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Effects of nootropic drugs on excitatory amino acid receptor-mediated responses expressed in Xenopus oocytes by guinea pig forebrain mRNA
$103 EFFECTS OF NOOTROPIC DRUGS ON EXCITATORY AMINO ACID RECEPTOR-MEDIATED RESPONSES EXPRESSED IN XENOPUS OOCYTES BY GUINEA PIG FOREBRAIN mRNA. SHUJ-[ KAN~KO'~ HIDEI~ TAKAHASHI*, MASUNOBU SUGIMURA" AND MASAMICHI SATOH~ Department of Pharmacology~ Facult,¢ of Pharmaceutical Sciences, K¥oto UrtiversiW, Sakvo-ku, Kyoto 606, Japan. The effects of various nootropic (or cerebroprotective) drugs on ionic conductance through N-methyl-Daspartate (NMDA) receptors were evaluated by the use of Xenopus ooeytes injected with poly(A)+mRNA from guinea pig forebrains, where distinguished properties of neuronal NMDA receptors were reproduced, including an increase in permeability of Ca 2+, a voltage-dependent blockade by Mg2+, a blockade by the NMDA antagonist D-2-amino-5-phosphonovaleric acid, and a potentiation by glycine. A NMDA-evoked current of the injected ooeytes in the presence of glyeine was reduced in a reversible manner by several nootropie agents (bifemelane, indeloxazine, vinpocetine, and vincamine) as well as by some other drugs like diltiazem, midazolam, phenytoin, and imipramine at a concentration of 100 /aM. Further experiments showed that the nootropies suppressed the NMDA-evoked current dose-dependently in a non-competitive manner, did not affect voltage-current relationship or desensitization rate of the NMDA response, and did not significantly reduced a kainate response of the injected oocytes. These results suggest that such nootropic agents may protect neurons from Ca2+-overload, through their actions on the Ca2+-permeable channel site of the NMDA receptor.
ONTOGENY OF STRYCHNINE-INSENSITIV~ [3H]GLYCINE BINDING S ITES IN RAT ^ 1 FOREBR~IN. KAZL'YUKI < ~HINOHARA *I, ", TOURU ~ ..'ISHIKAWA-, AND KIYOHISA TAKAHASHI-.1 1 _ D i v i s i o n ,.~f M e n t a l D i s o r d e r Research, National Institute of Neuroscience. NCNP. 4-1-1 0 K a w a - H i K a s h i . K0daira. 187. --'Department ~f Psychiatry, School c f Medicine. T0kai University. B0useidai, !sehara, 259-Ii, Japan. The d e v e l o p m e n t of [3H]glyeine b i n d i n g to s t r y c h n i n e - i n s e n s i t i v e glyeine receptors in b o t h brain h 0 m 0 g e n a t e and slic@s has been investigated in the rat. The specific b i n d i n g sites for [~H]glycine in the h o m o g e n a t e were a l r e a d y d e t e c t e d at p r e n a t a l stages and then steadily increased to a d u l t levels at postnatal day 14. A s i m i l a r developmental pattern was seen in autoradiography of [3H]glycine b i n d i n g . T h e r e was an i n c r e a s e in Bmax w i t h o u t c h a n g e s in t h e Kd o f [°H]glyeine binding and there w a s no c h a n g e in i n h i b i t i o n of the binding by glycine, D-serine, L-serine, and HA-966 (1-hydroxy-3amynopyrrolid-2-one) during postnatal maturation. These findings suggest an i n c r e a s e in density with no c h a n g e in affinity of strychnine-insensitive glycine receptors.
D I S T R I B U T I O N OF E X C I T A T O R Y AMINO ACID RECEPTORS ON V E N T R A L HORN NEURONS OF THE N E W B O R N RAT SPINAL CORD. , KAYOKO O N O D E R A *I AND AKIRA TAKEUCHI 2 ILab. of Physiol~, Juntendo Medical Colleqe o f Nursing, 2-2, Takasu, Urayasusi, Chiba 279, a n d ZDep. o f Physiol. J u n t e n d o Univ. Sch. of Med.2-1-1 Hongo t Tokyo t 113 t Japan A precise distribution of e x c i t a t o r y a m i n o a c i d r e c e p t o r s w a s s t u d i e d on v i s u a l i z e d neurons in slices of n e w b o r n rat spinal cord. Lucifer Yellow was injected into a neuron from a recording microelectrode. L-glutamate and other amino acids were i o n o p h o r e t i c a l l y applied through a d o u b l e - b a r r e l e d m i c r o p i p e t t e filled with Lucifer Yellow. Under a fluorescent microscope, the neuron and the tip of the pipette were clearly seen and the pipette was located to various parts of the neuron. Soma and dendrite membranes had high sensitivity to glutamate and quisqualate. On the other hand, s e n s i t i v i t i e s to NMDA and Kainate were relatively high in the soma, but low in the dendrites. Q u i s q u a l a t e applied close to the neuron by a short pulse(2-5 msec duration) evoked a fast response followed by a slow response that lasted for a few sec. The fast d e p o l a r i z a t i o n was shorter than the g l u t a m a t e p o t e n t i a l and w a s d e s e n s i t i z e d by a p r e c e d i n g application of glutamate. The slow response was d i m i n i s h e d by an i n t r a c e l l u l a r injection of EGTA. Q u i s q u a l a t e seems to activate two types of receptors: one is directly connected to ion channels and the other causes a slow response m e d i a t e d by second m e s s e n g e r systems.
ONTOGENY OF STRYCHNINE-INSENSITIV~ [3H]GLYCINE BINDING S ITES IN RAT ^ 1 FOREBR~IN. KAZL'YUKI < ~HINOHARA *I, ", TOURU ~ ..'ISHIKAWA-, AND KIYOHISA TAKAHASHI-.1 1 _ D i v i s i o n ,.~f M e n t a l D i s o r d e r Research, National Institute of Neuroscience. NCNP. 4-1-1 0 K a w a - H i K a s h i . K0daira. 187. --'Department ~f Psychiatry, School c f Medicine. T0kai University. B0useidai, !sehara, 259-Ii, Japan. The d e v e l o p m e n t of [3H]glyeine b i n d i n g to s t r y c h n i n e - i n s e n s i t i v e glyeine receptors in b o t h brain h 0 m 0 g e n a t e and slic@s has been investigated in the rat. The specific b i n d i n g sites for [~H]glycine in the h o m o g e n a t e were a l r e a d y d e t e c t e d at p r e n a t a l stages and then steadily increased to a d u l t levels at postnatal day 14. A s i m i l a r developmental pattern was seen in autoradiography of [3H]glycine b i n d i n g . T h e r e was an i n c r e a s e in Bmax w i t h o u t c h a n g e s in t h e Kd o f [°H]glyeine binding and there w a s no c h a n g e in i n h i b i t i o n of the binding by glycine, D-serine, L-serine, and HA-966 (1-hydroxy-3amynopyrrolid-2-one) during postnatal maturation. These findings suggest an i n c r e a s e in density with no c h a n g e in affinity of strychnine-insensitive glycine receptors.
D I S T R I B U T I O N OF E X C I T A T O R Y AMINO ACID RECEPTORS ON V E N T R A L HORN NEURONS OF THE N E W B O R N RAT SPINAL CORD. , KAYOKO O N O D E R A *I AND AKIRA TAKEUCHI 2 ILab. of Physiol~, Juntendo Medical Colleqe o f Nursing, 2-2, Takasu, Urayasusi, Chiba 279, a n d ZDep. o f Physiol. J u n t e n d o Univ. Sch. of Med.2-1-1 Hongo t Tokyo t 113 t Japan A precise distribution of e x c i t a t o r y a m i n o a c i d r e c e p t o r s w a s s t u d i e d on v i s u a l i z e d neurons in slices of n e w b o r n rat spinal cord. Lucifer Yellow was injected into a neuron from a recording microelectrode. L-glutamate and other amino acids were i o n o p h o r e t i c a l l y applied through a d o u b l e - b a r r e l e d m i c r o p i p e t t e filled with Lucifer Yellow. Under a fluorescent microscope, the neuron and the tip of the pipette were clearly seen and the pipette was located to various parts of the neuron. Soma and dendrite membranes had high sensitivity to glutamate and quisqualate. On the other hand, s e n s i t i v i t i e s to NMDA and Kainate were relatively high in the soma, but low in the dendrites. Q u i s q u a l a t e applied close to the neuron by a short pulse(2-5 msec duration) evoked a fast response followed by a slow response that lasted for a few sec. The fast d e p o l a r i z a t i o n was shorter than the g l u t a m a t e p o t e n t i a l and w a s d e s e n s i t i z e d by a p r e c e d i n g application of glutamate. The slow response was d i m i n i s h e d by an i n t r a c e l l u l a r injection of EGTA. Q u i s q u a l a t e seems to activate two types of receptors: one is directly connected to ion channels and the other causes a slow response m e d i a t e d by second m e s s e n g e r systems.