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Actions of excitatory amino acids and kynurenic acid in the primate hippocampus: A preliminary study
Neuroscience Letters, 52 (1984) 335-340
335
Elsevier Scientific Publishers Ireland Ltd. NSL 03071 A C T I O N S O F E X C I T A T O R Y A M I N O A C I D S A N D K Y N U R E N I C A C I D IN THE PRIMATE HIPPOCAMPUS: A PRELIMINARY STUDY
T.W. STONE* and M.N. PERKINS Dept. of Physiology, St. George's Hospital Medical School, University of London, London SW17, (U.K.)
(Received September 7th, 1984; Revised version received and accepted October 8th, 1984)
Key words." amino acids - quinolinic acid - kynurenic acid - hippocampus
Orthodromic evoked potentials of CA1 pyramidal cells were studied in superfused slices of marmoset hippocampus. N-methylaspartate, quinolinic acid and quisqualic acid depressed the responses, but only the former two compounds appeared to be antagonized by 2-amino-5-phosphonovalerate. Kynurenic acid also reduced the orthodromic evoked responses but had no effect on antidromic potentials, the blocking action therefore probably resulting from an interference with synaptic transmission. The study reveals receptors for N-methylaspartate, quisqualate, quinolinate and kynurenic acid in the primate hippocampus broadly comparable with those previously studied in non-primate vertebrates. Receptors within the central nervous system for excitatory amino acids and related c o m p o u n d s have been classified into three possible types, preferentially activated by N-methylaspartate ( N M A ) , quisqualic and kainic acids [10, 11, 13, 21]. This classification has received strong s u p p o r t f r o m studies using specific antagonists such as 2 - a m i n o - 5 - p h o s p h o n o v a l e r i c acid (2-APV), 2 - a m i n o - 7 - p h o s p h o n o h e p t a n o i c acid ( 2 - A P H ) and ~/-D-glutamylglycine ( D G G ) [1, 17, 21]. However, virtually all o f this i n f o r m a t i o n has c o m e f r o m experiments on frogs, rats and cats. W h e n the o p p o r t u n i t y arose to study the primate h i p p o c a m p u s we therefore examined the effects o f some o f these a m i n o acid agonists and antagonists on evoked potentials using a slice preparation in vitro. Emphasis was placed on the e n d o g e n o u s excitant quinolinic acid [15, 16, 20] and the related c o m p o u n d kynurenic acid [14]. In spite o f the small n u m b e r o f animals available, the results suggest m a r k e d similarities between the brains o f primates and lower animals in the nature o f their a m i n o acid receptors. H i p p o c a m p a l slices (500/~m) were prepared f r o m anesthetized marmosets using a Mcllwain tissue c h o p p e r and placed on a filter paper bed saturated with physiological solution (in mM): NaC1 124, KC1 5, KH2PO4 1.2, MgSO4 1.3,
*Author for correspondence. 0304-3940/84/$ 03.00 © 1984 Elsevier Scientific Publishers Ireland Ltd.
336
NaHCO3 26, CaC12 2.4 and glucose 11, in an atmosphere of water-saturated 95% 0 2 - 5 % CO2 at room temperature until required. After an equilibration period of 2 h, a slice was transferred onto a nylon net in a l-ml perfusion chamber and perfused with oxygenated solution at 35°C at a rate of 5-10 ml/min. Drugs were applied to the slices in the perfusion fluid for 5 min and at least 20 min was allowed between each application. A concentric bipolar stimulating electrode was placed so as to stimulate the Schaffer collateral-commissural fibers and a glass recording electrode filled with 3 M potassium acetate (electrode resistances 5-10 M~2) was positioned so as to record the orthodromically evoked population spike of the CA1 pyramids. Stimuli (0.1 ms, 100-500 #A, 0.5 Hz) were delivered from a stimulus isolator unit driven by a Grass $44 stimulator. The evoked field potentials were amplified and displayed on oscilloscopes, and in addition 16 consecutive responses were averaged using a Neurolog Signal Averager and plotted on a chart recorder. The size of the peak negative wave, reflecting the population spike was measured from the averaged records, and the effects of compounds have been expressed as the percentage change in the size of the preceding control response. Values for n are shown as the number of slices used. In all slices adenosine was perfused at 100/zM at some stage of the experiment in order to confirm the orthodromic nature of the recorded potential. Adenosine reduces the potential by reducing transmitter release [2, 18, 19] and has no effect on antidromic population spikes or axonal field potentials. N-methyl-DL-aspartate (NMA), quisqualic acid and quinolinic acid produced a reduction in size of the maximal evoked CA1 orthodromic population spike (Table TABLE 1 EFFECTS OF COMPOUNDS ON THE SIZE OF EVOKED POTENTIALS IN THE PRIMATE HIPPOCAMPUS *Values are mean +_ S.E.M. (n). +The effects of all the agonists used were significantly different from control levels at P < 0.01 (Student's t-test). Agonist
NMA
Quinolinate
Quisqualate
Kynurenate
Conc. ( t ~ M )
Antagonist
Conc. ( ~ t M )
Response Size (% control)
25 25 25
2-APV kynurenate
100 200
65.2_+ 5.7 (15)*t 86.0+_ 10 (5) 76.0+_ 10 (4)
200 200 200
2-APV kynurenate
--100 200
63.0_+ 3.4 (7) + 84.3 _+ 11.5 (5) 72.2_+ 8.2 (4)
25 25 25
2-APV kynurenate
-100 200
54.4_+ 9.9 (5) t 50.0+- 5 (5) 30.8 +z 17 (6)
200
78.5 +- 6 (8)t
337
I) when applied to the slice. Owing to severe limitations of time only one agonist concentration was used in most cases, selected from a series of pilot tests to determine a concentration producing between 30 and 7007o reduction of control responses. Within this limitation of single concentrations, quisqualate and NMA proved to be o f comparable potency (Table I) producing 35 and 46070 reduction of the evoked response, respectively, at 25 #M, while quinolinic acid produced only a 37°7o reduction at 200 #M. These effects were all statistically significant compared with controls ( P < 0 . 0 1 , Student's t-test). 2-APV at 200 ~tM tended to reduce the effects of NMA and quinolinate but not quisqualate (Table I) although because of the small number of slices these effects just failed to reach statistical significance. 2-APV itself had no effect on the CA1 response at 50 and 200 #M. Kynurenic acid produced a concentration-dependent reduction in the size of the evoked potential (Fig. l, Table I). Kynurenic acid (200 ttM) tended to reduce the responses to NMA and quinolinate though this was not statistically significant. The effects of 25 ttM quisqualic acid and 200/~M kynurenic acid, however, were additive, although it should be realized that this is not necessarily different from previous findings in the rat [14], in which kynurenate was being examined purely as an antagonist of exogenous compounds. In the present study kynurenate also acted as a blocker of the synaptic input under investigation. The additivity of kynurenate and quisqualate therefore indicates that at the concentration used, kynurenate is more selective as an antagonist of NMA, producing little antagonism of the postsynaptic quisqualate response. This would be entirely consistent with the findings in the rat hippocampus in vivo (Perkins and Stone, in preparation) and in vitro [5]. Interpretation of this study is difficult due to the limited material available and the long recovery times needed by the perfusion system. Nevertheless, it is clear that
A
B
C
KY.A. lmM Fig. 1. Orthodromic evoked potentials in the CA 1 region of the marmoset superfused hippocampal slice. Before (A), during (B) and 5 min (C) after perfusion with 1000 #M kynurenic acid. Calibrations: 500 /zV and 10 ms. Negativity upwards.
338
NMA, quinolinate and quisqualate reduce the CAI orthodromic evoked population spike. This action of amino acid agonists has been studied by several groups in lower mammals and is thought to reflect the depolarisation of the neuronal membrane, resulting in a reduction of action potential amplitude [3]. The activity of NMA and quisqualic acid thus indicates the existence of receptors for both agonists within the primate hippocampus. This is supported by the reduction of responses to NMA and quinolinate by 2-APV, a specific NMA-antagonist in lower mammals [1, 10, 17, 21]. The much weaker action of quinolinic acid compared with NMA would be consistent with other electrophysiological [6, 7, 15, 16, 20] and biochemical [9] studies on quinolinate which show that it acts on the NMA type of receptor but with a potency one-quarter to one-tenth that of NMA itself. The compound is of particular interest since it is the only endogenous compound in rats and primates thought to be a selective agonist at the NMA receptor [12, 22]. The antagonist action of kynurenic acid upon the primate CA1 orthodromic response is consistent with the evidence from work in rats [5, 14] that this compound blocks the action of the transmitter released at the Schaffer collateral-CAl synapse and the cortically evoked excitatory postsynaptic potential recorded from cat caudate neurons [8]. Kynurenic acid is known to exist in the brain [4], and it has been suggested that it could play a part in modifying cerebral excitability by regulating the degree of activation of amino acid receptors [14]. Fig. 2 illustrates the degree of comparability between the effects of kynurenate in the monkey hippocam-
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•
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3
1
2
3
4
5
6
7
8
9
10
KY.A. 10 - 4 M . Fig. 2. The inhibition of CAI orthodromically evoked synaptic responses by kynurenic acid. The results obtained in the present study on marmoset hippocampus (m) are shown alongside data obtained previously using rat tissue (A). Each point shows the mean and standard error of responses, and the numbers by the symbols indicate the number of preparations used.. All points except the lowest one were significantly different from controls ( P < 0.05) although corresponding points on the two curves were not significantly different.
339 pUS t e s t e d o v e r a r a n g e o f c o n c e n t r a t i o n s a n d o u r p r e v i o u s d a t a o b t a i n e d u s i n g r a t hippocampal
slices.
I n c o n c l u s i o n t h e s e e x p e r i m e n t s s u g g e s t t h a t t h e p r i m a t e h i p p o c a m p u s possesses r e c e p t o r s f o r N M A a n d q u i s q u a l a t e , w i t h q u i n o l i n i c a c i d a c t i n g at t h e N M A site. I n a d d i t i o n , k y n u r e n i c a c i d c a n b l o c k o r t h o d r o m i c s y n a p t i c a c t i v a t i o n o f C A 1 cells. T h e s e f e a t u r e s o f a m i n o a c i d , q u i n o l i n i c a c i d a n d k y n u r e n i c a c i d a c t i o n are b r o a d l y s i m i l a r to t h o s e d e m o n s t r a t e d
p r e v i o u s l y in t h e r a t . T h e p o s s i b i l i t y t h a t s o m e o f
t h e s e c o m p o u n d s m a y be i n v o l v e d in c o n v u l s a n t o r n e u r o d e g e n e r a t i v e c o n d i t i o n s in primates and man therefore deserves further investigation.
1 Davies, J., Francis, A.A., Jones, A.W. and Watkins, J.C., 2-Amino-5-phosphonovalerate (2-APV), a potent and selective antagonist of amino acid-induced and synaptic excitation, Neurosci. Lett., 21 (1981) 77-82. 2 Dunwiddie, T.V., Basile, A.S. and Palmer, M.R., Electrophysiological respOnses to adenosine analogs in rat hippocampus and cerebellum: evidence for mediation by adenosine receptors of the A1 subtype, Life Sci., 34 (1984) 37-48. 3 Fagni, L., Baudry, M. and Lynch, G., Classification and properties of acidic amino acid receptors in hippocampus. I. Electrophysiological studies of an apparent desensitisation and interactions with drugs which block transmission, J. Neurosci., 3 (1983) 1538-1546. 4 Gal, E.M. and Sherman, A.D., Synthesis and metabolism of L-kynurenine in rat brain, J. Neurochem., 30 (1978) 607-613. 5 Ganong, A.H., Lanthorn, T.H. and Cotman, C.W., Kynurenic acid inhibits synaptic and acidic amino acid induced responses in the rat hippocampus and spinal cord, Brain Res., 273 (1983) 170-174. 6 Ganong, A.H., Lanthorn, T.H. and Cotman, C.W., Agonist and antagonist properties of kynurenic acid and quinolinic acid in rat hippocampal slices, Soc. Neurosci. Abstr., 9 (1983) 1187. 7 Herding, P.L., Morris, R. and Salt, T.E., Effects of excitatory amino acids and their antagonists on membrane and action potentials of cat caudate neurons, J. Physiol. (Lond.), 339 (1983) 207-222. 8 Herding, P.L., Evidence that the cortically evoked EPSP in cat caudate neurones is mediated by nonNMDA excitatory amino acid receptor, J. Physiol. (Lond.), 353 (1984) 98P. 9 Lehmann, J., Schaefer, P., Ferkany, J.W. and Coyle, J.T., Quinolinic acid evoked [3H]acetylcholine release in striatal slices: mediation by NMDA-type excitatory amino acid receptors, Europ. J. Pharmacol., 96 (1983) 111-116. 10 McLennan, H., Receptors for the excitatory amino acids in the mammalian CNS, Prog. Neurobiol., 20 (1983) 251-272. 11 McLennan, H. and Lodge, D., The antagonism of amino acid induced excitation of spinal neurones in the cat, Brain Res., 169 (1979) 83-90. 12 Moroni, F., Lombardi, G., Carla, V. and Moneti, G., The excitotoxin quinoli'nic acid is present and unevenly distributed in the rat brain, Brain Res., 295 (1984) 352-355. 13 Perkins, M.N., Collins, J.F. and Stone, T.W., Isomers of 2-amino-7-phosphonoheptanoic acid as antagonists of neuronal excitants, Neurosci. lett., 32 (1982) 65-68. 14 Perkins, M.N. and Stone, T.W., An iontophoretic investigation of the actions of convulsant kynurenines and their interaction with the endogenous excitant quinoline acid, Brain Res., 247 (1982) 184-187. 15 Perkins, M.N. and Stone, T.W., Quinolinic acid: regional variations in neuronal sensitivity, Brain Res., 259 (1983) 172-176. 16 Perkins, M.N. and Stone, T.W., The pharmacology and regional variations of quinolinic acid evoked excitations in the rat CNS, J. Pharmacol. Exp. TheE, 226 (1983) 551-557.
340 17 Perkins, M.N., Stone, T.W., Collins, J.F. and Curry, K., Phosphonate analogues of carboxylic acids as amino acid antagonists on rat cortical neurones, Neurosci. Lett., 23 (1981) 333-336. 18 Schubert, P. and Mitzdorf, U., Analysis and quantitative evaluation of the depressive effect of adenosine on evoked potentials in hippocampal slices, Brain Res., 172 (1979) 186-190. 19 Stone, T.W., Physiological roles for adenosine and ATP in the nervous system, Neuroscience, 6 (1981) 523-555. 20 Stone, T.W. and Perkins, M.N., Quinolinic acid: a potent endogenous excitant at amino acid receptors in rat CNS, Europ. J. Pharmacol., 72 (1981) 411-412. 21 Watkins, J.C. and Evans, R.H., Excitatory amino acid transmitters, Ann. Rev. Pharmacol., 21 (1981) 165-204. 22 Wolfensberger, M., Amsler, U., Cuenod, M., Foster, A.C., Whetsell, W.O. and Schwarcz, R., Identification of quinolinic acid in rat and human brain tissue, Neurosci. Lett., 41 (1983) 247-252.
335
Elsevier Scientific Publishers Ireland Ltd. NSL 03071 A C T I O N S O F E X C I T A T O R Y A M I N O A C I D S A N D K Y N U R E N I C A C I D IN THE PRIMATE HIPPOCAMPUS: A PRELIMINARY STUDY
T.W. STONE* and M.N. PERKINS Dept. of Physiology, St. George's Hospital Medical School, University of London, London SW17, (U.K.)
(Received September 7th, 1984; Revised version received and accepted October 8th, 1984)
Key words." amino acids - quinolinic acid - kynurenic acid - hippocampus
Orthodromic evoked potentials of CA1 pyramidal cells were studied in superfused slices of marmoset hippocampus. N-methylaspartate, quinolinic acid and quisqualic acid depressed the responses, but only the former two compounds appeared to be antagonized by 2-amino-5-phosphonovalerate. Kynurenic acid also reduced the orthodromic evoked responses but had no effect on antidromic potentials, the blocking action therefore probably resulting from an interference with synaptic transmission. The study reveals receptors for N-methylaspartate, quisqualate, quinolinate and kynurenic acid in the primate hippocampus broadly comparable with those previously studied in non-primate vertebrates. Receptors within the central nervous system for excitatory amino acids and related c o m p o u n d s have been classified into three possible types, preferentially activated by N-methylaspartate ( N M A ) , quisqualic and kainic acids [10, 11, 13, 21]. This classification has received strong s u p p o r t f r o m studies using specific antagonists such as 2 - a m i n o - 5 - p h o s p h o n o v a l e r i c acid (2-APV), 2 - a m i n o - 7 - p h o s p h o n o h e p t a n o i c acid ( 2 - A P H ) and ~/-D-glutamylglycine ( D G G ) [1, 17, 21]. However, virtually all o f this i n f o r m a t i o n has c o m e f r o m experiments on frogs, rats and cats. W h e n the o p p o r t u n i t y arose to study the primate h i p p o c a m p u s we therefore examined the effects o f some o f these a m i n o acid agonists and antagonists on evoked potentials using a slice preparation in vitro. Emphasis was placed on the e n d o g e n o u s excitant quinolinic acid [15, 16, 20] and the related c o m p o u n d kynurenic acid [14]. In spite o f the small n u m b e r o f animals available, the results suggest m a r k e d similarities between the brains o f primates and lower animals in the nature o f their a m i n o acid receptors. H i p p o c a m p a l slices (500/~m) were prepared f r o m anesthetized marmosets using a Mcllwain tissue c h o p p e r and placed on a filter paper bed saturated with physiological solution (in mM): NaC1 124, KC1 5, KH2PO4 1.2, MgSO4 1.3,
*Author for correspondence. 0304-3940/84/$ 03.00 © 1984 Elsevier Scientific Publishers Ireland Ltd.
336
NaHCO3 26, CaC12 2.4 and glucose 11, in an atmosphere of water-saturated 95% 0 2 - 5 % CO2 at room temperature until required. After an equilibration period of 2 h, a slice was transferred onto a nylon net in a l-ml perfusion chamber and perfused with oxygenated solution at 35°C at a rate of 5-10 ml/min. Drugs were applied to the slices in the perfusion fluid for 5 min and at least 20 min was allowed between each application. A concentric bipolar stimulating electrode was placed so as to stimulate the Schaffer collateral-commissural fibers and a glass recording electrode filled with 3 M potassium acetate (electrode resistances 5-10 M~2) was positioned so as to record the orthodromically evoked population spike of the CA1 pyramids. Stimuli (0.1 ms, 100-500 #A, 0.5 Hz) were delivered from a stimulus isolator unit driven by a Grass $44 stimulator. The evoked field potentials were amplified and displayed on oscilloscopes, and in addition 16 consecutive responses were averaged using a Neurolog Signal Averager and plotted on a chart recorder. The size of the peak negative wave, reflecting the population spike was measured from the averaged records, and the effects of compounds have been expressed as the percentage change in the size of the preceding control response. Values for n are shown as the number of slices used. In all slices adenosine was perfused at 100/zM at some stage of the experiment in order to confirm the orthodromic nature of the recorded potential. Adenosine reduces the potential by reducing transmitter release [2, 18, 19] and has no effect on antidromic population spikes or axonal field potentials. N-methyl-DL-aspartate (NMA), quisqualic acid and quinolinic acid produced a reduction in size of the maximal evoked CA1 orthodromic population spike (Table TABLE 1 EFFECTS OF COMPOUNDS ON THE SIZE OF EVOKED POTENTIALS IN THE PRIMATE HIPPOCAMPUS *Values are mean +_ S.E.M. (n). +The effects of all the agonists used were significantly different from control levels at P < 0.01 (Student's t-test). Agonist
NMA
Quinolinate
Quisqualate
Kynurenate
Conc. ( t ~ M )
Antagonist
Conc. ( ~ t M )
Response Size (% control)
25 25 25
2-APV kynurenate
100 200
65.2_+ 5.7 (15)*t 86.0+_ 10 (5) 76.0+_ 10 (4)
200 200 200
2-APV kynurenate
--100 200
63.0_+ 3.4 (7) + 84.3 _+ 11.5 (5) 72.2_+ 8.2 (4)
25 25 25
2-APV kynurenate
-100 200
54.4_+ 9.9 (5) t 50.0+- 5 (5) 30.8 +z 17 (6)
200
78.5 +- 6 (8)t
337
I) when applied to the slice. Owing to severe limitations of time only one agonist concentration was used in most cases, selected from a series of pilot tests to determine a concentration producing between 30 and 7007o reduction of control responses. Within this limitation of single concentrations, quisqualate and NMA proved to be o f comparable potency (Table I) producing 35 and 46070 reduction of the evoked response, respectively, at 25 #M, while quinolinic acid produced only a 37°7o reduction at 200 #M. These effects were all statistically significant compared with controls ( P < 0 . 0 1 , Student's t-test). 2-APV at 200 ~tM tended to reduce the effects of NMA and quinolinate but not quisqualate (Table I) although because of the small number of slices these effects just failed to reach statistical significance. 2-APV itself had no effect on the CA1 response at 50 and 200 #M. Kynurenic acid produced a concentration-dependent reduction in the size of the evoked potential (Fig. l, Table I). Kynurenic acid (200 ttM) tended to reduce the responses to NMA and quinolinate though this was not statistically significant. The effects of 25 ttM quisqualic acid and 200/~M kynurenic acid, however, were additive, although it should be realized that this is not necessarily different from previous findings in the rat [14], in which kynurenate was being examined purely as an antagonist of exogenous compounds. In the present study kynurenate also acted as a blocker of the synaptic input under investigation. The additivity of kynurenate and quisqualate therefore indicates that at the concentration used, kynurenate is more selective as an antagonist of NMA, producing little antagonism of the postsynaptic quisqualate response. This would be entirely consistent with the findings in the rat hippocampus in vivo (Perkins and Stone, in preparation) and in vitro [5]. Interpretation of this study is difficult due to the limited material available and the long recovery times needed by the perfusion system. Nevertheless, it is clear that
A
B
C
KY.A. lmM Fig. 1. Orthodromic evoked potentials in the CA 1 region of the marmoset superfused hippocampal slice. Before (A), during (B) and 5 min (C) after perfusion with 1000 #M kynurenic acid. Calibrations: 500 /zV and 10 ms. Negativity upwards.
338
NMA, quinolinate and quisqualate reduce the CAI orthodromic evoked population spike. This action of amino acid agonists has been studied by several groups in lower mammals and is thought to reflect the depolarisation of the neuronal membrane, resulting in a reduction of action potential amplitude [3]. The activity of NMA and quisqualic acid thus indicates the existence of receptors for both agonists within the primate hippocampus. This is supported by the reduction of responses to NMA and quinolinate by 2-APV, a specific NMA-antagonist in lower mammals [1, 10, 17, 21]. The much weaker action of quinolinic acid compared with NMA would be consistent with other electrophysiological [6, 7, 15, 16, 20] and biochemical [9] studies on quinolinate which show that it acts on the NMA type of receptor but with a potency one-quarter to one-tenth that of NMA itself. The compound is of particular interest since it is the only endogenous compound in rats and primates thought to be a selective agonist at the NMA receptor [12, 22]. The antagonist action of kynurenic acid upon the primate CA1 orthodromic response is consistent with the evidence from work in rats [5, 14] that this compound blocks the action of the transmitter released at the Schaffer collateral-CAl synapse and the cortically evoked excitatory postsynaptic potential recorded from cat caudate neurons [8]. Kynurenic acid is known to exist in the brain [4], and it has been suggested that it could play a part in modifying cerebral excitability by regulating the degree of activation of amino acid receptors [14]. Fig. 2 illustrates the degree of comparability between the effects of kynurenate in the monkey hippocam-
100 90 8O
~ 7o
o
~6o ~ 5o 0
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4o
e-
c 20
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lO
",at
~
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•
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1
2
3
4
5
6
7
8
9
10
KY.A. 10 - 4 M . Fig. 2. The inhibition of CAI orthodromically evoked synaptic responses by kynurenic acid. The results obtained in the present study on marmoset hippocampus (m) are shown alongside data obtained previously using rat tissue (A). Each point shows the mean and standard error of responses, and the numbers by the symbols indicate the number of preparations used.. All points except the lowest one were significantly different from controls ( P < 0.05) although corresponding points on the two curves were not significantly different.
339 pUS t e s t e d o v e r a r a n g e o f c o n c e n t r a t i o n s a n d o u r p r e v i o u s d a t a o b t a i n e d u s i n g r a t hippocampal
slices.
I n c o n c l u s i o n t h e s e e x p e r i m e n t s s u g g e s t t h a t t h e p r i m a t e h i p p o c a m p u s possesses r e c e p t o r s f o r N M A a n d q u i s q u a l a t e , w i t h q u i n o l i n i c a c i d a c t i n g at t h e N M A site. I n a d d i t i o n , k y n u r e n i c a c i d c a n b l o c k o r t h o d r o m i c s y n a p t i c a c t i v a t i o n o f C A 1 cells. T h e s e f e a t u r e s o f a m i n o a c i d , q u i n o l i n i c a c i d a n d k y n u r e n i c a c i d a c t i o n are b r o a d l y s i m i l a r to t h o s e d e m o n s t r a t e d
p r e v i o u s l y in t h e r a t . T h e p o s s i b i l i t y t h a t s o m e o f
t h e s e c o m p o u n d s m a y be i n v o l v e d in c o n v u l s a n t o r n e u r o d e g e n e r a t i v e c o n d i t i o n s in primates and man therefore deserves further investigation.
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