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Modulation of dopamine D2 receptor and σbinding site in brain after chronic treatment of haloperidol in rat
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327
PHARMACOEICAL SVJDY OF D-SERINFONACTIVITY OF CLCNFDNMDARECEPIORS. TAKAAKIMATSUIl,MASAYUKISEKIG3CH11,ATSUSHI HASHIMYl+, Ui=N?A
TQ41TA2,'IWRU NISHIKA~2, AND KEIJI
WA&,
lDepartment of Dexnerative
NeurolcqicalDiseases,and 2Departmentof Mental DisorderResearch,National Instituteof Neuroscience,NCNP, Kcdaira,Tokyo 187.
D-Serinehas been previouslyreportedto potentiatethe activityof the N-methyl-D-aspartate Q&IDA)receptorby acting on the strychinine-insensitive glycine site of the NMDA receptor.However the role of free D-serinein the brain has not keen establishedyet. In the present study,we comparedthe activityof free D-serineon the potentiationof cloned IWDA receptorswith that of glycine using the Xenopus cxxyte expressionsystem.
PROPERTIES OF MITOCHONDRIAL BENZODIAZEPlNE RECEPTORS IN THE BRAIN OF NERVOUS MUTANT MICE. YURIE NAKAMOTO’, MITSUNOBU YOSHII’, SHIGEO WATABE2 AND TADASHI SHIOTAN12, ‘Department of Nemophysiology, Tokyo Institute of Psychiatry, 2-l-8 Kamikitazawa, Setagaya-ku, Tokyo 156, 2Tokyo R & D Center, Daiichi Pharmaceutical Co. Ltd., 1-16-13 Kitakasai, Edogawa-ku, Tokyo 134, Japan.
328
Peripheral-type benzodiazepine receptors (PBRs) in the brain have a proconvulsive role in epileptic and normal mice (Nakamoto et al., Neurosci. Res. Suppl. 17, S88, 1992). It remains to be seen, however, how much PBRs of mitochondria in neurons and glias are related to the proconvulsive action. To examine this, we have used nervous mutant mice, which develop a selective degeneration of cerebellar Purkinje cells with abnormal mitochondria. The specific PBR agonist Ro 5-4864 required to induce convulsions for nervous mice was >20 mg/kg, whereas that for controls (heterozygous littermates) was 10 mg/kg. In binding assay for the mitochondrial fraction of brain tissue, a marked reduction in the binding of [3H]Ro 5-4864 was observed in the cerebellum and, to a lesser extent, in the cerebrum of nervous mice, whereas the binding of the central-type [3H]flunitrazepam showed no difference. The results suggest that mitochondria in neurons might be responsible for the proconvulsive role of PBRs in the brain.
329
MODULATION OF DOPAMINE D RECEPTOR AND aBINDING SITE IN BRAIN AFTER CHRONIC TREATMENT OF HAL 8 PERIDOL IN RAT. MASAYUKI TAKIZAWA AND TOSHIFUMI YAMAMOTO, Laboratory of Molecular Recognition, Graduate School of Integrated Science, Yokohama City University, 22-2 Seto, Kanazawa-ku, Yokohama 236, Japan. The o binding sites have been implicated to be involved in the psychotomimetic effects of certain benzomorphans and in a potential site of action for antipsychoThe present study examined the modulation of obinding tics, such as haloperidol. Administration of haloperisite after repeated treatment of haloperidol in rat. do1 (4 mg/kg, i.p., twice a day, for 7 days or 14 days) resulted in 30 % and 35 % increase in the specific binding of [3H]YM-09151-2 to striatum, and in 18 % and 20 % decrease in that of [3H]1,3-di-o-tolylguanidine (DTG) to cerebral cortex, However, the treatment with haloperidol (4 mg/kg, i.p., once a day) respectively. induced no change of [3H]DTG binding ( c-binding site) after 7 or 14 days of administration, while it induced up-regulation of [3H]YM-09151-2 binding (dopamine These findings suggest that the down-regulation of a binding site D2 receptor). These results by haloperidol may depend on the interval of drug administration. are discussed in relation to the regulation of dopamine D2 receptor by haloperidol.
327
PHARMACOEICAL SVJDY OF D-SERINFONACTIVITY OF CLCNFDNMDARECEPIORS. TAKAAKIMATSUIl,MASAYUKISEKIG3CH11,ATSUSHI HASHIMYl+, Ui=N?A
TQ41TA2,'IWRU NISHIKA~2, AND KEIJI
WA&,
lDepartment of Dexnerative
NeurolcqicalDiseases,and 2Departmentof Mental DisorderResearch,National Instituteof Neuroscience,NCNP, Kcdaira,Tokyo 187.
D-Serinehas been previouslyreportedto potentiatethe activityof the N-methyl-D-aspartate Q&IDA)receptorby acting on the strychinine-insensitive glycine site of the NMDA receptor.However the role of free D-serinein the brain has not keen establishedyet. In the present study,we comparedthe activityof free D-serineon the potentiationof cloned IWDA receptorswith that of glycine using the Xenopus cxxyte expressionsystem.
PROPERTIES OF MITOCHONDRIAL BENZODIAZEPlNE RECEPTORS IN THE BRAIN OF NERVOUS MUTANT MICE. YURIE NAKAMOTO’, MITSUNOBU YOSHII’, SHIGEO WATABE2 AND TADASHI SHIOTAN12, ‘Department of Nemophysiology, Tokyo Institute of Psychiatry, 2-l-8 Kamikitazawa, Setagaya-ku, Tokyo 156, 2Tokyo R & D Center, Daiichi Pharmaceutical Co. Ltd., 1-16-13 Kitakasai, Edogawa-ku, Tokyo 134, Japan.
328
Peripheral-type benzodiazepine receptors (PBRs) in the brain have a proconvulsive role in epileptic and normal mice (Nakamoto et al., Neurosci. Res. Suppl. 17, S88, 1992). It remains to be seen, however, how much PBRs of mitochondria in neurons and glias are related to the proconvulsive action. To examine this, we have used nervous mutant mice, which develop a selective degeneration of cerebellar Purkinje cells with abnormal mitochondria. The specific PBR agonist Ro 5-4864 required to induce convulsions for nervous mice was >20 mg/kg, whereas that for controls (heterozygous littermates) was 10 mg/kg. In binding assay for the mitochondrial fraction of brain tissue, a marked reduction in the binding of [3H]Ro 5-4864 was observed in the cerebellum and, to a lesser extent, in the cerebrum of nervous mice, whereas the binding of the central-type [3H]flunitrazepam showed no difference. The results suggest that mitochondria in neurons might be responsible for the proconvulsive role of PBRs in the brain.
329
MODULATION OF DOPAMINE D RECEPTOR AND aBINDING SITE IN BRAIN AFTER CHRONIC TREATMENT OF HAL 8 PERIDOL IN RAT. MASAYUKI TAKIZAWA AND TOSHIFUMI YAMAMOTO, Laboratory of Molecular Recognition, Graduate School of Integrated Science, Yokohama City University, 22-2 Seto, Kanazawa-ku, Yokohama 236, Japan. The o binding sites have been implicated to be involved in the psychotomimetic effects of certain benzomorphans and in a potential site of action for antipsychoThe present study examined the modulation of obinding tics, such as haloperidol. Administration of haloperisite after repeated treatment of haloperidol in rat. do1 (4 mg/kg, i.p., twice a day, for 7 days or 14 days) resulted in 30 % and 35 % increase in the specific binding of [3H]YM-09151-2 to striatum, and in 18 % and 20 % decrease in that of [3H]1,3-di-o-tolylguanidine (DTG) to cerebral cortex, However, the treatment with haloperidol (4 mg/kg, i.p., once a day) respectively. induced no change of [3H]DTG binding ( c-binding site) after 7 or 14 days of administration, while it induced up-regulation of [3H]YM-09151-2 binding (dopamine These findings suggest that the down-regulation of a binding site D2 receptor). These results by haloperidol may depend on the interval of drug administration. are discussed in relation to the regulation of dopamine D2 receptor by haloperidol.