Inhibitory
Effect
of NMDA
Transmission of Rat
on Dopaminergic
in a Slice Globus
Preparation
Pallidus
Tomomi Shindoui°2, Shuichi Koizumi2, Yasufumi Kataoka3, Shigenori Watanabe2, Kenji Yamamoto' and Hiroshi Nakanishil•* Department of Pharmacology, Faculty of Dentistry, 2Department of Pharmacology, Faculty of Pharmaceutical Sciences, Kyushu University, Fukuoka 812, Japan ;Department of Pharmacology 2 , Nagasaki University School of Medicine, Nagasaki 852, Japan Received
July 27,
1991
Accepted
November
19, 1991
ABSTRACT-The effect of N-methyl-D-aspartate (NMDA) on KCl-evoked endog enous dopamine (DA) release from slices of rat globus pallidus (GP) was examined. NMDA inhibited the KCI-evoked DA release in a dose-dependent manner. This in hibition was blocked by CPP, an NMDA antagonist. Tetrodotoxin partially antago nized the effect of NMDA. The NMDA-induced inhibition was also partially antago nized by bicuculline methiodide and was mimicked by muscimol. These results strong ly suggest that 1) an activation of NMDA receptors exerts an inhibitory effect on dopaminergic transmission in GP and 2) GABAergic transmission is involved in the effect of NMDA.
Glutamatergic transmission mediated by N methyl-D-aspartate (NMDA) receptors in the globus pallidus (GP) has been suggested to play an important role in motor and posture control. A behavioral study in rats showed that blockade of glutamatergic neurotransmis sion mediated by NMDA receptors in GP pro duced rigidity and catalepsy, while a focal in jection of NMDA into GP increased motility (1). Recently it has been demonstrated that NMDA receptors interact with dopaminergic transmissions in the neostriatum (2), substan tia nigra (3) and frontal cortex (4) of rats. Furthermore, NMDA antagonists have been shown to facilitate locomotor activity in monoamine-depleted mice (5) and reverse neuroleptic induced catalepsy in rats (6). GP
also has a sparse but widespread dopaminergic innervation from the substantia nigra (7), but the role of NMDA receptors of GP in dopa minergic transmissions is poorly understood. It is thus considered of interest to investigate a possible interaction between glutamatergic and dopaminergic systems in GP. The present study was undertaken to examine the effects of NMDA on endogenous dopamine (DA) re lease from slices of rat GP. Male Wistar rats weighing 150 200 g were decapitated under light ether anesthesia, and the brains were rapidly removed and placed in ice-cold Krebs Ringer solution of the following composition: 118.0 mM NaCI, 4.7 mM KCI, 1.3 mM CaC12, 1.2 mM MgC12, LO MM NaH2PO4, 25.0 mM NaHCO3 and 11.0 MM D glucose. Each brain was trimmed with a razor blade to a block containing the region of GP. Parasagittal slices of 400 ,um thickness
were cut from the block with a vibratome. The slices were preincubated at 37°C for 1 hr before they were used in the release study. Each slice was stimulated by changing the medium with 100 ,ul of Mg-free Krebs Ringer solution containing 30 mM KCl for 10 min at 37°C. Following the termination of the stim ulation, the medium was quickly collected in a sample cup on ice to determine the amount of released DA. The slices were sonicated im mediately on ice with 1001al of ice-cold 0.1 M perchloric acid containing 0.1% Na2EDTA and 0.1 % of Na2S2O5 and then centrifugated at 10,000 X g for 10 min at 4°C. The super natant was filtered through a membrane filter and then its DA content was determined by liquid chromatography. DA release was ex pressed as a percentage of the total DA con tent (the medium plus slice content). DA re lease induced by 30 mM KC1 in the absence of drug was 29.2 ± 2.2% (mean ± S.E.M., n = 52). Drugs were applied for 10 min during which the tissues were stimulated with 30 mM KCI. Dunnett's t-test was used following a one-analysis of variance, and numerical data
are presented as means ± S.E.M. The drugs used in this study were NMDA (Sigma), 3 [(±)-2-carboxypiperazin-4-yl]-propyl-l-phospho nic acid (CPP, Tocris Neuramin), tetrodotoxin (TTX, Wako), bicuculline methiodide (Sigma) and muscimol (a gift from Yoshitomi Phar maceutical Industries, Ltd.). Figure 1 shows that NMDA had an inhibi tory effect on 30 mM KCl-evoked endogenous DA release from slices of GP in a dose-depend ent manner. The inhibitory effect of 100 ,uM NMDA was significantly blocked by 100 ,uM CPP (P < 0.01, Fig. 2). CPP at 100,aM had no significant effect on KCI-induced DA re lease. CCP at 20 pM partially but not signifi cantly antagonized the inhibitory effect of 100 ,uM NMDA (57.5 ± 9.2% of control, n = 11). The effect of NMDA was also examined in the presence of TTX in order to determine
Fig.
2.
Effects
of
100 ,u M
100 M M bicuculline duced effect Fig.
1.
Concentration-response
NMDA
on
DA
release
slices
of GP.
Each
mean
and
S.E.M.,
observations point. control
are
induced
point
and
for
by
30 mM
vertical
respectively.
indicated
curve
in
bar The
parenthesis
the
effect
of
KCI
from
represent
the
number above
* P < 0.05, **P < 0.01, as compared value of 30 mM KCI-evoked DA release.
of each
to
the
inhibition slices
sent
the
as
of GP.
mean
compared
evoked value
of
the
to
DA of
presence methiodide,
and release.
30 mM of
Each
on
DA
release
evoked
and
control
KC1-evoked
100,uM NMDA. MUS: muscimol.
and
and DA
vertical
respectively. value
# # P < 0.01,
TTX
100,u M NMDA-in
the
column
S.E.M., the
100,uM
on
evoked
of 100 ,u M muscimol
from
CPP,
methiodide
bar **P
of
DA
release
BICC:
repre < 0.01,
30 mM
as compared
the
release
KCl to the in
the
bicuculline
whether the inhibitory effect of NMDA is mediated through an activation of voltage-de pendent Na+ channels. TTX at 100,uM had no significant effect on KCI-evoked DA re lease but partially antagonized the inhibitory effect of NMDA. Bicuculline methiodide at 100 ,uM also partially antagonized the inhibi tory effect of NMDA and slighty, but not sig nificantly, increased DA release. Furthermore, 100 ,uM muscimol significantly depressed 30 mM KCI-evoked DA release (P < 0.01, Fig. 2). The present result shows that activation of NMDA receptors exerts an inhibitory effect on the dopaminergic transmission in the GP. The effect of NMDA was antagonized by bicuculline methiodide, a GABAA receptor antagonist, as well as by CPP, an NMDA re ceptor antagonist. Furthermore, the effect of NMDA was mimicked by muscimol, a GABAA receptor agonist. Thus, it is likely that GABAergic transmission is involved in the inhibitory effect of NMDA on DA re lease. Recent studies have suggested that the subthalamus sends glutamatergic fibers to the GP (8, 9). Most GP neurons are GABAergic neurons projecting to the subthalamus (10) and have extensive local axon collaterals, as demonstrated by an intracellular HRP study (11). Therefore, the inhibitory effect of NMDA on DA release may be through an activation of GABAergic GP projection neurons whose axon collaterals make synaptic contacts with DA nerve terminals. Similar in direct inhibitory effects of NMDA on trans mitter release mediated through GABA have been reported by in vivo release studies utiliz ing push-pull canula. Becquet et al. have re ported that NMDA inhibits the release of [3H]serotonin through an activation of GABAergic interneurons in the cat caudate nucleus (12). Hata et al. also suggested an in volvement of GABAergic neurons in the in hibitory effect of NMDA on dopaminergic transmission in rat medial frontal cortex (4). In an electrophysiological study, Gallagher and Hasuo have suggested that NMDA could hyperpolarize the membrane of dorsolateral
septal nucleus neurons by an activation of lo cal GABAergic inhibitory interneurons (13). The existence of a TTX-insensitive compo nent in the inhibitory effect of NMDA, however, suggests other sources of GABA which can be released by NMDA without an activation of voltage-dependent Na+ channels. Intracellular accumulation of Na+ through NMDA receptor-channels may cause the carrier-mediated GABA release from GABAergic GP neurons. Another possible source of GABA is cut terminals of GABAer gic striato-pallidal fibers. Other mechanisms without induction of GABA release, however, also can not be ruled out for the TTX-insensi tive effect of NMDA. For example, NMDA could modulate DA turnover through an activation of calmodulin-dependent protein kinase which activates tyrosine hydroxylase (14). Furthermore, NMDA has been shown to selectively block N-type Ca2+ channels (15) which are thought to be involved in transmit ter release. The different mode of NMDA action on dopaminergic transmissions in the neostriatum and GP may reflect the different distributions of NMDA receptors in these two brain re gions. The facilitatory effect of NMDA on DA release in the neostriatum is explained by an activation of NMDA receptors located on DA nerve terminals (2), while the inhibitory effect of NMDA on DA release in GP can be considered to involve activation of NMDA re ceptors mainly located on GABAergic projec tion neurons. The precise functional signifi cance of the present result remains to be de termined, but the present study provides evi dence for the possible interaction between these three neurotransmitters in the basal ganglia.
REFERENCES
1
Turski,
L.,
Schwarz,
M.
citatory
Sontag,
T., K.-H.:
neurotransmission
induces tions
Klockgether, and
rigidity for
and
excitatory
in akinesia
the in
neurotransmission
Turski,
W.A.,
Blockade
of
globus the
ex
pallidus
rat:
implica in
patho
2
3
4
5
6
7
8
genesis of Parkinson's disease. Brain Res. 512, 125 -131 (1990) Snell, L.D. and Johnson, K.M.: Characterization of the inhibition of excitatory amino acid-induced neurotransmitter release in the rat striatum by phencyclidine-like drugs. J. Pharmacol. Exp. Ther. 238, 938-946 (1986) Andrade, R. and Bustos, G.: Modulation of den dritic release of dopamine by N-methyl-D-aspartate receptors in rat substantia nigra. J. Neurochem. 52, 962-970 (1989) Hata, N., Nishikawa, T., Umino, A. and Taka hashi, K.: Evidence for involvement of N-methyl D-aspartate receptor in tonic inhibitory control of dopaminergic transmission in rat medial frontal cortex. Neurosci. Lett. 120, 101-104 (1990) Carlsson, M. and Carlsson, A.: The NMDA antago nist MK-801 causes marked locomotor stimulation in monoamine-depleted mice. J. Neural Transm. 75, 221 -226 (1989) Schmidt, W.J. and Bischoff, C.: Dopaminergic be havioral responses modulated by NMDA receptor antagonists. Psychopharmacology (Berlin) 96, S51 (1988) Lindvall, O. and Bjorklund, A.: Dopaminergic in nervation of the globus pallidus by collaterals from the nigrostriatal pathway. Brain Res. 172, 169 173 (1979) Nakanishi, H. and Yamamoto, K.: NMDA receptor-mediated neurotransmission in the basal ganglia and limbic system of the rat. In NMDA Receptor Related Agents: Biochemistry, Pharma
9
10
11
12
13
14
15
cology and Behavior, Edited by Kameyama, T., Nabeshima, T. and Domino, E.F., p. 141-151, NPP Books, Ann Arbor (1991) Robledo, P. and Feger, J.: Excitatory influence of rat subthalamic nucleus to substantia nigra pars re ticulata and the pallidal complex: electrophysiolo gical data. Brain Res. 518, 47-54 (1990) Kita, H., Chang, H.T. and Kitai, S.T.: Pallidal in puts to subthalamus: intracellular analysis. Brain Res. 264, 255-265 (1983) Park, M.R., Fall, W.N. and Kitai, S.T.: An in tracellular HRP study of the rat globus pallidus. 1. Responses and light microscopic analysis. J. Comp. Neurol. 211, 284-294 (1982) Becquet, D., Fandon, M. and Hery, F.: In vivo evidence for an inhibitory glutamatergic control of serotonin release in the cat caudate nucleus: involvement of GABA neurons. Brain Res. 519, 82 88 (1989) Gallagher, J.P. and Hasuo, H.: Bicuculline and phaclofen-sensitive components of N-methyl-D aspartate-induced hyperpolarizations in rat doro lateral septal nucleus neurons. J. Physiol. (Lond.) 418, 367-377 (1989) Yamauchi, T. and Fujiwara, H.: Involvement of calmodulin in the Ca'+-dependent activation of rat brainstem tyrosine 3-monoxygenase. Biochem. Int. 1, 98-104 (1980) Chernevskaya, N.I., Obukhov, A.G. and Krishtal, O.A.: NMDA receptor agonists selectively block N-type calcium channels in hippocampal neurons. Nature 349, 418-420 (1991)
Effect
of NMDA
Transmission of Rat
on Dopaminergic
in a Slice Globus
Preparation
Pallidus
Tomomi Shindoui°2, Shuichi Koizumi2, Yasufumi Kataoka3, Shigenori Watanabe2, Kenji Yamamoto' and Hiroshi Nakanishil•* Department of Pharmacology, Faculty of Dentistry, 2Department of Pharmacology, Faculty of Pharmaceutical Sciences, Kyushu University, Fukuoka 812, Japan ;Department of Pharmacology 2 , Nagasaki University School of Medicine, Nagasaki 852, Japan Received
July 27,
1991
Accepted
November
19, 1991
ABSTRACT-The effect of N-methyl-D-aspartate (NMDA) on KCl-evoked endog enous dopamine (DA) release from slices of rat globus pallidus (GP) was examined. NMDA inhibited the KCI-evoked DA release in a dose-dependent manner. This in hibition was blocked by CPP, an NMDA antagonist. Tetrodotoxin partially antago nized the effect of NMDA. The NMDA-induced inhibition was also partially antago nized by bicuculline methiodide and was mimicked by muscimol. These results strong ly suggest that 1) an activation of NMDA receptors exerts an inhibitory effect on dopaminergic transmission in GP and 2) GABAergic transmission is involved in the effect of NMDA.
Glutamatergic transmission mediated by N methyl-D-aspartate (NMDA) receptors in the globus pallidus (GP) has been suggested to play an important role in motor and posture control. A behavioral study in rats showed that blockade of glutamatergic neurotransmis sion mediated by NMDA receptors in GP pro duced rigidity and catalepsy, while a focal in jection of NMDA into GP increased motility (1). Recently it has been demonstrated that NMDA receptors interact with dopaminergic transmissions in the neostriatum (2), substan tia nigra (3) and frontal cortex (4) of rats. Furthermore, NMDA antagonists have been shown to facilitate locomotor activity in monoamine-depleted mice (5) and reverse neuroleptic induced catalepsy in rats (6). GP
also has a sparse but widespread dopaminergic innervation from the substantia nigra (7), but the role of NMDA receptors of GP in dopa minergic transmissions is poorly understood. It is thus considered of interest to investigate a possible interaction between glutamatergic and dopaminergic systems in GP. The present study was undertaken to examine the effects of NMDA on endogenous dopamine (DA) re lease from slices of rat GP. Male Wistar rats weighing 150 200 g were decapitated under light ether anesthesia, and the brains were rapidly removed and placed in ice-cold Krebs Ringer solution of the following composition: 118.0 mM NaCI, 4.7 mM KCI, 1.3 mM CaC12, 1.2 mM MgC12, LO MM NaH2PO4, 25.0 mM NaHCO3 and 11.0 MM D glucose. Each brain was trimmed with a razor blade to a block containing the region of GP. Parasagittal slices of 400 ,um thickness
were cut from the block with a vibratome. The slices were preincubated at 37°C for 1 hr before they were used in the release study. Each slice was stimulated by changing the medium with 100 ,ul of Mg-free Krebs Ringer solution containing 30 mM KCl for 10 min at 37°C. Following the termination of the stim ulation, the medium was quickly collected in a sample cup on ice to determine the amount of released DA. The slices were sonicated im mediately on ice with 1001al of ice-cold 0.1 M perchloric acid containing 0.1% Na2EDTA and 0.1 % of Na2S2O5 and then centrifugated at 10,000 X g for 10 min at 4°C. The super natant was filtered through a membrane filter and then its DA content was determined by liquid chromatography. DA release was ex pressed as a percentage of the total DA con tent (the medium plus slice content). DA re lease induced by 30 mM KC1 in the absence of drug was 29.2 ± 2.2% (mean ± S.E.M., n = 52). Drugs were applied for 10 min during which the tissues were stimulated with 30 mM KCI. Dunnett's t-test was used following a one-analysis of variance, and numerical data
are presented as means ± S.E.M. The drugs used in this study were NMDA (Sigma), 3 [(±)-2-carboxypiperazin-4-yl]-propyl-l-phospho nic acid (CPP, Tocris Neuramin), tetrodotoxin (TTX, Wako), bicuculline methiodide (Sigma) and muscimol (a gift from Yoshitomi Phar maceutical Industries, Ltd.). Figure 1 shows that NMDA had an inhibi tory effect on 30 mM KCl-evoked endogenous DA release from slices of GP in a dose-depend ent manner. The inhibitory effect of 100 ,uM NMDA was significantly blocked by 100 ,uM CPP (P < 0.01, Fig. 2). CPP at 100,aM had no significant effect on KCI-induced DA re lease. CCP at 20 pM partially but not signifi cantly antagonized the inhibitory effect of 100 ,uM NMDA (57.5 ± 9.2% of control, n = 11). The effect of NMDA was also examined in the presence of TTX in order to determine
Fig.
2.
Effects
of
100 ,u M
100 M M bicuculline duced effect Fig.
1.
Concentration-response
NMDA
on
DA
release
slices
of GP.
Each
mean
and
S.E.M.,
observations point. control
are
induced
point
and
for
by
30 mM
vertical
respectively.
indicated
curve
in
bar The
parenthesis
the
effect
of
KCI
from
represent
the
number above
* P < 0.05, **P < 0.01, as compared value of 30 mM KCI-evoked DA release.
of each
to
the
inhibition slices
sent
the
as
of GP.
mean
compared
evoked value
of
the
to
DA of
presence methiodide,
and release.
30 mM of
Each
on
DA
release
evoked
and
control
KC1-evoked
100,uM NMDA. MUS: muscimol.
and
and DA
vertical
respectively. value
# # P < 0.01,
TTX
100,u M NMDA-in
the
column
S.E.M., the
100,uM
on
evoked
of 100 ,u M muscimol
from
CPP,
methiodide
bar **P
of
DA
release
BICC:
repre < 0.01,
30 mM
as compared
the
release
KCl to the in
the
bicuculline
whether the inhibitory effect of NMDA is mediated through an activation of voltage-de pendent Na+ channels. TTX at 100,uM had no significant effect on KCI-evoked DA re lease but partially antagonized the inhibitory effect of NMDA. Bicuculline methiodide at 100 ,uM also partially antagonized the inhibi tory effect of NMDA and slighty, but not sig nificantly, increased DA release. Furthermore, 100 ,uM muscimol significantly depressed 30 mM KCI-evoked DA release (P < 0.01, Fig. 2). The present result shows that activation of NMDA receptors exerts an inhibitory effect on the dopaminergic transmission in the GP. The effect of NMDA was antagonized by bicuculline methiodide, a GABAA receptor antagonist, as well as by CPP, an NMDA re ceptor antagonist. Furthermore, the effect of NMDA was mimicked by muscimol, a GABAA receptor agonist. Thus, it is likely that GABAergic transmission is involved in the inhibitory effect of NMDA on DA re lease. Recent studies have suggested that the subthalamus sends glutamatergic fibers to the GP (8, 9). Most GP neurons are GABAergic neurons projecting to the subthalamus (10) and have extensive local axon collaterals, as demonstrated by an intracellular HRP study (11). Therefore, the inhibitory effect of NMDA on DA release may be through an activation of GABAergic GP projection neurons whose axon collaterals make synaptic contacts with DA nerve terminals. Similar in direct inhibitory effects of NMDA on trans mitter release mediated through GABA have been reported by in vivo release studies utiliz ing push-pull canula. Becquet et al. have re ported that NMDA inhibits the release of [3H]serotonin through an activation of GABAergic interneurons in the cat caudate nucleus (12). Hata et al. also suggested an in volvement of GABAergic neurons in the in hibitory effect of NMDA on dopaminergic transmission in rat medial frontal cortex (4). In an electrophysiological study, Gallagher and Hasuo have suggested that NMDA could hyperpolarize the membrane of dorsolateral
septal nucleus neurons by an activation of lo cal GABAergic inhibitory interneurons (13). The existence of a TTX-insensitive compo nent in the inhibitory effect of NMDA, however, suggests other sources of GABA which can be released by NMDA without an activation of voltage-dependent Na+ channels. Intracellular accumulation of Na+ through NMDA receptor-channels may cause the carrier-mediated GABA release from GABAergic GP neurons. Another possible source of GABA is cut terminals of GABAer gic striato-pallidal fibers. Other mechanisms without induction of GABA release, however, also can not be ruled out for the TTX-insensi tive effect of NMDA. For example, NMDA could modulate DA turnover through an activation of calmodulin-dependent protein kinase which activates tyrosine hydroxylase (14). Furthermore, NMDA has been shown to selectively block N-type Ca2+ channels (15) which are thought to be involved in transmit ter release. The different mode of NMDA action on dopaminergic transmissions in the neostriatum and GP may reflect the different distributions of NMDA receptors in these two brain re gions. The facilitatory effect of NMDA on DA release in the neostriatum is explained by an activation of NMDA receptors located on DA nerve terminals (2), while the inhibitory effect of NMDA on DA release in GP can be considered to involve activation of NMDA re ceptors mainly located on GABAergic projec tion neurons. The precise functional signifi cance of the present result remains to be de termined, but the present study provides evi dence for the possible interaction between these three neurotransmitters in the basal ganglia.
REFERENCES
1
Turski,
L.,
Schwarz,
M.
citatory
Sontag,
T., K.-H.:
neurotransmission
induces tions
Klockgether, and
rigidity for
and
excitatory
in akinesia
the in
neurotransmission
Turski,
W.A.,
Blockade
of
globus the
ex
pallidus
rat:
implica in
patho
2
3
4
5
6
7
8
genesis of Parkinson's disease. Brain Res. 512, 125 -131 (1990) Snell, L.D. and Johnson, K.M.: Characterization of the inhibition of excitatory amino acid-induced neurotransmitter release in the rat striatum by phencyclidine-like drugs. J. Pharmacol. Exp. Ther. 238, 938-946 (1986) Andrade, R. and Bustos, G.: Modulation of den dritic release of dopamine by N-methyl-D-aspartate receptors in rat substantia nigra. J. Neurochem. 52, 962-970 (1989) Hata, N., Nishikawa, T., Umino, A. and Taka hashi, K.: Evidence for involvement of N-methyl D-aspartate receptor in tonic inhibitory control of dopaminergic transmission in rat medial frontal cortex. Neurosci. Lett. 120, 101-104 (1990) Carlsson, M. and Carlsson, A.: The NMDA antago nist MK-801 causes marked locomotor stimulation in monoamine-depleted mice. J. Neural Transm. 75, 221 -226 (1989) Schmidt, W.J. and Bischoff, C.: Dopaminergic be havioral responses modulated by NMDA receptor antagonists. Psychopharmacology (Berlin) 96, S51 (1988) Lindvall, O. and Bjorklund, A.: Dopaminergic in nervation of the globus pallidus by collaterals from the nigrostriatal pathway. Brain Res. 172, 169 173 (1979) Nakanishi, H. and Yamamoto, K.: NMDA receptor-mediated neurotransmission in the basal ganglia and limbic system of the rat. In NMDA Receptor Related Agents: Biochemistry, Pharma
9
10
11
12
13
14
15
cology and Behavior, Edited by Kameyama, T., Nabeshima, T. and Domino, E.F., p. 141-151, NPP Books, Ann Arbor (1991) Robledo, P. and Feger, J.: Excitatory influence of rat subthalamic nucleus to substantia nigra pars re ticulata and the pallidal complex: electrophysiolo gical data. Brain Res. 518, 47-54 (1990) Kita, H., Chang, H.T. and Kitai, S.T.: Pallidal in puts to subthalamus: intracellular analysis. Brain Res. 264, 255-265 (1983) Park, M.R., Fall, W.N. and Kitai, S.T.: An in tracellular HRP study of the rat globus pallidus. 1. Responses and light microscopic analysis. J. Comp. Neurol. 211, 284-294 (1982) Becquet, D., Fandon, M. and Hery, F.: In vivo evidence for an inhibitory glutamatergic control of serotonin release in the cat caudate nucleus: involvement of GABA neurons. Brain Res. 519, 82 88 (1989) Gallagher, J.P. and Hasuo, H.: Bicuculline and phaclofen-sensitive components of N-methyl-D aspartate-induced hyperpolarizations in rat doro lateral septal nucleus neurons. J. Physiol. (Lond.) 418, 367-377 (1989) Yamauchi, T. and Fujiwara, H.: Involvement of calmodulin in the Ca'+-dependent activation of rat brainstem tyrosine 3-monoxygenase. Biochem. Int. 1, 98-104 (1980) Chernevskaya, N.I., Obukhov, A.G. and Krishtal, O.A.: NMDA receptor agonists selectively block N-type calcium channels in hippocampal neurons. Nature 349, 418-420 (1991)
