A simple rodent assay for the in vivo identification of agents with potential to reduce levodopa-induced dyskinesia in Parkinson's disease.
l-DOPA-induced dyskinesia (LID) remains a major complication of the treatment of Parkinson's disease (PD). Whilst the MPTP-lesioned primate provides an excellent animal model in which to develop new therapies, however, it is logistically difficult to employ widely. Thus, a simple rodent assay to screen multiple compounds as candidates for further study of their potential in LID would be a valuable addition to the drug development process. Here, we investigate how agents with demonstrated ability to reduce LID in man and monkey can regulate l-DOPA-induced behaviours in the reserpine-treated rat. Administration of l-DOPA (125 mg/kg) to reserpine-treated rats elicited high levels of both horizontal and vertical movement. Drugs that have previously been found to reduce LID in parkinsonian primates and PD patients without compromising the anti-parkinsonian efficacy of l-DOPA selectively and dose-dependently reduce vertical components of activity when co-administered with l-DOPA in the reserpine-treated rat. For instance, amantadine (1 mg/kg) and idazoxan (3 mg/kg) reduced vertical activity by 59% and 83%, respectively, while neither drug had significant effects on horizontal activity. In contrast, haloperidol (1 mg/kg), an agent lacking the ability to selectively reduce LID without compromising the anti-parkinsonian actions of l-DOPA, reduced both horizontal and vertical activity, by 98% and 99%, respectively. We also assessed the actions of an NMDA antagonist, a class of compound proposed to have potential as anti-dyskinetic agents. The effects of MK-801 were dose-dependent (0.01-0.5 mg/kg), at some doses (e.g., 0.05 mg/kg), providing selective reduction of vertical activity (90%), at others (e.g., 0.5 mg/kg), non-selective reduction of vertical and horizontal (99% and 77%, respectively). These observations highlight the association between potential anti-dyskinetic action and a selective reduction in l-DOPA-induced vertical activity in the reserpine-treated rat.
Johnston
Tom H
TH
Toronto Western Research Institute, Toronto Western Hospital, University Health Network, Toronto, Ontario, Canada.
Lee
Joohyung
J
Gomez-Ramirez
Jordi
J
Fox
Susan H
SH
Brotchie
Jonathan M
JM
D018759:Adrenergic Uptake Inhibitors / Q000494:pharmacology; D000317:Adrenergic alpha-Antagonists / Q000627:therapeutic use*; D000547:Amantadine / Q000627:therapeutic use; D000818:Animals; D018726:Anti-Dyskinesia Agents / Q000627:therapeutic use*; D000978:Antiparkinson Agents / Q000009:adverse effects / Q000627:therapeutic use; D016291:Dizocilpine Maleate / Q000627:therapeutic use; D015259:Dopamine Agents / Q000627:therapeutic use*; D004305:Dose-Response Relationship, Drug; D004353:Drug Evaluation, Preclinical / Q000379:methods*; D004409:Dyskinesia, Drug-Induced / Q000188:drug therapy*; D018691:Excitatory Amino Acid Antagonists / Q000627:therapeutic use; D006220:Haloperidol / Q000627:therapeutic use; D019329:Idazoxan / Q000627:therapeutic use; D007980:Levodopa / Q000009:adverse effects* / Q000627:therapeutic use; D008297:Male; D009043:Motor Activity / Q000187:drug effects; D010300:Parkinson Disease / Q000188:drug therapy; D051381:Rats; D017207:Rats, Sprague-Dawley; D012110:Reserpine / Q000494:pharmacology
D018759:Adrenergic Uptake Inhibitors; D000317:Adrenergic alpha-Antagonists; D018726:Anti-Dyskinesia Agents; D000978:Antiparkinson Agents; D015259:Dopamine Agents; D018691:Excitatory Amino Acid Antagonists; D007980:Levodopa; D016291:Dizocilpine Maleate; D012110:Reserpine; D000547:Amantadine; D006220:Haloperidol; D019329:Idazoxan