Evaluation of levodopa dose and magnitude of dopamine depletion as risk factors for levodopa-induced dyskinesia in a rat model of Parkinson's disease.
Levodopa dose and severity of Parkinson's disease (PD) are recognized risk factors for levodopa-induced dyskinesia (LID) in humans. The purpose of the present study was to evaluate the ability of these variables to predict severity of LID in a rat model of PD. Varied concentrations of 6-hydroxy-dopamine were injected into the midbrain to produce wide ranges of dopamine depletion in striatum. Three weeks later, rats were given daily injections of levodopa (2-10 mg/kg i.p.) plus benserazide (12.5 mg/kg i.p.) for 15 days. Abnormal involuntary movements (AIMs) were measured for limb, axial, orolingual, and rotatory movements. Dose-response analysis for total AIM scores yielded a levodopa ED50 value of 3.2 mg/kg on treatment day 15. There were strong interrelated correlations between individual AIM categories (rho > 0.7) and for each AIM category in regard to total AIM score (rho > 0.7). In rats that received levodopa doses that were greater than the ED50, rates of amphetamine-induced rotation were significantly correlated with total AIM scores (rho = 0.413). However, of those rotating >5 times/min, 34% had relatively low AIM scores (<8). Likewise, there was a significant correlation between percentages of tyrosine hydroxylase (TH) loss and total AIM scores (rho = 0.388). However, in those rats that had >85% TH loss, 30% had AIM scores <8. Our results show that given an adequate dose and magnitude of striatal dopamine depletion, levodopa produces dyskinesia with a continuous spectrum of severity. Although levodopa dose and level of dopamine depletion are significant risk factors for LID, we conclude that other factors must contribute to LID susceptibility.
Research Service, Portland VA Medical Center, RD-61, 3710 SW U.S. Veterans Hospital Rd., Portland, OR 97207, USA.
Daniel B
DB
Putterman
Adam C
AC
Munhall
Laura B
LB
Kozell
John K
JK
Belknap
Steven W
SW
Johnson
D000661:Amphetamine / Q000494:pharmacology; D000818:Animals; D000978:Antiparkinson Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use; D001522:Behavior, Animal / Q000187:drug effects; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D004195:Disease Models, Animal; D004298:Dopamine / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D004409:Dyskinesia, Drug-Induced / Q000209:etiology* / Q000378:metabolism / Q000503:physiopathology; D007980:Levodopa / Q000008:administration & dosage / Q000009:adverse effects / Q000627:therapeutic use; D008297:Male; D010300:Parkinson Disease / Q000150:complications / Q000188:drug therapy* / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D012307:Risk Factors; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism
D000978:Antiparkinson Agents; D007980:Levodopa; D000661:Amphetamine; D014446:Tyrosine 3-Monooxygenase; D004298:Dopamine