Neuroscience Letters, 146 (1992) 215-218
215
© 1992 Elsevier Scientific Publishers Ireland Ltd. All rights reserved 0304-3940/92/$ 05.00
NSL 09078
D-Cycloserine, a modulator of the N-methyl-D-aspartate receptor, improves spatial learning in rats treated with muscarinic antagonist Jouni Sirvi0, Tommi Ekonsalo, P a a v o Riekkinen Jr., Hannele Lahtinen and P a a v o Riekkinen Sr. Department of Neurology and A.I. Virtanen Institute, University of Kuopio, Kuopio (Finland) (Received 11 May 1992; Revised version received 3 August 1992; Accepted 17 August 1992)
Key words: Alzheimer's disease; Cholinergic system; D-Cycloserine; N-Methyl-o-aspartate; Learning; Rat; Scopolamine The results of the present study indicate that D-cycloserine, a partial agonist at the glycine binding site, which is a positive modulation site of the N-methyl-D-aspartate receptor, could improve dose dependently the acquisition of a water maze task in rats treated with scopolamine, a muscarinic antagonist. The low to moderate doses of D-cycloserine which improved learning did not affect swimming speed in scopolamine-treated rats. The higher dose did not improve learning, but it increased swimming speed in scopolamine-treated rats. These results show a dissociation between impaired acquisition and abnormal behavioral activity in scopolamine-treated rats in the water maze task. Furthermore, the present results suggest that D-cycloserine can act as a cognitive enhancer at the appropriate doses.
N-Methyl-D-aspartate (NMDA) type of excitatory amino acid receptors are involved in neural plasticity underlying learning and memory. Intraventricular administration of N M D A antagonists impair long-term synaptic enhancement in the hippocampus and spatial learning in rats [5]. Furthermore, systemic administration of noncompetitive or competitive N M D A antagonists impairs the performance of rats in spatial learning task [1]. In addition to its glutamate/aspartate binding site, the N M D A receptor possesses modulatory sites sensitive to glycine and polyamines [12]. Glycine can act as a positive, allosteric modulator at the N M D A receptor [12]. D-Cycloserine, a partial agonist of the glycine binding site [2], has been found to improve learning/memory in experimental animals [4]. Furthermore, milacemide, a glycine prodrug, may enhance memory storage and/or retrieval in humans and experimental animals [3, 6, 10]. There is a great interest in the effects of putative cognitive enhancers on cholinergic hypofunction in experimental animals, since the cholinergic system is affected in patients with Alzheimer's disease which is the predominant form of dementia in elderly humans [7]. Scopolamine, a muscarinic receptor antagonist, impairs the performance of rats in tasks used to assess learning/memory [8, 11]. The present study investigated whether D-cycloCorrespondence: J. Sirvi6, Department of Neurology, University of Kuopio, Canthia Building, P.O.B. 1627, SF-70211 Kuopio, Finland. Fax: 358-71-162048.
serine could alleviate the learning deficit induced by scopolamine, a model of amnesia which is widely used in experimental research for the symptomatic therapy of age-associated cognitive dysfunctions [11]. Adult male Wistar rats (250-300 g) were used in these studies. Rats were housed in Makrolon cages (2 or 3 rats/cage) under a temperature (20°C) and humidity (5060%) controlled environment. Lights were on from 7.00 h to 19.00 h. Water and food pellets were given ad libitum. Scopolamine (scop) and D-cycloserine (DCS) (Searle, R&D Division, Skokie, IL, USA) were dissolved in saline. Drug solutions were injected (2.0 ml/kg) 30 min before behavioral testing. Treated groups consisted of saline-saline (n=8), scop 0.4 mg/kg-saline (n=8), scop 0.4 mg/kg-DCS 0.3 mg/kg (n=8), scop 0.4 mg/kg-DCS 1.0 mg/kg (n=8) and scop 0.4 mg/kg-DCS 3.0 mg/kg (n=8). For the assessment of spatial learning, we used a modified version of the Morris water maze task (black pool filled with clear water). The water maze pool was a circular fiberglass tank, 150 cm in diameter, 74 cm deep, and filled to a height of 52 cm with water at room temperature. The platform was made of a Plexiglas tube and the top surface was composed of black rubber which was 1.5 cm below the water line. The starting locations were called north, east, south and west, and they were located arbitrarily at equal distances on the pool rim. The platform was located in the south-west quadrant during every training day. The swim paths were monitored by a
216
3500
70 []
60
50
"' .),',
3000
~- ~ T '
~ ~X:,,i~ \ \ \'
2500
--O--
SAL-SAL
\
"5" u~ >0 z LLI
~
215
© 1992 Elsevier Scientific Publishers Ireland Ltd. All rights reserved 0304-3940/92/$ 05.00
NSL 09078
D-Cycloserine, a modulator of the N-methyl-D-aspartate receptor, improves spatial learning in rats treated with muscarinic antagonist Jouni Sirvi0, Tommi Ekonsalo, P a a v o Riekkinen Jr., Hannele Lahtinen and P a a v o Riekkinen Sr. Department of Neurology and A.I. Virtanen Institute, University of Kuopio, Kuopio (Finland) (Received 11 May 1992; Revised version received 3 August 1992; Accepted 17 August 1992)
Key words: Alzheimer's disease; Cholinergic system; D-Cycloserine; N-Methyl-o-aspartate; Learning; Rat; Scopolamine The results of the present study indicate that D-cycloserine, a partial agonist at the glycine binding site, which is a positive modulation site of the N-methyl-D-aspartate receptor, could improve dose dependently the acquisition of a water maze task in rats treated with scopolamine, a muscarinic antagonist. The low to moderate doses of D-cycloserine which improved learning did not affect swimming speed in scopolamine-treated rats. The higher dose did not improve learning, but it increased swimming speed in scopolamine-treated rats. These results show a dissociation between impaired acquisition and abnormal behavioral activity in scopolamine-treated rats in the water maze task. Furthermore, the present results suggest that D-cycloserine can act as a cognitive enhancer at the appropriate doses.
N-Methyl-D-aspartate (NMDA) type of excitatory amino acid receptors are involved in neural plasticity underlying learning and memory. Intraventricular administration of N M D A antagonists impair long-term synaptic enhancement in the hippocampus and spatial learning in rats [5]. Furthermore, systemic administration of noncompetitive or competitive N M D A antagonists impairs the performance of rats in spatial learning task [1]. In addition to its glutamate/aspartate binding site, the N M D A receptor possesses modulatory sites sensitive to glycine and polyamines [12]. Glycine can act as a positive, allosteric modulator at the N M D A receptor [12]. D-Cycloserine, a partial agonist of the glycine binding site [2], has been found to improve learning/memory in experimental animals [4]. Furthermore, milacemide, a glycine prodrug, may enhance memory storage and/or retrieval in humans and experimental animals [3, 6, 10]. There is a great interest in the effects of putative cognitive enhancers on cholinergic hypofunction in experimental animals, since the cholinergic system is affected in patients with Alzheimer's disease which is the predominant form of dementia in elderly humans [7]. Scopolamine, a muscarinic receptor antagonist, impairs the performance of rats in tasks used to assess learning/memory [8, 11]. The present study investigated whether D-cycloCorrespondence: J. Sirvi6, Department of Neurology, University of Kuopio, Canthia Building, P.O.B. 1627, SF-70211 Kuopio, Finland. Fax: 358-71-162048.
serine could alleviate the learning deficit induced by scopolamine, a model of amnesia which is widely used in experimental research for the symptomatic therapy of age-associated cognitive dysfunctions [11]. Adult male Wistar rats (250-300 g) were used in these studies. Rats were housed in Makrolon cages (2 or 3 rats/cage) under a temperature (20°C) and humidity (5060%) controlled environment. Lights were on from 7.00 h to 19.00 h. Water and food pellets were given ad libitum. Scopolamine (scop) and D-cycloserine (DCS) (Searle, R&D Division, Skokie, IL, USA) were dissolved in saline. Drug solutions were injected (2.0 ml/kg) 30 min before behavioral testing. Treated groups consisted of saline-saline (n=8), scop 0.4 mg/kg-saline (n=8), scop 0.4 mg/kg-DCS 0.3 mg/kg (n=8), scop 0.4 mg/kg-DCS 1.0 mg/kg (n=8) and scop 0.4 mg/kg-DCS 3.0 mg/kg (n=8). For the assessment of spatial learning, we used a modified version of the Morris water maze task (black pool filled with clear water). The water maze pool was a circular fiberglass tank, 150 cm in diameter, 74 cm deep, and filled to a height of 52 cm with water at room temperature. The platform was made of a Plexiglas tube and the top surface was composed of black rubber which was 1.5 cm below the water line. The starting locations were called north, east, south and west, and they were located arbitrarily at equal distances on the pool rim. The platform was located in the south-west quadrant during every training day. The swim paths were monitored by a
216
3500
70 []
60
50
"' .),',
3000
~- ~ T '
~ ~X:,,i~ \ \ \'
2500
--O--
SAL-SAL
\
"5" u~ >0 z LLI
~
