Enhanced histamine H2 excitation of striatal cholinergic interneurons in L-DOPA-induced dyskinesia.
Neurobiol Dis
; 76: 67-76, 2015 Apr.
Article
em En
| MEDLINE
| ID: mdl-25661301
ABSTRACT
Levodopa is the most effective therapy for the motor deficits of Parkinson's disease (PD), but long term treatment leads to the development of L-DOPA-induced dyskinesia (LID). Our previous studies indicate enhanced excitability of striatal cholinergic interneurons (ChIs) in mice expressing LID and reduction of LID when ChIs are selectively ablated. Recent gene expression analysis indicates that stimulatory H2 histamine receptors are preferentially expressed on ChIs at high levels in the striatum, and we tested whether a change in H2 receptor function might contribute to the elevated excitability in LID. Using two different mouse models of PD (6-hydroxydopamine lesion and Pitx3(ak/ak) mutation), we chronically treated the animals with either vehicle or l-DOPA to induce dyskinesia. Electrophysiological recordings indicate that histamine H2 receptor-mediated excitation of striatal ChIs is enhanced in mice expressing LID. Additionally, H2 receptor blockade by systemic administration of famotidine decreases behavioral LID expression in dyskinetic animals. These findings suggest that ChIs undergo a pathological change in LID with respect to histaminergic neurotransmission. The hypercholinergic striatum associated with LID may be dampened by inhibition of H2 histaminergic neurotransmission. This study also provides a proof of principle of utilizing selective gene expression data for cell-type-specific modulation of neuronal activity.
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Base de dados:
MEDLINE
Assunto principal:
Doença de Parkinson
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Receptores Histamínicos H2
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Corpo Estriado
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Discinesia Induzida por Medicamentos
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Neurônios Colinérgicos
Tipo de estudo:
Prognostic_studies
Limite:
Animals
Idioma:
En
Ano de publicação:
2015
Tipo de documento:
Article