Europetm Journal of P~r~rrnucol~, 224 ( 1992) 97-98 0 1992 Elsevier Science Publishers B.V. At! rights reserved OUt4-2999/92/$05.00
97
EJP G380R
Rapid ,~ommurti~ation
D-Cycloserine reverses the working memory impairment of hippocampal-lesioned rats in a spatial learning task Gertrud M. Schuster a,b and Werner J. Schmidt ’ *Deparfmenf ofPharmacoiogy, Merz + Co.GmbN & Co., Eckenheimcr Landstrasse IO@- 104, 6000 Frankfurt and h Reptwtment qf Nertropharmacology, Zoological Itzsriture, University
of Tiibingen
/M&I I, Germu~ly Mohistrasse 54 / I. 7400 Tiibingetz, Gertmm)
Received 22 October 1992, accepted 23 October 1YY2
is shown that D-cycloserine has cognition-enhancing properties in quinolinic acid hippocampal-icsionrd rats. Lesioned rats a were impairment of working memory in an allocentric spatial rcvcrsal paradigm in the 8-arm maze, and performance could be restored with 12 mg/kg i.p. D-cycloserinc, given 30 min before testing. The present findings favour the testing of D-cycloserine for clinical efficacy in patients with Alzheimer’s disease with loss of pyramidal neurons and disconnected It
had
#~yc~ne-~~D_4 receptor activation, Quinolinic
acid; Learning
The antibiotic D-cycloserine has recently been shown to possess partial agonist properties at the strychnineinsensitive glycine binding site of the N-methyl-Daspartate (N~DA) subtype of glutamate receptors (Hood et al., 1989) and to potentiate NMDA-mediated transmission in the brain (Thomson, 1989), without augmenting excitotoxiciry. Procter and coworkers (1989) found that the coupling of glycine binding to the N~DA receptor complex is disrupted in brains of patients with Alzheimer’s disease. .__ ~~ , D-Cycioserine can improve this impaired NMDA recepror activation in cortieai pyramidai ceiis of brains from patients with Alzheimer’s disease (Chessell et al., 1991) and counteracts scopolamine-induced amnesia in a word retrieval test in normal young and elderly humans (Wesnes et al., 1991). As bilateral intrahippocampai quinolinic acid-lesioned rats show some of the neuropathoiogic signs of Alzheimer’s disease and some of the cognitive deficits such 2: working memory impairment and spatial disorientation, we examined whether D-cycloserine is able to restore the functional deficit of these lesioned animals in a spatial ailacentric orientation task. Male Sprague-Dawley rats (250-300 g) were housed in groups of four to five under constant conditions with water ad libitum and 12 g iaborato~ chow each dajr in
Correspondcncc to: G.M. Schuster, Dcpartmenr of Phurmncology. Merx f Co,GmhH & Co., Eckentacimc; Landstrasse 100-104, hOO(l ~r~lllkf~irl/Miitn t, F.R,G. I’&. 4Y (69) tS(t3-~t4, ~UX 49 (60) SW215fl.
deficit;
D-Cycloscrinc
the late afternoon or after the experimental session. TWO days before surgery, the handled animals were allowed to get used to the S-arm maze for 5 min per day, For surgery, animals were anesthetized with chloralhydrate (350 mg/kg i.p.1 and mounted in a stereotaxic apparatus CTrent Wells). A Hamilton syringe needie was inscIted through ti buie hole driiied in <r: calvarium. Injection coordinates were chosen according to the atlas of Paxinos and Watson (l986)3 AP = -3, L = A2, V = -3 (mm from brcgmaf. Quinolinic acid (0.5 ~1, 60 nmol) obtained from Sigma (Deisenhofi.n, F.R.G.) or phosphate-buffered saline (PBS), as control, was injected over 1 min; the needle was left in place for an additional 30 s and then slowly removed. DCycloserine (Fluka., Neu-~lrn, F.R.G.) (12 mg/kg i.p.1 was dissolved in carbonate buffer. Four days after surgery, animals were tesrcd in the spatial silocentric orientation paradigm with icily reversal in the &arm maze (= alloccntric reversal test). The rats had 10 trials per day to learn lo go frllm different randomly chosen arms to one baited goal arm, The position of the baited arm was chan,;ed cvcry day relative to the room coordinates (allocentric reversal) on 10 consecutive days. Double errors, wnich r?present working memory impairment, are dr:fined as re-entries in unbaited arms during each trial. Data are presented as means 5 S.E.M., summed over the trials. Statistical analysis was done with a one-way analysis of variance (ANQVA), followed by Tukcy’s protected ttest. Bilateral dorsal hippocampal lesions made with qu~noliu~itc(60 nmoif ~oltsistcittly increased the num-
0
0
12
3
4
5
6
7
6
9 today
Fig. I. Allocrntric reversal test. Number of double errors tre-entries) summrd over 10 trials amcans+ S.E.M.I. Quinolinic acid-lesioned rals treated with vehicle tN = 7) (I_. ). QUIN-lesioned rals treated with D-cycloserinc 12 mg/‘kg i.p. 30 min prior to testing (N = 9) !a) arm PBS-injectrd sham-lcsi~~ncdcontrol rats receiving vehic!e fN = 7) (A 1.Data were unalyscd by a one-way ANOVA followed by Tukey’s t-test: *P C O.OF . . + * P < 0.01. * * * P < O.~lOIcompared to controls.
ber Of double errors (fig. 1) in a statistically significant vvay. Lcsiuned animals that had received D-cycloserine (12 mg/kg i.p.) 30 min prior to the learning session made significantly fewer double errors (working memory errors) than to lcsioncd rats receiving vehicle and were statistically not distinguishable from sham-lesioned controls. Histological examination of five different plants of the dorsal hippocampus shcnvcd no differences in the pattern of destruction in both lesioned groups. To our knowledge this is the first study to shols t:;I;t D-cycloserine is able to reverse a functional deficit in lesioned subjects. If the well-established giutamatcrgic hippO~m~1 ~thoIo~ associated with these Iesions shou!d prove to occur in patients with Alzhcimer’s
disease a: the onset of symptoms, there would be a good rationale for the proposed treatment (Bowen et al., 1992). The present findings favoor the testing of D-cycloserine for clinical efficacy in patients with Alzheimer’s disease, even in those patients with a massive loss of pyramidal neurons. The partial agonist property of D-cycloserine may restore the receptor function of the remaining cells or even substitute for diminished glutamatergic projections without reaching neurotoxic levels of activation and thus may have cognition-enhancing properties in patients with Alzheimer’s disease.
References Bowen, D.M.. P.T. Francis, M.N. Pangalos, P.H. Stephens and A.W. Procter, 1992, Treatmen! strategies for Alzheimer’s disease, Lancet 339, 132. Chessell, I.P., A.W. Procter, P.T. Francis and D.M. Bowen, 1991, D-cycloserine, a tutative cognitive enhancer, facilitates activation of the N-rn~thy1.D.aspartate receptor-ic~nopltoree complex in Alzheimer brain, Brain Res. 565, 345. Hood, W.F., R.P. Compton and J.B. Monahan, 19x9, D-Cycloserine: a ligand For the N-methyl-D-aspartatc coupled glycine receptor has partial agonist characteristics, Neurosci. Lett. 98, 91. Paxinos, G. and C. Watson, I9%, The Rat Brain in Stereotaxic Coordinates (Academic Press. San Diego). Procter, A.W., J.M. Stirling, E.1t.F. Wang, G.C. Str~itmann, S.L. Lowe and D.M. Bowcn, 19X9. Reduced glycine stimul~lti(~n of t’H)MK-XOt binding in Alzhcimer’s disease. J. Neurocham. 53, 69X. Thomc-n, A.M., 10x9. Glycinr modulation of the NMDA receptor/ channel complex, Trends Neurosci. 12, 349. Wesncs, K., R.W. Jones and J. Kirhy, 19Y1, The effects af Dcycloserine, a glycine agonist, in a human model of the cognitive deficits associated with ageing and dementia, Br. J. Clin. Pharmacol. 3?. 577.
97
EJP G380R
Rapid ,~ommurti~ation
D-Cycloserine reverses the working memory impairment of hippocampal-lesioned rats in a spatial learning task Gertrud M. Schuster a,b and Werner J. Schmidt ’ *Deparfmenf ofPharmacoiogy, Merz + Co.GmbN & Co., Eckenheimcr Landstrasse IO@- 104, 6000 Frankfurt and h Reptwtment qf Nertropharmacology, Zoological Itzsriture, University
of Tiibingen
/M&I I, Germu~ly Mohistrasse 54 / I. 7400 Tiibingetz, Gertmm)
Received 22 October 1992, accepted 23 October 1YY2
is shown that D-cycloserine has cognition-enhancing properties in quinolinic acid hippocampal-icsionrd rats. Lesioned rats a were impairment of working memory in an allocentric spatial rcvcrsal paradigm in the 8-arm maze, and performance could be restored with 12 mg/kg i.p. D-cycloserinc, given 30 min before testing. The present findings favour the testing of D-cycloserine for clinical efficacy in patients with Alzheimer’s disease with loss of pyramidal neurons and disconnected It
had
#~yc~ne-~~D_4 receptor activation, Quinolinic
acid; Learning
The antibiotic D-cycloserine has recently been shown to possess partial agonist properties at the strychnineinsensitive glycine binding site of the N-methyl-Daspartate (N~DA) subtype of glutamate receptors (Hood et al., 1989) and to potentiate NMDA-mediated transmission in the brain (Thomson, 1989), without augmenting excitotoxiciry. Procter and coworkers (1989) found that the coupling of glycine binding to the N~DA receptor complex is disrupted in brains of patients with Alzheimer’s disease. .__ ~~ , D-Cycioserine can improve this impaired NMDA recepror activation in cortieai pyramidai ceiis of brains from patients with Alzheimer’s disease (Chessell et al., 1991) and counteracts scopolamine-induced amnesia in a word retrieval test in normal young and elderly humans (Wesnes et al., 1991). As bilateral intrahippocampai quinolinic acid-lesioned rats show some of the neuropathoiogic signs of Alzheimer’s disease and some of the cognitive deficits such 2: working memory impairment and spatial disorientation, we examined whether D-cycloserine is able to restore the functional deficit of these lesioned animals in a spatial ailacentric orientation task. Male Sprague-Dawley rats (250-300 g) were housed in groups of four to five under constant conditions with water ad libitum and 12 g iaborato~ chow each dajr in
Correspondcncc to: G.M. Schuster, Dcpartmenr of Phurmncology. Merx f Co,GmhH & Co., Eckentacimc; Landstrasse 100-104, hOO(l ~r~lllkf~irl/Miitn t, F.R,G. I’&. 4Y (69) tS(t3-~t4, ~UX 49 (60) SW215fl.
deficit;
D-Cycloscrinc
the late afternoon or after the experimental session. TWO days before surgery, the handled animals were allowed to get used to the S-arm maze for 5 min per day, For surgery, animals were anesthetized with chloralhydrate (350 mg/kg i.p.1 and mounted in a stereotaxic apparatus CTrent Wells). A Hamilton syringe needie was inscIted through ti buie hole driiied in <r: calvarium. Injection coordinates were chosen according to the atlas of Paxinos and Watson (l986)3 AP = -3, L = A2, V = -3 (mm from brcgmaf. Quinolinic acid (0.5 ~1, 60 nmol) obtained from Sigma (Deisenhofi.n, F.R.G.) or phosphate-buffered saline (PBS), as control, was injected over 1 min; the needle was left in place for an additional 30 s and then slowly removed. DCycloserine (Fluka., Neu-~lrn, F.R.G.) (12 mg/kg i.p.1 was dissolved in carbonate buffer. Four days after surgery, animals were tesrcd in the spatial silocentric orientation paradigm with icily reversal in the &arm maze (= alloccntric reversal test). The rats had 10 trials per day to learn lo go frllm different randomly chosen arms to one baited goal arm, The position of the baited arm was chan,;ed cvcry day relative to the room coordinates (allocentric reversal) on 10 consecutive days. Double errors, wnich r?present working memory impairment, are dr:fined as re-entries in unbaited arms during each trial. Data are presented as means 5 S.E.M., summed over the trials. Statistical analysis was done with a one-way analysis of variance (ANQVA), followed by Tukcy’s protected ttest. Bilateral dorsal hippocampal lesions made with qu~noliu~itc(60 nmoif ~oltsistcittly increased the num-
0
0
12
3
4
5
6
7
6
9 today
Fig. I. Allocrntric reversal test. Number of double errors tre-entries) summrd over 10 trials amcans+ S.E.M.I. Quinolinic acid-lesioned rals treated with vehicle tN = 7) (I_. ). QUIN-lesioned rals treated with D-cycloserinc 12 mg/‘kg i.p. 30 min prior to testing (N = 9) !a) arm PBS-injectrd sham-lcsi~~ncdcontrol rats receiving vehic!e fN = 7) (A 1.Data were unalyscd by a one-way ANOVA followed by Tukey’s t-test: *P C O.OF . . + * P < 0.01. * * * P < O.~lOIcompared to controls.
ber Of double errors (fig. 1) in a statistically significant vvay. Lcsiuned animals that had received D-cycloserine (12 mg/kg i.p.) 30 min prior to the learning session made significantly fewer double errors (working memory errors) than to lcsioncd rats receiving vehicle and were statistically not distinguishable from sham-lesioned controls. Histological examination of five different plants of the dorsal hippocampus shcnvcd no differences in the pattern of destruction in both lesioned groups. To our knowledge this is the first study to shols t:;I;t D-cycloserine is able to reverse a functional deficit in lesioned subjects. If the well-established giutamatcrgic hippO~m~1 ~thoIo~ associated with these Iesions shou!d prove to occur in patients with Alzhcimer’s
disease a: the onset of symptoms, there would be a good rationale for the proposed treatment (Bowen et al., 1992). The present findings favoor the testing of D-cycloserine for clinical efficacy in patients with Alzheimer’s disease, even in those patients with a massive loss of pyramidal neurons. The partial agonist property of D-cycloserine may restore the receptor function of the remaining cells or even substitute for diminished glutamatergic projections without reaching neurotoxic levels of activation and thus may have cognition-enhancing properties in patients with Alzheimer’s disease.
References Bowen, D.M.. P.T. Francis, M.N. Pangalos, P.H. Stephens and A.W. Procter, 1992, Treatmen! strategies for Alzheimer’s disease, Lancet 339, 132. Chessell, I.P., A.W. Procter, P.T. Francis and D.M. Bowen, 1991, D-cycloserine, a tutative cognitive enhancer, facilitates activation of the N-rn~thy1.D.aspartate receptor-ic~nopltoree complex in Alzheimer brain, Brain Res. 565, 345. Hood, W.F., R.P. Compton and J.B. Monahan, 19x9, D-Cycloserine: a ligand For the N-methyl-D-aspartatc coupled glycine receptor has partial agonist characteristics, Neurosci. Lett. 98, 91. Paxinos, G. and C. Watson, I9%, The Rat Brain in Stereotaxic Coordinates (Academic Press. San Diego). Procter, A.W., J.M. Stirling, E.1t.F. Wang, G.C. Str~itmann, S.L. Lowe and D.M. Bowcn, 19X9. Reduced glycine stimul~lti(~n of t’H)MK-XOt binding in Alzhcimer’s disease. J. Neurocham. 53, 69X. Thomc-n, A.M., 10x9. Glycinr modulation of the NMDA receptor/ channel complex, Trends Neurosci. 12, 349. Wesncs, K., R.W. Jones and J. Kirhy, 19Y1, The effects af Dcycloserine, a glycine agonist, in a human model of the cognitive deficits associated with ageing and dementia, Br. J. Clin. Pharmacol. 3?. 577.
