Overexpression of the dopamine D3 receptor in the rat dorsal striatum induces dyskinetic behaviors.
L-DOPA-induced dyskinesias (LID) are motor side effects associated with treatment of Parkinson's disease (PD). The etiology of LID is not clear; however, studies have shown that the dopamine D3 receptor is upregulated in the basal ganglia of mice, rats and non-human primate models of LID. It is not known if the upregulation of D3 receptor is a cause or result of LID. In this paper we tested the hypothesis that overexpression of the dopamine D3 receptor in dorsal striatum, in the absence of dopamine depletion, will elicit LID. Replication-deficient recombinant adeno-associated virus-2 expressing the D3 receptor or enhanced green fluorescent protein (EGFP) were stereotaxically injected, unilaterally, into the dorsal striatum of adult rats. Post-hoc immunohistochemical analysis revealed that ectopic expression of the D3 receptor was limited to neurons near the injection sites in the dorsal striatum. Following a 3-week recovery period, rats were administered saline, 6 mg/kg L-DOPA, 0.1 mg/kg PD128907 or 10 mg/kg ES609, i.p., and motor behaviors scored. Rats overexpressing the D3 receptor specifically exhibited contralateral axial abnormal involuntary movements (AIMs) following administration of L-DOPA and PD128907 but not saline or the novel agonist ES609. Daily injection of 6 mg/kg L-DOPA to the rats overexpressing the D3 receptor also caused increased vacuous chewing behavior. These results suggest that overexpression of the D3 receptor in the dorsal striatum results in the acute expression of agonist-induced axial AIMs and chronic L-DOPA-induced vacuous chewing behavior. Agonists such as ES609 might provide a novel therapeutic approach to treat dyskinesia.
Department of Pharmacology and Physiology, Rutgers-New Jersey Medical School, Newark, NJ 07101, USA.
Samantha R
SR
Cote
Department of Neurological Surgery, Rutgers-New Jersey Medical School, Newark, NJ 07101, USA.
Vineet C
VC
Chitravanshi
Department of Pharmacology and Physiology, Rutgers-New Jersey Medical School, Newark, NJ 07101, USA.
Carina
C
Bleickardt
Department of Neurological Surgery, Rutgers-New Jersey Medical School, Newark, NJ 07101, USA.
Hreday N
HN
Sapru
Department of Pharmacology and Physiology, Rutgers-New Jersey Medical School, Newark, NJ 07101, USA. Electronic address: kuzhikev@njms.rutgers.edu.
Eldo V
EV
Kuzhikandathil
D000818:Animals; D000978:Antiparkinson Agents / Q000009:adverse effects; D001545:Benserazide / Q000494:pharmacology; D001578:Benzopyrans / Q000494:pharmacology; D003342:Corpus Striatum / Q000378:metabolism*; D000229:Dependovirus; D004298:Dopamine / Q000378:metabolism; D018491:Dopamine Agonists / Q000494:pharmacology; D004409:Dyskinesia, Drug-Induced / Q000378:metabolism*; D005260:Female; D005822:Genetic Vectors; D049452:Green Fluorescent Proteins / Q000235:genetics / Q000378:metabolism; D007150:Immunohistochemistry; D007980:Levodopa / Q000009:adverse effects; D008409:Mastication / Q000187:drug effects; D009043:Motor Activity / Q000187:drug effects / Q000502:physiology; D009474:Neurons / Q000378:metabolism*; D010078:Oxazines / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D050637:Receptors, Dopamine D3 / Q000235:genetics / Q000378:metabolism*; D014162:Transfection
D000978:Antiparkinson Agents; D001578:Benzopyrans; D018491:Dopamine Agonists; D010078:Oxazines; D050637:Receptors, Dopamine D3; C485184:enhanced green fluorescent protein; C062458:3,4,4a,10b-tetrahydro-4-propyl-2H,5H-(1)benzopyrano(4,3-b)-1,4-oxazin-9-ol; D049452:Green Fluorescent Proteins; D007980:Levodopa; D001545:Benserazide; D004298:Dopamine
Adeno-associated virus; Dopamine receptor agonist; Levodopa-induced dyskinesia; Parkinson's disease; Tolerance