Genetic suppression of the dopamine D3 receptor in striatal D1 cells reduces the development of L-DOPA-induced dyskinesia.
Exp Neurol
; 336: 113534, 2021 02.
Article
en En
| MEDLINE
| ID: mdl-33249031
ABSTRACT
Parkinson's Disease (PD) is symptomatically managed with L-DOPA but chronic use results in L-DOPA-induced dyskinesia (LID) characterized by abnormal involuntary movements (AIMs). In LID, dopamine D3 receptors (D3R) are upregulated on D1 receptor (D1R)-bearing medium spiny neurons where the can synergistically drive downstream signaling and motor behaviors. Despite evidence implying D1R-D3R cooperativity in LID, the dyskinesiogenic role of D3R has never been directly tested. To this end, we developed a specific cre-dependent microRNA (miRNA) to irreversibly prevent D3R upregulation in D1R striatal cells. D1-Cre rats received unilateral 6-hydroxydopamine lesions. Three weeks later, rats received an adeno-associated virus expressing either D3R miRNA or a scrambled (SCR) miRNA delivered into the striatum. After 4 weeks, rats received chronic L-DOPA (6 mg/kg) or vehicle. AIMs development and motor behaviors were assayed throughout treatment. At the conclusion of the experiment, efficacy and fidelity of the miRNA strategy was analyzed using in situ hybridization (ISH). ISH analyses demonstrated that D1R+/D3R+ cells were upregulated in LID and that the selective D3R miRNA reduced D1R+/D3R+ co-expression. Importantly, silencing of D3R also significantly attenuated LID development without impacting L-DOPA efficacy or other locomotion. These data highlight a dyskinesiogenic role of D3R within D1R cells in LID and highlight aberrant D1R-D3R interactions as targets of LID management.
Palabras clave
Texto completo:
1
Colección:
01-internacional
Base de datos:
MEDLINE
Asunto principal:
Dopaminérgicos
/
Levodopa
/
Receptores de Dopamina D1
/
Neostriado
/
Discinesia Inducida por Medicamentos
/
Receptores de Dopamina D3
Límite:
Animals
Idioma:
En
Revista:
Exp Neurol
Año:
2021
Tipo del documento:
Article