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Evidence for the involvement of kainate receptors in synaptic transmission in the avian cochlear nucleus
Neuroscience Letters, 59 (1985) 297-301
297
Elsevier Scientific Publishers Ireland Ltd.
NSL 03496
EVIDENCE FOR THE INVOLVEMENT OF KAINATE RECEPTORS IN SYNAPTIC TRANSMISSION IN THE AVIAN COCHLEAR NUCLEUS
E.F. NEMETH*, HUNTER JACKSON** and THOMAS N. PARKS
Department of Anatomy, University of Utah School of Medicine, Salt Lake City, UT 84132 ( U.S.A. ) (Received March 21st, 1985; Revised version received May 29th, 1985; Accepted June 7th, 1985)
Key words: quisqualate - glutamate - DL-~t-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)
-
amino acid receptor - neurotransmitter - auditory system - chicken
Previous studies using various excitatory amino acid antagonists have shown that synaptic transmission between the auditory nerve and the cochlear nucleus of chickens (nuc. magnocellularis; NM) is mediated by non-N-methyl-D-aspartate (non-NMDA) receptors. In the present study we have attempted to define the subclass of non-NMDA receptor in the NM by examining the effects of various excitatory amino acid agonists on synaptically evoked field potentials in an in vitro preparation of the chicken brain stem. Both quisqualate and r~L-~-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA), whose actions operationally define the quisqualate receptor class, caused variable and weak depression of evoked responses in the NM, as did L-glutamate. Kainic acid, on the other hand, completely blocked postsynaptic responses at micromolar concentrations. We conclude that kainate-preferring non-NMDA receptors play a predominant role in mediating transmission in the NM.
Excitatory effects of glutamate and aspartate in the central nervous system (CNS) are differentially sensitive to inhibition by various antagonists, and it is generally held that these two amino acids preferentially act on pharmacologically distinct postsynaptic receptors [14, 20] (but see ref. 17). L-Asparate shows a preference for a class of receptors selectively activated by N-methyl-D-aspartate (NMDA) whereas L-glutamate preferentially interacts with non-NMDA receptors particularly sensitive to activation by quisqualate. Both NMDA and non-NMDA receptors have been shown to mediate synaptic transmission at diverse sites in the vertebrate CNS [3]. Another receptor subclass, characterized by its sensitivity to activation by kainate, has also been postulated, although the endogenous ligand acting on these receptors and the physiological significance of such receptors in synaptic transmission is less clear [14]. A variety of studies indicate that an excitatory amino acid may be the transmitter of the auditory nerve (for reviews see refs. 5, 8 and 21). Our studies in the avian nucleus magnocellularis (NM), homologue of the mammalian anteroventral cochlear nucleus, have shown that non-NMDA receptors mediate transmission at auditory *Present address: Department of Biochemistry and Biophysics, University of Pennsylvania School of Medicine, Philadelphia, PA 19104, U.S.A. **Author for correspondence. 0304-3940/85/$ 03.30 © 1985 Elsevier Scientific Publishers Ireland Ltd.
298 nerve synapses [7, 16]. Because of the lack of selective antagonists, however, it is uncertain if these non-NMDA receptors are of the quisqualate- or kainate-preferring subclass. In the present study, we have examined the effect on synaptically evoked responses in the NM of various neuronal excitants that selectively activate nonNMDA receptors of the quisqualate- or kainate-preferring subclass. Experiments were performed on in vitro preparations of the brain stem from hatchling chickens as described in detail elsewhere [7]. Transmission at auditory nerve-NM synapses was assessed by recording field potentials evoked by direct electrical stimulation of the auditory nerve. The preparation was superfused with avian Tyrode, and the effects of various neuronal excitants were evaluated by changing the normal Tyrode solution to one containing the test substance. Superfusion with the test substance was routinely maintained for 30 rain or until the amplitude of the evoked field potential showed no further change. The recorded field potential comprises two components reflecting the auditory nerve afferent volley (AV) and synaptic currents in the NM (N1) (see ref. 7). Compounds acting on NM receptors should depress the evoked response due to desensitization and/or depolarization block (cf. ref. 18). The novel compound m-carboxyphenylalanine (m-CPA), which has been shown to excite frog spinal motorneurons by an action that is resistant to inhibition by the selective NMDA receptor antagonist (+)-2-amino-5-phosphonovalerate (APV) [2], produced similar effects in NM. 5 mM AVP failed to affect evoked responses in the NM, yet transmission was suppressed following superfusion with 5 mM m-CPA for 10 min and recovery to control values was obtained after a 10-min washout with drug-free Tyrode. The inhibitory effect of this compound on the N 1 potential was not accompanied by any change in the AV. Although the results obtained with m-CPA strengthen our view that non-NMDA receptors underlie transmission in the NM, it is unknown if this compound acts preferentially on quisqualate or kainate receptors [2]. We therefore examined the effects of more selective agonists that operationally define these non-NMDA receptors. The first of these was DL-~-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA), a heterocyclic analogue of L-glutamate believed to act mainly at quisqualate receptors [9, 10]. We found that AMPA produced variable effects on transmission. In one experiment, 0.05 mM AMPA rapidly and completely suppressed evoked transmission, yet in two other experiments this same concentration of AMPA was without effect and suppression was obtained only at much higher concentrations (70% inhibition at 0.25 mM; complete suppression at 0.5 and 1.0 mM). The variable and rather low inhibitory potency of AMPA contrasts with the results obtained with AMPA at other CNS loci [9, 11] and could signal the lack of involvement of quisqualate receptors in the NM. We therefore tested quisqualate itself, which inhibited evoked responses in a dose-dependent manner (Fig. 1); these inhibitory effects were readily reversed (within 10 min) by superfusion with normal Tyrode. Although this might suggest that quisqualate receptors mediate transmission in the NM, there are several reasons to suppose otherwise. First is the failure of AMPA to reliably and potently block, in a selective manner, evoked responses in NM. Second is the finding
299
100
80
~ j g
-
J
e-
~- 60 .__
/
40
20
_
I
0.5
I
I
I
I
2.5
4
Quisqualate
_
(raM)
Fig. 1. Dose-dependentinhibitionof NM responsesby quisqualate.The preparationwas superfusedwith 0.5 mM quisqualateuntil the responseshowedno furtherdecrease(about 20 rnin) and the concentration was then increased. The resultsof 3 separate brainstempreparations are shown.At 1 rnM quisqualate, the responsewas depressedby 50.3_+6.0%.
that high concentrations of quisqualate are required to inhibit transmission in the NM, whereas, in other regions of the CNS, this compound is considerably more potent [14, 19]. Moreover, glutamic acid diethylester (GDEE), which antagonizes quisqualate- and AMPA-induced excitation [9, 15], fails to selectively inhibit transmission in the NM [16]. Finally, given the generally held view that L-glutamate acts preferentially at quisqualate-type receptors [3, 14], it would be expected that Lglutamate should likewise affect transmission in the NM. We found, however, that L-glutamate affected evoked transmission in the NM variably and marginally and did so, moreover, only at very high concentrations. Application of l0 mM L-glutamate depressed the evoked response by only 18.3+3.6% (n=3). Lower concentrations were ineffective and, even at l0 raM, L-glutamate showed a meager effect in only 3 of 5 separate preparations. The failure of L-glutamate to effectively block transmission in the NM, together with the other findings, renders improbable the view that quisqualate receptors, at least by themselves, mediate transmission in the NM. Furthermore, the results provide no evidence that L-glutamate is the transmitter of the auditory nerve in the NM. Finally, we examined the effects of kainate. Of the many compounds we have tested in this and previous studies, kainate is by far the most potent inhibitor of evoked transmission. Inhibitory effects of kainate were seen in each of 5 preparations, and concentrations between 4 and 6 #M routinely depressed evoked responses by 50%. Moreover, the inhibitory effect of kainate in the NM does not
300
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/
m/,.._.m/, _. ,/
_
././
e-,
g.
,
0
,
10
,_
_
20
30 Time
50
70
(min)
Fig. 2. Kainate causes completeand reversiblesuppression of NM responses. Superfusionwith kainate (10/~M) was beff~nat t = 0 and continued for 20 (0), 28 (n) or 4~(~ min beforechan~g todrug-free Tyrode. Resultsfrom 3 separateprelmmtions are shown.
appear to result from a toxic action because even complete inhibition was readily reversed by superfusion with drug-free Tyrode (Fig. 2). Although kainate has been reported to cause the release of glutamate and aspartate [4], this action is unlikely to explain kainate's inhibitory effects in the NM because it occurs only at concentrations 50-100-fold higher than those found effective in the NM. A presynaptic action that causes release of glutamate is likewise inconsistentwith the failure of this amino acid to affect transmission in the NM. Moreover, in the deafferented cochlear nucleus of the guinea pig, injections of kainate still elicit a degenerative change [1], indicating that, at least in that species, kainate receptors are located postsynaptically. Because N M neurons axe affected by both kainate and quisquatate, we cannot definitively single out either kainate- or quisqualate-preferring receptors as being exclusively involved in transmission. However, the m u ~ greater potency of kainate suggests that kainate-preferring receptors are physiologically predominant. Also, postsynaptic receptors for kainate rather than quisqualate would explain the failure of L-glutamate to affect t r m o n since kainate and L-glutamate act at pharmacologically distinct receptors [6]. Finally, the ability of qttisqaalate to affect r ~ s e s in NM could reflect the mixed agonist p r o ~ o f high ~ o n s o f this compound exerted at both quisqualate and kainate receptor; kainate does not~thow similar mixed agonist properties [19]. The available data, then, lead us to su$1pgtt that kainate receptors mediate transmission at synapses o f the auditory nerve in the lqM. We thank Drs. P. Krogs41aatd-Larsen and J.F. Collins f o r g m e t o ~ p r ~ samples of AMPA and m-carboxyphenylalanine, respectively. Supported by grants
301
from the USPHS (NS 17257 and NS 07216) and the University of Utah Research Committee. 1 Bird, S.J. and Gulley, R.L., Evidence against a presynaptic mechanism for kalnate neurotoxicity in the cochlear nucleus, Neurosci. Lett., 15 (1979) 55--60. 2 Davies, J., Evans, R.H., Jones, A.W., Smith, D.A.S. and Watkins, J.C., Differential activation and blockade of excitatory amino acid receptors in the mammalian and amphibian central nervous systems, Comp. Biochem. Physiol., 72 0982) 211-224. 3 Fagg, G.E. and Foster, A.C., Amino acid neurotransmitters and their pathways in the mammalian central nervous system, Neuroscience, 9 0983) 701-719. 4 Ferkany, J.W. and Coyle, J.T., Kainic acid selectively stimulates the release of endogenous excitatory amino acids, J. Pharmacol. Exp. Ther., 225 (1983) 399-406. 5 Guth, P.S. and Melamed, B., Neurotransmission in the auditory system: a primer for pharmacologists, Ann. Rev. Pharmacol. Toxicol., 22 0982) 383-412. 6 Hall, J.G., Hicks, T.P. and McLennan, H., Kainic acid and the glutamate receptor, Neurosci. Lett., 8 (1978) 171-175. 7 Jackson, H., Nemeth, E.F. and Parks, T.N., Non-N-methyl-v-aspartate receptors mediating synaptic transmission in the avian cochlear nucleus: effects of kynurenic acid, dipicolinic acid, and streptomycin, Neuroscience, in press. 8 Klinke, R., Neurotransmitters in the cochlea and the cochlear nucleus, Acta Otolaryngol., 91 (1981) 541-554. 9 Krogsgaard-Larsen, P., Hansen, J.J., Lauridsen, J., Peet, M.J., Leah, J.D. and Curtis, D.R., Glutamic acid agonists. Stereochemical and conformational studies of DL-,,-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) and related compounds, Neurosei. Lett., 31 0982) 313-317. l0 Krogsgaard-Larsen, P. and Honore, T., Glutamate receptors and new glutamate agunists, TIPS, 4 (1983) 31-33. 11 Lambert, J.D.C., Hansen, J.J., Engberg, I. and Flatman, J.A., The action of the glutamate analogue OL-~-amino-3-hydroxy-5-methyl-4-isozaxolepropionate (AMPA) on cat spinal motoneurones, Nenroscience, Suppl. 7 (1982) S126. 12 Martin, M.R., Preliminary observations on a tissue preparation of the mouse cochlear nucleus, J. Physiol. (Lond.), 334 0983) 25P-26P. 13 Martin, M.R. and Adams, J.C., Effects of DL-~-aminoadipate on synaptically evoked excitation of anteroventral cochlear nucleus neurons of the cat, Nenroscience, 4 (1979) 1097-1105. 14 McLennan, H., Receptors for the excitatory amino acids in the mammalian central nervous system, Prog. Neurobiol., (1983) 251-271. 15 McLennan, H. and Lodge, D., The antagonism of amino acid-induced excitation of spinal neurones in the cat, Brain Res., 169 (1979) 83-90. 16 Nemeth, E.F., Jackson, H. and Parks, T.N., Pharmacological evidence for synaptic transmission mediated by non-N-methyl-D-aspartate receptors in the avian cochlear nucleus, Neurosci. Lett., 40 (1983) 39-44. 17 Olverman, H.J., Jones, A.W. and Watkins, J.C., L-Glutamate has higher affinity than other amino acids for [3H]-D-AP5 binding sites in rat brain membranes, Nature (Lond.), 307 (1984) 460-462. 18 Rowe, J.S. and Ruddock, K.H., Depolarization of retinal horizontal cells by excitatory amino acid neurotransmitter agonists, Nenrosci. Lett., 30 (1982) 257-262. 19 Watkins, J.C., Pharmacology of excitatory amino acid receptors. In P.J. Roberts, J. Storm-Mathisen and G.A.R. Johnston (Eds.), Glutamate: Transmitter in the Central Nervous System, John Wiley and Sons, New York, 1981, pp. 1-24. 20 Watkins, J.C. and Evans, R.H., Excitatory amino acid transmitters, Ann. Rev. Pharmacol. Toxicol., 21 (1981) 165-204. 21 Wenthold, R.J., Glutamate and aspartate as neurotransmitters for the auditory nerve. In G. DiChiara and G.L. Gessa (Eds.), Glutamate as a Neurotransmitter, Raven Press, New York, 1981, pp. 69-78.
297
Elsevier Scientific Publishers Ireland Ltd.
NSL 03496
EVIDENCE FOR THE INVOLVEMENT OF KAINATE RECEPTORS IN SYNAPTIC TRANSMISSION IN THE AVIAN COCHLEAR NUCLEUS
E.F. NEMETH*, HUNTER JACKSON** and THOMAS N. PARKS
Department of Anatomy, University of Utah School of Medicine, Salt Lake City, UT 84132 ( U.S.A. ) (Received March 21st, 1985; Revised version received May 29th, 1985; Accepted June 7th, 1985)
Key words: quisqualate - glutamate - DL-~t-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)
-
amino acid receptor - neurotransmitter - auditory system - chicken
Previous studies using various excitatory amino acid antagonists have shown that synaptic transmission between the auditory nerve and the cochlear nucleus of chickens (nuc. magnocellularis; NM) is mediated by non-N-methyl-D-aspartate (non-NMDA) receptors. In the present study we have attempted to define the subclass of non-NMDA receptor in the NM by examining the effects of various excitatory amino acid agonists on synaptically evoked field potentials in an in vitro preparation of the chicken brain stem. Both quisqualate and r~L-~-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA), whose actions operationally define the quisqualate receptor class, caused variable and weak depression of evoked responses in the NM, as did L-glutamate. Kainic acid, on the other hand, completely blocked postsynaptic responses at micromolar concentrations. We conclude that kainate-preferring non-NMDA receptors play a predominant role in mediating transmission in the NM.
Excitatory effects of glutamate and aspartate in the central nervous system (CNS) are differentially sensitive to inhibition by various antagonists, and it is generally held that these two amino acids preferentially act on pharmacologically distinct postsynaptic receptors [14, 20] (but see ref. 17). L-Asparate shows a preference for a class of receptors selectively activated by N-methyl-D-aspartate (NMDA) whereas L-glutamate preferentially interacts with non-NMDA receptors particularly sensitive to activation by quisqualate. Both NMDA and non-NMDA receptors have been shown to mediate synaptic transmission at diverse sites in the vertebrate CNS [3]. Another receptor subclass, characterized by its sensitivity to activation by kainate, has also been postulated, although the endogenous ligand acting on these receptors and the physiological significance of such receptors in synaptic transmission is less clear [14]. A variety of studies indicate that an excitatory amino acid may be the transmitter of the auditory nerve (for reviews see refs. 5, 8 and 21). Our studies in the avian nucleus magnocellularis (NM), homologue of the mammalian anteroventral cochlear nucleus, have shown that non-NMDA receptors mediate transmission at auditory *Present address: Department of Biochemistry and Biophysics, University of Pennsylvania School of Medicine, Philadelphia, PA 19104, U.S.A. **Author for correspondence. 0304-3940/85/$ 03.30 © 1985 Elsevier Scientific Publishers Ireland Ltd.
298 nerve synapses [7, 16]. Because of the lack of selective antagonists, however, it is uncertain if these non-NMDA receptors are of the quisqualate- or kainate-preferring subclass. In the present study, we have examined the effect on synaptically evoked responses in the NM of various neuronal excitants that selectively activate nonNMDA receptors of the quisqualate- or kainate-preferring subclass. Experiments were performed on in vitro preparations of the brain stem from hatchling chickens as described in detail elsewhere [7]. Transmission at auditory nerve-NM synapses was assessed by recording field potentials evoked by direct electrical stimulation of the auditory nerve. The preparation was superfused with avian Tyrode, and the effects of various neuronal excitants were evaluated by changing the normal Tyrode solution to one containing the test substance. Superfusion with the test substance was routinely maintained for 30 rain or until the amplitude of the evoked field potential showed no further change. The recorded field potential comprises two components reflecting the auditory nerve afferent volley (AV) and synaptic currents in the NM (N1) (see ref. 7). Compounds acting on NM receptors should depress the evoked response due to desensitization and/or depolarization block (cf. ref. 18). The novel compound m-carboxyphenylalanine (m-CPA), which has been shown to excite frog spinal motorneurons by an action that is resistant to inhibition by the selective NMDA receptor antagonist (+)-2-amino-5-phosphonovalerate (APV) [2], produced similar effects in NM. 5 mM AVP failed to affect evoked responses in the NM, yet transmission was suppressed following superfusion with 5 mM m-CPA for 10 min and recovery to control values was obtained after a 10-min washout with drug-free Tyrode. The inhibitory effect of this compound on the N 1 potential was not accompanied by any change in the AV. Although the results obtained with m-CPA strengthen our view that non-NMDA receptors underlie transmission in the NM, it is unknown if this compound acts preferentially on quisqualate or kainate receptors [2]. We therefore examined the effects of more selective agonists that operationally define these non-NMDA receptors. The first of these was DL-~-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA), a heterocyclic analogue of L-glutamate believed to act mainly at quisqualate receptors [9, 10]. We found that AMPA produced variable effects on transmission. In one experiment, 0.05 mM AMPA rapidly and completely suppressed evoked transmission, yet in two other experiments this same concentration of AMPA was without effect and suppression was obtained only at much higher concentrations (70% inhibition at 0.25 mM; complete suppression at 0.5 and 1.0 mM). The variable and rather low inhibitory potency of AMPA contrasts with the results obtained with AMPA at other CNS loci [9, 11] and could signal the lack of involvement of quisqualate receptors in the NM. We therefore tested quisqualate itself, which inhibited evoked responses in a dose-dependent manner (Fig. 1); these inhibitory effects were readily reversed (within 10 min) by superfusion with normal Tyrode. Although this might suggest that quisqualate receptors mediate transmission in the NM, there are several reasons to suppose otherwise. First is the failure of AMPA to reliably and potently block, in a selective manner, evoked responses in NM. Second is the finding
299
100
80
~ j g
-
J
e-
~- 60 .__
/
40
20
_
I
0.5
I
I
I
I
2.5
4
Quisqualate
_
(raM)
Fig. 1. Dose-dependentinhibitionof NM responsesby quisqualate.The preparationwas superfusedwith 0.5 mM quisqualateuntil the responseshowedno furtherdecrease(about 20 rnin) and the concentration was then increased. The resultsof 3 separate brainstempreparations are shown.At 1 rnM quisqualate, the responsewas depressedby 50.3_+6.0%.
that high concentrations of quisqualate are required to inhibit transmission in the NM, whereas, in other regions of the CNS, this compound is considerably more potent [14, 19]. Moreover, glutamic acid diethylester (GDEE), which antagonizes quisqualate- and AMPA-induced excitation [9, 15], fails to selectively inhibit transmission in the NM [16]. Finally, given the generally held view that L-glutamate acts preferentially at quisqualate-type receptors [3, 14], it would be expected that Lglutamate should likewise affect transmission in the NM. We found, however, that L-glutamate affected evoked transmission in the NM variably and marginally and did so, moreover, only at very high concentrations. Application of l0 mM L-glutamate depressed the evoked response by only 18.3+3.6% (n=3). Lower concentrations were ineffective and, even at l0 raM, L-glutamate showed a meager effect in only 3 of 5 separate preparations. The failure of L-glutamate to effectively block transmission in the NM, together with the other findings, renders improbable the view that quisqualate receptors, at least by themselves, mediate transmission in the NM. Furthermore, the results provide no evidence that L-glutamate is the transmitter of the auditory nerve in the NM. Finally, we examined the effects of kainate. Of the many compounds we have tested in this and previous studies, kainate is by far the most potent inhibitor of evoked transmission. Inhibitory effects of kainate were seen in each of 5 preparations, and concentrations between 4 and 6 #M routinely depressed evoked responses by 50%. Moreover, the inhibitory effect of kainate in the NM does not
300
>
4 t |~'-"-~-
,/,•.o-e
./
\
E
/
m/,.._.m/, _. ,/
_
././
e-,
g.
,
0
,
10
,_
_
20
30 Time
50
70
(min)
Fig. 2. Kainate causes completeand reversiblesuppression of NM responses. Superfusionwith kainate (10/~M) was beff~nat t = 0 and continued for 20 (0), 28 (n) or 4~(~ min beforechan~g todrug-free Tyrode. Resultsfrom 3 separateprelmmtions are shown.
appear to result from a toxic action because even complete inhibition was readily reversed by superfusion with drug-free Tyrode (Fig. 2). Although kainate has been reported to cause the release of glutamate and aspartate [4], this action is unlikely to explain kainate's inhibitory effects in the NM because it occurs only at concentrations 50-100-fold higher than those found effective in the NM. A presynaptic action that causes release of glutamate is likewise inconsistentwith the failure of this amino acid to affect transmission in the NM. Moreover, in the deafferented cochlear nucleus of the guinea pig, injections of kainate still elicit a degenerative change [1], indicating that, at least in that species, kainate receptors are located postsynaptically. Because N M neurons axe affected by both kainate and quisquatate, we cannot definitively single out either kainate- or quisqualate-preferring receptors as being exclusively involved in transmission. However, the m u ~ greater potency of kainate suggests that kainate-preferring receptors are physiologically predominant. Also, postsynaptic receptors for kainate rather than quisqualate would explain the failure of L-glutamate to affect t r m o n since kainate and L-glutamate act at pharmacologically distinct receptors [6]. Finally, the ability of qttisqaalate to affect r ~ s e s in NM could reflect the mixed agonist p r o ~ o f high ~ o n s o f this compound exerted at both quisqualate and kainate receptor; kainate does not~thow similar mixed agonist properties [19]. The available data, then, lead us to su$1pgtt that kainate receptors mediate transmission at synapses o f the auditory nerve in the lqM. We thank Drs. P. Krogs41aatd-Larsen and J.F. Collins f o r g m e t o ~ p r ~ samples of AMPA and m-carboxyphenylalanine, respectively. Supported by grants
301
from the USPHS (NS 17257 and NS 07216) and the University of Utah Research Committee. 1 Bird, S.J. and Gulley, R.L., Evidence against a presynaptic mechanism for kalnate neurotoxicity in the cochlear nucleus, Neurosci. Lett., 15 (1979) 55--60. 2 Davies, J., Evans, R.H., Jones, A.W., Smith, D.A.S. and Watkins, J.C., Differential activation and blockade of excitatory amino acid receptors in the mammalian and amphibian central nervous systems, Comp. Biochem. Physiol., 72 0982) 211-224. 3 Fagg, G.E. and Foster, A.C., Amino acid neurotransmitters and their pathways in the mammalian central nervous system, Neuroscience, 9 0983) 701-719. 4 Ferkany, J.W. and Coyle, J.T., Kainic acid selectively stimulates the release of endogenous excitatory amino acids, J. Pharmacol. Exp. Ther., 225 (1983) 399-406. 5 Guth, P.S. and Melamed, B., Neurotransmission in the auditory system: a primer for pharmacologists, Ann. Rev. Pharmacol. Toxicol., 22 0982) 383-412. 6 Hall, J.G., Hicks, T.P. and McLennan, H., Kainic acid and the glutamate receptor, Neurosci. Lett., 8 (1978) 171-175. 7 Jackson, H., Nemeth, E.F. and Parks, T.N., Non-N-methyl-v-aspartate receptors mediating synaptic transmission in the avian cochlear nucleus: effects of kynurenic acid, dipicolinic acid, and streptomycin, Neuroscience, in press. 8 Klinke, R., Neurotransmitters in the cochlea and the cochlear nucleus, Acta Otolaryngol., 91 (1981) 541-554. 9 Krogsgaard-Larsen, P., Hansen, J.J., Lauridsen, J., Peet, M.J., Leah, J.D. and Curtis, D.R., Glutamic acid agonists. Stereochemical and conformational studies of DL-,,-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) and related compounds, Neurosei. Lett., 31 0982) 313-317. l0 Krogsgaard-Larsen, P. and Honore, T., Glutamate receptors and new glutamate agunists, TIPS, 4 (1983) 31-33. 11 Lambert, J.D.C., Hansen, J.J., Engberg, I. and Flatman, J.A., The action of the glutamate analogue OL-~-amino-3-hydroxy-5-methyl-4-isozaxolepropionate (AMPA) on cat spinal motoneurones, Nenroscience, Suppl. 7 (1982) S126. 12 Martin, M.R., Preliminary observations on a tissue preparation of the mouse cochlear nucleus, J. Physiol. (Lond.), 334 0983) 25P-26P. 13 Martin, M.R. and Adams, J.C., Effects of DL-~-aminoadipate on synaptically evoked excitation of anteroventral cochlear nucleus neurons of the cat, Nenroscience, 4 (1979) 1097-1105. 14 McLennan, H., Receptors for the excitatory amino acids in the mammalian central nervous system, Prog. Neurobiol., (1983) 251-271. 15 McLennan, H. and Lodge, D., The antagonism of amino acid-induced excitation of spinal neurones in the cat, Brain Res., 169 (1979) 83-90. 16 Nemeth, E.F., Jackson, H. and Parks, T.N., Pharmacological evidence for synaptic transmission mediated by non-N-methyl-D-aspartate receptors in the avian cochlear nucleus, Neurosci. Lett., 40 (1983) 39-44. 17 Olverman, H.J., Jones, A.W. and Watkins, J.C., L-Glutamate has higher affinity than other amino acids for [3H]-D-AP5 binding sites in rat brain membranes, Nature (Lond.), 307 (1984) 460-462. 18 Rowe, J.S. and Ruddock, K.H., Depolarization of retinal horizontal cells by excitatory amino acid neurotransmitter agonists, Nenrosci. Lett., 30 (1982) 257-262. 19 Watkins, J.C., Pharmacology of excitatory amino acid receptors. In P.J. Roberts, J. Storm-Mathisen and G.A.R. Johnston (Eds.), Glutamate: Transmitter in the Central Nervous System, John Wiley and Sons, New York, 1981, pp. 1-24. 20 Watkins, J.C. and Evans, R.H., Excitatory amino acid transmitters, Ann. Rev. Pharmacol. Toxicol., 21 (1981) 165-204. 21 Wenthold, R.J., Glutamate and aspartate as neurotransmitters for the auditory nerve. In G. DiChiara and G.L. Gessa (Eds.), Glutamate as a Neurotransmitter, Raven Press, New York, 1981, pp. 69-78.