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Striatal dopamine function in rodent models of human movement disorders : an antisense approach

University of British Columbia

The dopamine transporter (DAT) functions primarily as a means for the termination of dopaminergic neurotransmission, but may also play a role in the pathogenesis of Parkinson's disease. Recent studies have implicated the DAT in the uptake of two experimental neurotoxins, 1-methyl-4-phenyl-l,2,3,6-tetrahydropyridine (MPTP) and 6-hydroxydopamine. Here, in vivo administration of phosphorothioate antisense oligonucleotides targeting DAT mRNA in the left substantia nigra pars compacta resulted in reduced [3H] WIN 35,428 binding to DAT in the left striatum and significant levodopa and amphetamine-induced contralateral rotations. Unilateral pretreatment with DAT antisense prior to bilateral intrastriatal infusion of either neurotoxin resulted in asymmetrical striatal DAT binding and dopamine content indicating significant preservation ipsilateral to antisense pretreatment. As well, significant apomorphine-induced ipsilateral rotations were observed, suggesting neuroprotection of nigrostriatal neurons on the antisense-treated side. Thus, the DAT appears to play a critical role in determining susceptibility to these experimental neurotoxins and may prove useful as a marker for susceptibility to Parkinson's disease and as a target for therapeutic intervention. Regulation of dopamine neurotransmission by the DAT may also be an important factor in the development of drug-induced dyskinesias. Dyskinesias are abnormal involuntary movements which develop as a side-effect of long-term treatment with either levodopa for Parkinson's (levodopa-induced dyskinesias) or antipsychotics (tardive dyskinesia) for schizophrenia. The mechanism underlying these dyskinesias remains unclear but may involve heightened activity in dopamine D1 receptor-bearing striatonigral neurons. Here, intrastriatal infusion of antisense targeting dopamine D1A receptor mRNA significantly reduced striatal D1 receptor binding and attenuated behavioural responses in rodent models of both levodopa-induced dyskinesia and tardive dyskinesia. Thus, the dopamine D1A receptor may play a significant role in the expression of drug-induced dyskinesias. Recently, chronic pulsatile levodopa treatment in a rodent model of levodopa-induced dyskinesias has been associated with increased expression of striatal dopamine D3 receptors. These receptors are localized with D1 receptors on striatonigral neurons and their induction is dependent on dopamine D1 receptor activity. Here intrastriatal infusion of oligonucleotide antisense to dopamine D3 receptor mRNA effectively reduced chronic levodopa-induced elevations in D3 receptor expression and significantly reduced behavioural responses in this model. Thus, expression of levodopa-induced dyskinesias may also involve dopamine D3 receptor activity, possibly through interaction with D1 receptors.

Thesis/Dissertation

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2009-07-20

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http://hdl.handle.net/2429/10971

Neuroscience

University of British Columbia

UBCV

DSpace