Antagonizing L-type Ca2+ channel reduces development of abnormal involuntary movement in the rat model of L-3,4-dihydroxyphenylalanine-induced dyskinesia

Biol Psychiatry. 2009 Mar 15;65(6):518-26. doi: 10.1016/j.biopsych.2008.09.008. Epub 2008 Oct 23.

Abstract

Background: Chronic L-3,4-dihydroxyphenylalanine (L-DOPA) treatment of Parkinson's disease (PD) leads to debilitating involuntary movements, termed L-DOPA-induced dyskinesia. Striatofugal medium spiny neurons (MSN) lose their dendritic spines and cortico-striatal glutamatergic synapses in PD and in experimental models of DA depletion. This loss of connectivity is triggered by a dysregulation of intraspine Cav1.3 L-type Ca2+ channels. Here we address the possible implication of DA denervation-induced spine pruning in the development of L-DOPA-induced dyskinesia.

Methods: The L-type Ca2+ antagonist, isradipine was subcutaneously delivered to rats at the doses of .05, .1, or .2 mg/kg/day, for 4 weeks, starting the day after a unilateral nigrostriatal 6-hydroxydopamine (6-OHDA) lesion. Fourteen days later, L-DOPA treatment was initiated.

Results: Isradipine-treated animals displayed a dose-dependent reduction in L-DOPA-induced rotational behavior and abnormal involuntary movements. Dendritic spine counting at electron microscopy level showed that isradipine (.2 mg/kg/day) prevented the 6-OHDA-induced spine loss and normalized preproenkephalin-A messenger RNA expression. Involuntary movements were not reduced when isradipine treatment was started concomitantly with L-DOPA.

Conclusions: These results indicate that isradipine, at a therapeutically relevant dose, might represent a treatment option for preventing L-DOPA-induced dyskinesia in PD.

MeSH terms

  • Animals
  • Calcium Channel Blockers / administration & dosage
  • Calcium Channel Blockers / pharmacology*
  • Calcium Channels, L-Type / drug effects*
  • Cerebrum / metabolism
  • Cerebrum / ultrastructure
  • Dendritic Spines / drug effects
  • Dendritic Spines / ultrastructure
  • Disease Models, Animal
  • Dose-Response Relationship, Drug
  • Dyskinesia, Drug-Induced / metabolism
  • Dyskinesia, Drug-Induced / prevention & control*
  • Enkephalins / metabolism
  • Isradipine / administration & dosage
  • Isradipine / pharmacology
  • Isradipine / therapeutic use*
  • Levodopa / adverse effects*
  • Levodopa / pharmacology
  • Male
  • Motor Activity / drug effects
  • Nimodipine / pharmacology
  • Oxidopamine
  • Protein Precursors / metabolism
  • RNA, Messenger / metabolism
  • Rats
  • Rats, Wistar
  • Sympatholytics / administration & dosage*

Substances

  • Calcium Channel Blockers
  • Calcium Channels, L-Type
  • Enkephalins
  • Protein Precursors
  • RNA, Messenger
  • Sympatholytics
  • Levodopa
  • Nimodipine
  • Oxidopamine
  • preproenkephalin
  • Isradipine