were littermates of the transgenic mice, in a standard artificial cerebrospinal fluid (ACSF) (in mM: 125 NaCl, 5 KCl, 1.24 KH 2 PO 4 , 1.3 MgSO 4 , 2 CaCl 2 , 26 NaHCO 3 , 10 glucose) oxygenated with 95% O 2 and 5% CO 2 at 34 8C. The strength of the stimulus was adjusted to elicit a PS with an amplitude approximately 50% of the maximum. Slices were allowed to stabilize for at least 30 min prior to baseline recording. To induce perforant path LTP, highfrequency stimulation (100 Hz for 1 s, three trains with an inter-train interval of 15 s) was applied to slices. We initially examined whether nefiracetam exerts its facilitatory action on hippocampal postsynaptic responses in wild-type mice. As is the case in rats [3,6], nefiracetam (1 mM) induced a gradually-developing and sustained enhancement in the PS amplitude, reaching 281618% of basal levels 50 min after 10-min treatment (Fig. 1A). No further increase in the PS amplitude was obtained with the ensuing high-frequency stimulation (Fig. 1B). High-frequency stimulation at the perforant path induced LTP (total average6S.E.M., 28161% of basal levels), and the LTP occluded the potentiation induced by nefiracetam (Fig. 1B). These results suggest that nefiracetam facilitates hippocampal postsynaptic responses by a mechanism sharing with the LTP. If this is true, one would think that the facilitatory action of nefiracetam is not obtained with mice lacking the NMDA receptor e1 subunit. Nefiracetam (1 mM), however, persistently facilitated hippocampal postsynaptic responses to an extent similar to that achieved in wild-type mice (284624% of basal levels 50 min after 10-min treatment) (Fig. 2A), indicating that nefiracetam is still capable of facilitating hippocampal postsynaptic responses in e1 subunit knock-out mice. In contrast, high-frequency stimulation did not generate the initial phase of the LTP, but an increase in the PS amplitude, with much lesser extent as compared with the increase in wild-type mice, was obtained in the late phase (140620% of basal levels 60 min after high-frequency stimulation) (Fig. 2B). This may imply that expression of perforant path LTP is mainly dependent upon e1 NMDA receptors but that other types of NMDA receptors, other receptors, or ion channels are employed in the expression. These results, taken together with the fact that the nefiracetam action on hippocampal synaptic transmission is not inhibited by a selective inhibitor of NMDA receptors [3], suggest that nefiracetam induces an ‘LTP-like’ facilitation, regardless of activation of NMDA receptors. The question to address is as to why the nefiracetam action, in spite of a common mechanism with LTP, is independent of NMDA receptors. With respect to the NMDA receptor-dependent LTPs, perforant path LTP and Schaffer collateral-CA1 LTP, we have shown that those
179
Fig. 1. Effects of nefiracetam on hippocampal postsynaptic responses and perforant path LTP in normal mice. (A) PSs were recorded in the granular cell layer by stimulating the perforant path, slices were treated with nefiracetam (1 mM) for 10 min. In the graph, each point represents the mean (6S.E.M.) percentage of basal PS amplitude (0 min) (n56). Inset, PSs recorded at 0 and 60 min. (B) High frequency stimulation was applied to slices before (open circle) and after 10-min treatment with nefiracetam (1 mM) (closed circle). In the graph, each point represents the mean (6S.E.M.) percentage of basal PS amplitude (0 min) (n 5 5). Inset, PSs recorded at 0, 60, and 120 min. HS, high frequency stimulation.
LTPs are induced by activating presynaptic nicotinic ACh receptors in the presence of APV [7]. Arachidonic acid, that is a potential retrograde messenger for the expression of LTP, is produced via NMDA receptors [12], and the free fatty acid is released following a huge increase in the glutamate release after tetanic stimulation [9]. Arachidonic acid induced a sustained enhancement in the activity of
180
S. Matsumoto et al. / Brain Research 956 (2002) 178–181
receptors, therefore, could facilitate hippocampal postsynaptic responses, independently of NMDA receptors. In conclusion, the results of the present study suggest that nefiracetam induces a long-lasting facilitation of hippocampal postsynaptic responses in an NMDA receptor-independent manner.
Acknowledgements We are grateful to Prof. M. Mishina (University of Tokyo) for providing us with mice lacking the NMDA receptor e1 subunit.
References
Fig. 2. Effects of nefiracetam on hippocampal postsynaptic responses in mice lacking the NMDA receptor e1 subunit. (A) PSs were recorded in the granular cell layer by stimulating the perforant path, slices were treated with nefiracetam (1 mM) for 10 min. In the graph, each point represents the mean (6S.E.M.) percentage of basal PS amplitude (0 min) (n55). Inset, PSs recorded at 0 and 60 min. (B) High frequency stimulation was applied to slices in the absence of nefiracetam. In the graph, each point represents the mean (6S.E.M.) percentage of basal PS amplitude (0 min) (n 5 5). Inset, PSs recorded at 0 and 60 min. HS, high frequency stimulation.
nicotinic ACh receptors, thereby increasing glutamate release from presynaptic terminals, and then leading to a long-lasting facilitation of CA1 hippocampal synaptic transmission, that occludes tetanic LTP [2,5,8]. Presynaptic nicotinic ACh receptors, thus, would serve as a downstream target of NMDA receptor signal in the LTP pathway. Nefiracetam functionally targeting nicotinic ACh
[1] S.M. Deford, M.S. Wilson, C.J. Gibson, A. Baranova, R.J. Hamm, Nefiracetam improves Morris water maze performance following traumatic brain injury in rats, Pharmacol. Biochem. Behav. 69 (2001) 611–616. [2] Y. Ikeuchi, T. Nishizaki, T. Matsuoka, K. Sumikawa, Arachidonic acid potentiates ACh receptor currents by protein kinase C activation but not by receptor phosphorylation, Biochem. Biophys. Res. Commun. 221 (1996) 716–721. [3] T. Nishizaki, T. Matsuoka, T. Nomura, S. Matsuyama, S. Watabe, T. Shiotani, M. Yoshii, A ‘long-term-potentiation-like’ facilitation of hippocampal synaptic transmission induced by the nootropic nefiracetam, Brain Res. 826 (1999) 281–288. [4] T. Nishizaki, T. Matsuoka, T. Nomura, K. Sumikawa, T. Shiotani, S. Watabe, M. Yoshii, Nefiracetam modulates acetylcholine receptor currents via two different signal transduction pathways, Mol. Pharmacol. 53 (1998) 1–5. [5] T. Nishizaki, T. Nomura, T. Matsuoka, G. Enikolopov, K. Sumikawa, Arachidonic acid induces a long-lasting facilitation of hippocampal synaptic transmission by modulating PKC activity and nicotinic ACh receptors, Mol. Brain Res. 69 (1999) 263–272. [6] T. Nishizaki, T. Nomura, T. Matsuoka, T. Kondoh, G. Enikolopov, K. Sumikawa, S. Watabe, T. Shiotani, M. Yoshii, The anti-dementia drug nefiracetam facilitates hippocampal synaptic transmission by functionally targeting presynaptic nicotinic ACh receptors, Mol. Brain Res. 80 (2000) 53–62. [7] T. Nishizaki, T. Nomura, S. Matsuyama, T. Kondoh, E. Fujimoto, M. Yoshii, Critical role of presynaptic nicotinic ACh receptors in the formation of long-term potentiation: implication for development of anti-dementia drugs, Psychogeriatrics 1 (2001) 209–217. [8] T. Nishizaki, T. Matsuoka, T. Nomura, K. Sumikawa, Modulation of ACh receptor currents by arachidonic acid, Mol. Brain Res. 57 (1998) 173–179. [9] T. Nishizaki, T. Nomura, T. Matsuoka, Y. Tsujishita, Arachidonic acid as a messenger for the expression of long-term potentiation, Biochem. Biophys. Res. Commun. 254 (1999) 446–449. [10] T. Nomura, T. Nishizaki, Nefiracetam facilitates hippocampal neurotransmission by a mechanism independent of the piracetam and aniracetam action, Brain Res. 870 (2000) 157–162. [11] K. Sakimura, T. Kutsuwada, I. Ito, T. Manabe, C. Takayama, E. Kushiya, T. Yagi, S. Aizawa, Y. Inoue, H. Sugiyama, M. Mishina, Reduced hippocampal LTP and spatial learning in mice lacking NMDA receptor e1 subunit, Nature 373 (1995) 151–155. [12] N. Stella, L. Pellerin, P.J. Magistretti, Modulation of the glutamateevoked release of arachidonic acid from mouse cortical neurons: involvement of a pH-sensitive membrane phospholipase A 2 , J. Neurosci. 15 (1995) 3307–3317.
S. Matsumoto et al. / Brain Research 956 (2002) 178–181 [13] D.S. Woodruff-Pak, Y.T. Li, R.M. Hinchliffe, R.L. Port, Hippocampus in delay eyeblink classical conditioning: essential for nefiracetam amelioration of learning in older rabbits, Brain Res. 747 (1997) 207–218.
181
[14] K. Yamada, T. Tanaka, T. Mamiya, T. Shiotani, T. Kameyama, T. Nabeshima, Improvement by nefiracetam of b-amyloid 1 – 42 -induced learning and memory impairments in rats, Br. J. Pharmacol. 126 (1999) 235–244.