- Email: [email protected]
In vivo test of two new non-NMDA-receptor antagonist against kainic acid neurotoxicity
28
9 CENTRAL
RECEPTOR
MEDIATION
OF NMDA-INDUCED
DISPOGENESIS
IN PIGEONS.
S c o t t P. B a r o n a n d J a m e s H. Woods, Departments of P h a r m a c o l o g y and P s y c h o l o g y , U n i v e r s i t y of M i c h i g a n , A n n Arbor, MI 4 8 1 0 9 - 0 6 2 6 , U.S.A. A large dipsogenic r e s p o n s e o c c u r s in p i g e o n s f o l l o w i n g i n t r a m u s c u l a r administ r a t i o n of N M D A a n d k a i n a t e (Baron a n d Woods, P h a r m a c o l . B i o c h e m . Behav. 32 [1989] 1080). The intramuscular administration of CGS 19755, the competitive NMDAselective antagonist ( L e h m a n n et al., J. P h a r m a c o l . Exp. Ther. 245 [1988] 65), produced selective antagonism of N M D A - i n d u c e d drinking. H e r e i n we r e p o r t t h e e f f e c t s of c e n t r a l l y a d m i n i s t e r e d CGS 19755 (0.32 a n d 1.0 ug) p r o d u c e d a n t a g o n i s m of d r i n k i n g following NMDA while having a markedly reduced e f f e c t on d r i n k i n g following kainate administration. Doses of CGS 19755 h i g h e r t h a n 1.0 ug p r o d u c e d profound ataxia and catalepsy (as d e f i n e d as loss of r i g h t i n g r e f l e x w i t h o u t h e a d drop). NMDA-induced drinking in p i g e o n s appears to be m e d i a t e d via receptors l o c a t e d w i t h i n t h e c e n t r a l n e r v o u s system. (This r e s e a r c h w a s s u p p o r t e d by N I D A G r a n t s DA 05325 a n d DA 05358.)
i0 IN VIVO TEST OF TWO NEW NON-NMDA-RECEPTOR ANTAGONIST AGAINST KAINIC ACID NEUROTOXICITY. M.Berg, T.Bruhn, F.F.Johansen, P.Krogsgaard-Larsen & N.H.Diemer. PharmaBiotec Research Center and Cerebral Ischemia Group, Institute of Neuropathology, University of Copenhagen, Denmark. The neuroprotective effects of two new non-NMDA receptor antagonists were determined by quantitative light microscopy after intracerebral injection of kainic acid (KA) into two rat brain regions. KA alone or KA in combination with either AMOA or AMNH, was stereotaxically injected into the striatum or into the CA3 region of hippocampus. Compounds were dissolved in Kreb's buffer and l~al of the solution containing KA (0.2 pg) with or without AMOA (3.6 pg) or AMNH (4.5 ~g) were fnfused over a periode of I min. Histologically examination were performed 7 days after the injection and included cells counts in the respective regions. In striatum AMOA almost completely attenauted KA induced cell damage (p< 0.05), whereas AMNH showed no protective effect. In the CA3 region of hippocampus none of the test compounds possesed neuroprotective properties against KA induced pyramidal cell damage. These results indicate a difference in the mechanisms responsible for the neurotoxic action of KA in hippocampus compared to striatum. NNDA: N-methyl-D-aspartate. AMOA: o-amino-3-carboxymethoxy-5-methyl-4-isoaxazolepropionic acid. ANNH: ~-amin~-2(3hydr~xy-5-methyl-4-is~xaz~lyl)methyl-5-methy~-3-~x~-4-is~xaz~line-4-pr~pi~nic acid.
ii NONE OF THE KNOWN EXCITATORY AMINO ACID AGONISTS INDUCES CHEMICAL KINDLING Michael L. Berger, Institute of Biochemical Pharmacology, University Vienna, Austria. Recently, chemical kindling by repeated intra-amygdaloid (i.am.) injections of glutamate(glu) and/ or aspartate(asp) has been described by 2 laboratories (Mori&Wada ]987, Brain Res.425,45; Croucher &Bradford 1989, Brain Res.50],58). In this poster, (up to now fruitless) efforts to induce a similar effect by repeated i.am. injections of several excitatory amino acid agonists are described. The studies were started with low doses of one of the most potent glu agonists, kainic acid (KA). 9 rats received more than 20 i.am. injections of 5 ng KA via chronically implanted fused silica cannulas. Occasionally, limbic motor seizures were induced, but in only one case the phenomenon was behaviourally reminiscent of electrical kindling (reproducible maximal seizure response after the ]2 th injection). 7 rats received repeated injections of ;O0 ng N-CH3-D-as p (NMDA); again, we observed occasionally limbic motor seizures, but without any progression in severity, In the same way, 6 rats received repeatedly lOO ng quisqualic acid (quis), and 5 rats were injected each 2nd day with IOO ng (RS)-~-NH2-3-OH-5-CH3-4-isoxazole propionic acid (AMPA), Occasionally, limbic seizures were induced, but no chemical kindling. Finally, we tried the following combinations: NMDA + KA, NMDA + quis, and NMDA + AMPA; without any success. One possible explanation for our negative resuits could be, that extremely high glu and/or asp doses induce chemical kindling by interaction with receptors different from k,own excitatory amino acid receptors, or that other brain regions close to the injected amygdala and reached by diffused glu and/or asp are involved.
9 CENTRAL
RECEPTOR
MEDIATION
OF NMDA-INDUCED
DISPOGENESIS
IN PIGEONS.
S c o t t P. B a r o n a n d J a m e s H. Woods, Departments of P h a r m a c o l o g y and P s y c h o l o g y , U n i v e r s i t y of M i c h i g a n , A n n Arbor, MI 4 8 1 0 9 - 0 6 2 6 , U.S.A. A large dipsogenic r e s p o n s e o c c u r s in p i g e o n s f o l l o w i n g i n t r a m u s c u l a r administ r a t i o n of N M D A a n d k a i n a t e (Baron a n d Woods, P h a r m a c o l . B i o c h e m . Behav. 32 [1989] 1080). The intramuscular administration of CGS 19755, the competitive NMDAselective antagonist ( L e h m a n n et al., J. P h a r m a c o l . Exp. Ther. 245 [1988] 65), produced selective antagonism of N M D A - i n d u c e d drinking. H e r e i n we r e p o r t t h e e f f e c t s of c e n t r a l l y a d m i n i s t e r e d CGS 19755 (0.32 a n d 1.0 ug) p r o d u c e d a n t a g o n i s m of d r i n k i n g following NMDA while having a markedly reduced e f f e c t on d r i n k i n g following kainate administration. Doses of CGS 19755 h i g h e r t h a n 1.0 ug p r o d u c e d profound ataxia and catalepsy (as d e f i n e d as loss of r i g h t i n g r e f l e x w i t h o u t h e a d drop). NMDA-induced drinking in p i g e o n s appears to be m e d i a t e d via receptors l o c a t e d w i t h i n t h e c e n t r a l n e r v o u s system. (This r e s e a r c h w a s s u p p o r t e d by N I D A G r a n t s DA 05325 a n d DA 05358.)
i0 IN VIVO TEST OF TWO NEW NON-NMDA-RECEPTOR ANTAGONIST AGAINST KAINIC ACID NEUROTOXICITY. M.Berg, T.Bruhn, F.F.Johansen, P.Krogsgaard-Larsen & N.H.Diemer. PharmaBiotec Research Center and Cerebral Ischemia Group, Institute of Neuropathology, University of Copenhagen, Denmark. The neuroprotective effects of two new non-NMDA receptor antagonists were determined by quantitative light microscopy after intracerebral injection of kainic acid (KA) into two rat brain regions. KA alone or KA in combination with either AMOA or AMNH, was stereotaxically injected into the striatum or into the CA3 region of hippocampus. Compounds were dissolved in Kreb's buffer and l~al of the solution containing KA (0.2 pg) with or without AMOA (3.6 pg) or AMNH (4.5 ~g) were fnfused over a periode of I min. Histologically examination were performed 7 days after the injection and included cells counts in the respective regions. In striatum AMOA almost completely attenauted KA induced cell damage (p< 0.05), whereas AMNH showed no protective effect. In the CA3 region of hippocampus none of the test compounds possesed neuroprotective properties against KA induced pyramidal cell damage. These results indicate a difference in the mechanisms responsible for the neurotoxic action of KA in hippocampus compared to striatum. NNDA: N-methyl-D-aspartate. AMOA: o-amino-3-carboxymethoxy-5-methyl-4-isoaxazolepropionic acid. ANNH: ~-amin~-2(3hydr~xy-5-methyl-4-is~xaz~lyl)methyl-5-methy~-3-~x~-4-is~xaz~line-4-pr~pi~nic acid.
ii NONE OF THE KNOWN EXCITATORY AMINO ACID AGONISTS INDUCES CHEMICAL KINDLING Michael L. Berger, Institute of Biochemical Pharmacology, University Vienna, Austria. Recently, chemical kindling by repeated intra-amygdaloid (i.am.) injections of glutamate(glu) and/ or aspartate(asp) has been described by 2 laboratories (Mori&Wada ]987, Brain Res.425,45; Croucher &Bradford 1989, Brain Res.50],58). In this poster, (up to now fruitless) efforts to induce a similar effect by repeated i.am. injections of several excitatory amino acid agonists are described. The studies were started with low doses of one of the most potent glu agonists, kainic acid (KA). 9 rats received more than 20 i.am. injections of 5 ng KA via chronically implanted fused silica cannulas. Occasionally, limbic motor seizures were induced, but in only one case the phenomenon was behaviourally reminiscent of electrical kindling (reproducible maximal seizure response after the ]2 th injection). 7 rats received repeated injections of ;O0 ng N-CH3-D-as p (NMDA); again, we observed occasionally limbic motor seizures, but without any progression in severity, In the same way, 6 rats received repeatedly lOO ng quisqualic acid (quis), and 5 rats were injected each 2nd day with IOO ng (RS)-~-NH2-3-OH-5-CH3-4-isoxazole propionic acid (AMPA), Occasionally, limbic seizures were induced, but no chemical kindling. Finally, we tried the following combinations: NMDA + KA, NMDA + quis, and NMDA + AMPA; without any success. One possible explanation for our negative resuits could be, that extremely high glu and/or asp doses induce chemical kindling by interaction with receptors different from k,own excitatory amino acid receptors, or that other brain regions close to the injected amygdala and reached by diffused glu and/or asp are involved.