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L-DOPA persuades enhanced GABA release in the medial globus pallidus in a rat model of L-DOPA-induced dyskinesia
Abstracts / Neuroscience Research 58S (2007) S1–S244
O2P-EØ5 L-DOPA persuades enhanced GABA release in the medial globus pallidus in a rat model of L-DOPA-induced dyskinesia Tomiyama 1 ,
Arai 1 ,
Zhu 2 ,
Masahiko Akira Gang Tamaki Kimura 1 , Mikio Shoji 1 1 Department of Neurology, Hirosaki University, Hirosaki, Japan; 2 Department of Neuropsychiatry, Hirosaki University, Japan L-DOPA is the most effective agent used for symptomatic relief in patients with Parkinson disease (PD) but long term L-DOPA treatment often accompanies problematic L-DOPA-induced dyskinesia (LID). We have shown that a rat model of LID (the 6-OHDA-lesioned rat, the PD model, repeatedly treated with L-DOPA) has enlarged axon terminals of the GABAergic projection from the striatum to the medial globus pallidus (MGP) (the direct pathway) and increased density of synaptic vesicles in the enlarged terminals. These findings suggest that amplified GABAergic neurotransmission in the MGP is involved in the genesis of LID. The present study, using in vivo microdialysis, evaluated the effect of a LDOPA injection on GABA release in the MGP of the PD and LID models. L-DOPA-induced increase in extracellular GABA levels in the MGP was significantly higher in the LID model than in the PD model. This result strongly indicates that enhanced GABA release in the MGP is related to the occurrence of LID.
O2P-EØ6 Involvement of endogenous dopamine in dopaminergic neuronal death induced by glutamate Izumi 1 ,
Sawada 2 ,
O2P-EØ8 A reevaluation of the network via patch and matrix compartments of rat neostriatum Fumino Fujiyama 1 , Jaerin Sohn 1 , Tomo Unzai 1 , Takeshi Kaneko 1,2 1 Department of Morphological Brain Science, Kyoto University, Kyoto, Japan; 2 CREST, Japan The current model of basal ganglia rests on the idea that the striofugal system is composed of two separate (direct and indirect) pathways originating from distinct cell populations in the striatum. The striatum itself is divided into two major compartments, the patch and matrix, which differ by their neurochemical characters and input/output connections. Here, the differences in the synaptic organization of these striatopetal afferents between the striatal compartments were examined with two kinds of vesicular glutamate transporters. Furthermore, the labeled axons from single neurons located in either patch or matrix were entirely reconstructed. Our findings are at odds with the previous concept of a dual striatofugal system: direct/indirect and patch/matrix, and call for a reevaluation of the organization striatofugal projection system. Research funds: KAKENHI 16500217, 1600025, 17022020, 17650100, 17022024
O2P-EØ9 Molecular basis for impulsive and self-controlled behaviors in delay-discounting task
Yamamoto 1 ,
Yasuhiko Hideyuki Noriyuki Yoshiaki Kume 1 , Hiroshi Katsuki 1 , Akinori Akaike 1 1 Department of Pharmacology, Graduate School of Pharmaceutical Sciences, Kyoto University, Kyoto, Japan; 2 Clinical Research Center, Utano Nat. Hosp., Kyoto, Japan It has been proposed that endogenous dopamine could serve as a susceptibility factor in dopaminergic neurodegeneration in Parkinson disease. Although hyperactivation of glutamatergic transmission may be involved in the degenerative process, a role of dopamine in glutamate excitotoxicity has not yet been elucidated. We demonstrated that dopaminergic neurons were more vulnerable to glutamate toxicity than non-dopaminergic neurons in primary mesencephalic cultures. Depletion of intracellular dopamine by ␣-methyl-p-tyrosine, an inhibitor of tyrosine hydroxylase (TH), suppressed dopaminergic neuronal death induced by glutamate. Exposure to glutamate caused phosphorylation of TH which facilitates dopamine synthesis. PD98059, an inhibitor of MEK, suppressed phosphorylation of TH and protected dopaminergic neurons from glutamate toxicity. These results suggest that the vulnerability of dopaminergic neurons to glutamate toxicity is dependent on endogenous dopamine.
O2P-EØ7 Effects of zonisamide on experimental tremors in rats Hideto Miwa, Kiwa Hama, Yoshinori Kajimoto, Ichiro Nakanishi, Tomoyoshi Kondo Department of Neurology, Wakayama Medical University, Wakayama, Japan Recent clinical studies have suggested that zonisamide, an antiepileptic, may be effective for the treatment of Parkinson disease and essential tremor. The present study aimed to study the effect of zonisamide on experimental tremors in rats. Methods: Three representative rodent tremor models were used. Harmaline- or oxotremorine-induced tremors, and cholinomimeticinduced tremulous jaw movements (TJMs), which have been proposed as a rodent model of pharmacologically induced parkinsonian tremor. Results: Zonisamide significantly suppressed both harmaline- and oxotremorine-induced tremors dose-dependently. Zonisamide also significantly suppressed tacrine-induced TJMs, and this effect was not lost under conditions of monoamine-depletion by reserpine or dopaminergic blockade by a cataleptic dose of haloperidol. Conclusions: Although zonisamide is knowns as a dopamine release enhancer, the anti-tremor effects of zonisamide may be achieved by a non-dopaminergic mechanism. Zonisamide may be a non-specific, antitremor drug. Research funds: KAKENHI: 17590889
S59
Seiji Hayashizaki, Yumi Ito, Masahiko Takada Tokyo Metropolitan Institute for Neuroscience, Tokyo, Japan When two alternatives are available in instrumental behavior, animal behavior is biased toward responding on one lever with which each behavioral response results in delayed but large reward, and against responding on the other lever with which each response results in immediate but small reward. This has been used as an index of impulsive behavior and is known to be sensitive to lesions of the nucleus accumbens (NAC). Pharmacological studies with systemic administration of antagonists have shown that dopaminergic transmission is involved in controlling choice behavior in a delay-discounting task. Thus, a major question arises as to whether dopamine in the NAC is really involved in controlling behaviors in the task. To this end, we implanted cannulas into the NAC to identify neuronal substances in controlling behavior. We confirmed dopamine as the chemical substance in the NAC that controls choice behaviors in the task. Dopamine transmission is converted to second messengers through dopamine receptors. We are identifying which of them are responsible for choice behaviors in the task.
O2P-E1Ø Dynamical modes in a computational model of the subthalamo-pallidal circuit Katsunori Kitano 1 , Tomoki Fukai 2 1 Department of Human and Computer Intelligence, Ritsumeikan University, Kusatsu, Japan; 2 Laboratory for Neural Circuit Theory, RIKEN Brain Science Institute, Japan Recent findings of the basal ganglia, especially from the pathological studies on the circuit, have suggested that temporal properties of the neural activity such as rhythmicity and synchronicity are involved in the functions. Therefore, understanding of dynamical properties of the circuit is increasing in importance. We investigated stability of synchronous spike activity of subthalamic nucleus (STN) and the external segment of global pallidus (GPe) applying the phase analysis to their model neurons. The result showed interconnected STN neurons tended to synchronize whereas GPe neurons essentially desynchronized within the range of experimentally observed in vivo firing rates. In addition, we conducted numerical simulations of mutually connected STN-GPe network changing some parameters, which suggested pallido-subthalamic synapses are one of the crucial factors to control dynamical modes of the nuclei. Research funds: KAKENHI (18019036)
O2P-EØ5 L-DOPA persuades enhanced GABA release in the medial globus pallidus in a rat model of L-DOPA-induced dyskinesia Tomiyama 1 ,
Arai 1 ,
Zhu 2 ,
Masahiko Akira Gang Tamaki Kimura 1 , Mikio Shoji 1 1 Department of Neurology, Hirosaki University, Hirosaki, Japan; 2 Department of Neuropsychiatry, Hirosaki University, Japan L-DOPA is the most effective agent used for symptomatic relief in patients with Parkinson disease (PD) but long term L-DOPA treatment often accompanies problematic L-DOPA-induced dyskinesia (LID). We have shown that a rat model of LID (the 6-OHDA-lesioned rat, the PD model, repeatedly treated with L-DOPA) has enlarged axon terminals of the GABAergic projection from the striatum to the medial globus pallidus (MGP) (the direct pathway) and increased density of synaptic vesicles in the enlarged terminals. These findings suggest that amplified GABAergic neurotransmission in the MGP is involved in the genesis of LID. The present study, using in vivo microdialysis, evaluated the effect of a LDOPA injection on GABA release in the MGP of the PD and LID models. L-DOPA-induced increase in extracellular GABA levels in the MGP was significantly higher in the LID model than in the PD model. This result strongly indicates that enhanced GABA release in the MGP is related to the occurrence of LID.
O2P-EØ6 Involvement of endogenous dopamine in dopaminergic neuronal death induced by glutamate Izumi 1 ,
Sawada 2 ,
O2P-EØ8 A reevaluation of the network via patch and matrix compartments of rat neostriatum Fumino Fujiyama 1 , Jaerin Sohn 1 , Tomo Unzai 1 , Takeshi Kaneko 1,2 1 Department of Morphological Brain Science, Kyoto University, Kyoto, Japan; 2 CREST, Japan The current model of basal ganglia rests on the idea that the striofugal system is composed of two separate (direct and indirect) pathways originating from distinct cell populations in the striatum. The striatum itself is divided into two major compartments, the patch and matrix, which differ by their neurochemical characters and input/output connections. Here, the differences in the synaptic organization of these striatopetal afferents between the striatal compartments were examined with two kinds of vesicular glutamate transporters. Furthermore, the labeled axons from single neurons located in either patch or matrix were entirely reconstructed. Our findings are at odds with the previous concept of a dual striatofugal system: direct/indirect and patch/matrix, and call for a reevaluation of the organization striatofugal projection system. Research funds: KAKENHI 16500217, 1600025, 17022020, 17650100, 17022024
O2P-EØ9 Molecular basis for impulsive and self-controlled behaviors in delay-discounting task
Yamamoto 1 ,
Yasuhiko Hideyuki Noriyuki Yoshiaki Kume 1 , Hiroshi Katsuki 1 , Akinori Akaike 1 1 Department of Pharmacology, Graduate School of Pharmaceutical Sciences, Kyoto University, Kyoto, Japan; 2 Clinical Research Center, Utano Nat. Hosp., Kyoto, Japan It has been proposed that endogenous dopamine could serve as a susceptibility factor in dopaminergic neurodegeneration in Parkinson disease. Although hyperactivation of glutamatergic transmission may be involved in the degenerative process, a role of dopamine in glutamate excitotoxicity has not yet been elucidated. We demonstrated that dopaminergic neurons were more vulnerable to glutamate toxicity than non-dopaminergic neurons in primary mesencephalic cultures. Depletion of intracellular dopamine by ␣-methyl-p-tyrosine, an inhibitor of tyrosine hydroxylase (TH), suppressed dopaminergic neuronal death induced by glutamate. Exposure to glutamate caused phosphorylation of TH which facilitates dopamine synthesis. PD98059, an inhibitor of MEK, suppressed phosphorylation of TH and protected dopaminergic neurons from glutamate toxicity. These results suggest that the vulnerability of dopaminergic neurons to glutamate toxicity is dependent on endogenous dopamine.
O2P-EØ7 Effects of zonisamide on experimental tremors in rats Hideto Miwa, Kiwa Hama, Yoshinori Kajimoto, Ichiro Nakanishi, Tomoyoshi Kondo Department of Neurology, Wakayama Medical University, Wakayama, Japan Recent clinical studies have suggested that zonisamide, an antiepileptic, may be effective for the treatment of Parkinson disease and essential tremor. The present study aimed to study the effect of zonisamide on experimental tremors in rats. Methods: Three representative rodent tremor models were used. Harmaline- or oxotremorine-induced tremors, and cholinomimeticinduced tremulous jaw movements (TJMs), which have been proposed as a rodent model of pharmacologically induced parkinsonian tremor. Results: Zonisamide significantly suppressed both harmaline- and oxotremorine-induced tremors dose-dependently. Zonisamide also significantly suppressed tacrine-induced TJMs, and this effect was not lost under conditions of monoamine-depletion by reserpine or dopaminergic blockade by a cataleptic dose of haloperidol. Conclusions: Although zonisamide is knowns as a dopamine release enhancer, the anti-tremor effects of zonisamide may be achieved by a non-dopaminergic mechanism. Zonisamide may be a non-specific, antitremor drug. Research funds: KAKENHI: 17590889
S59
Seiji Hayashizaki, Yumi Ito, Masahiko Takada Tokyo Metropolitan Institute for Neuroscience, Tokyo, Japan When two alternatives are available in instrumental behavior, animal behavior is biased toward responding on one lever with which each behavioral response results in delayed but large reward, and against responding on the other lever with which each response results in immediate but small reward. This has been used as an index of impulsive behavior and is known to be sensitive to lesions of the nucleus accumbens (NAC). Pharmacological studies with systemic administration of antagonists have shown that dopaminergic transmission is involved in controlling choice behavior in a delay-discounting task. Thus, a major question arises as to whether dopamine in the NAC is really involved in controlling behaviors in the task. To this end, we implanted cannulas into the NAC to identify neuronal substances in controlling behavior. We confirmed dopamine as the chemical substance in the NAC that controls choice behaviors in the task. Dopamine transmission is converted to second messengers through dopamine receptors. We are identifying which of them are responsible for choice behaviors in the task.
O2P-E1Ø Dynamical modes in a computational model of the subthalamo-pallidal circuit Katsunori Kitano 1 , Tomoki Fukai 2 1 Department of Human and Computer Intelligence, Ritsumeikan University, Kusatsu, Japan; 2 Laboratory for Neural Circuit Theory, RIKEN Brain Science Institute, Japan Recent findings of the basal ganglia, especially from the pathological studies on the circuit, have suggested that temporal properties of the neural activity such as rhythmicity and synchronicity are involved in the functions. Therefore, understanding of dynamical properties of the circuit is increasing in importance. We investigated stability of synchronous spike activity of subthalamic nucleus (STN) and the external segment of global pallidus (GPe) applying the phase analysis to their model neurons. The result showed interconnected STN neurons tended to synchronize whereas GPe neurons essentially desynchronized within the range of experimentally observed in vivo firing rates. In addition, we conducted numerical simulations of mutually connected STN-GPe network changing some parameters, which suggested pallido-subthalamic synapses are one of the crucial factors to control dynamical modes of the nuclei. Research funds: KAKENHI (18019036)