The dopamine D(2) receptor partial agonist aplindore improves motor deficits in MPTP-treated common marmosets alone and combined with L-dopa - PubMed (original) (raw)

The dopamine D(2) receptor partial agonist aplindore improves motor deficits in MPTP-treated common marmosets alone and combined with L-dopa

Michael John Jackson et al. J Neural Transm (Vienna). 2010 Jan.

Abstract

Dopamine replacement therapy in Parkinson's disease (PD) using L-dopa is invariably associated with a loss of drug efficacy ("wearing off") and the onset of dyskinesia. The use of dopamine receptor partial agonists might improve therapeutic benefit without increased dyskinesia expression but may antagonise the effects of L-dopa. We now examine the effects of the novel high affinity, dopamine D(2) receptor partial agonist, aplindore alone and in combination with L-dopa in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated common marmoset. In non-dyskinetic MPTP treated animals, aplindore (0.05-1.0 mg/kg p.o.) produced a dose-dependent reversal of motor disability and an increase in locomotor activity that was maximal at doses of 0.2 mg/kg and above. In animals previously exposed to L: -dopa to induce dyskinesia, escalating and repeated dosing of aplindore (0.05-0.5 mg/kg p.o.) produced a sustained, dose-related improvement in motor disability and an increase in locomotor activity. The effects were maximal at a dose of 0.1 mg/kg and above and not different from those produced by L-dopa (12.5 mg/kg plus carbidopa 12.5 mg/kg p.o.). Aplindore administration also led to dose-dependent expression of dyskinesia but at 0.1 mg/kg, this was significantly less intense than that produced by L-dopa. Administration of aplindore (1.0 mg/kg p.o.) in combination with L-dopa (2.5 mg/kg plus carbidopa 12.5 mg/kg p.o.) did not inhibit the reversal of motor deficits but improved motor disability and increased both locomotor activity and dyskinesia expression equivalent to that produced by L-dopa (12.5 mg/kg plus carbidopa 12.5 mg/kg p.o.). These data suggest that dopamine receptor partial agonists would be effective in the treatment of Parkinson's disease and would not inhibit the beneficial actions of L-dopa.

PubMed Disclaimer

Cited by

Update on the Mechanism of Action of Aripiprazole: Translational Insights into Antipsychotic Strategies Beyond Dopamine Receptor Antagonism.
de Bartolomeis A, Tomasetti C, Iasevoli F. de Bartolomeis A, et al. CNS Drugs. 2015 Sep;29(9):773-99. doi: 10.1007/s40263-015-0278-3. CNS Drugs. 2015. PMID: 26346901 Free PMC article. Review.
Animal models of Parkinson's disease: a source of novel treatments and clues to the cause of the disease.
Duty S, Jenner P. Duty S, et al. Br J Pharmacol. 2011 Oct;164(4):1357-91. doi: 10.1111/j.1476-5381.2011.01426.x. Br J Pharmacol. 2011. PMID: 21486284 Free PMC article. Review.
Therapy for Parkinson's disease: what is in the pipeline?
Stocchi F. Stocchi F. Neurotherapeutics. 2014 Jan;11(1):24-33. doi: 10.1007/s13311-013-0242-1. Neurotherapeutics. 2014. PMID: 24343458 Free PMC article. Review.

References

1. Mov Disord. 2003 May;18(5):487-95 - PubMed
1. Ann Neurol. 2003;53 Suppl 3:S3-12; discussion S12-5 - PubMed
1. J Pharmacol Exp Ther. 1995 Apr;273(1):309-14 - PubMed
1. Mov Disord. 1995 Nov;10(6):731-40 - PubMed
1. Synapse. 2006 Dec 15;60(8):599-608 - PubMed

The dopamine D(2) receptor partial agonist aplindore improves motor deficits in MPTP-treated common marmosets alone and combined with L-dopa - PubMed (original) (raw)