Reversal of reserpine-induced catalepsy by selective D1 and D2 dopamine agonists.
To gain insight into the antiparkinsonian effects of selective D1 and D2 dopamine receptor stimulation, we examined the ability of D1 (SKF 38393) and D2 (quinpirole) agonists to reverse catalepsy induced by the combined administration of reserpine and alpha-methyl-p-tyrosine (AMPT) in rats. Catalepsy, the failure to correct an externally imposed posture, is a measure of akinesia and was assessed using the bar test. Rats injected with reserpine alone (2.5 mg/kg i.p.) developed akinesia and ptosis within 60-90 min. The D1 agonist SKF 38393 (30 mg/kg i.v.) rapidly reversed ptosis and restored near-normal mobility when administered 24 h after reserpine and AMPT; catalepsy was reversed for 90 min, after which the drug effect wore off. Quinpirole (1 mg/kg i.v.) reversed catalepsy for the duration of the test period (4 h) but did not consistently reverse ptosis or promote normal mobility; the rats continued to exhibit kyphotic postures with little spontaneous locomotion. These results indicate that selective D1 stimulation is sufficient to reverse reserpine-induced akinesia and highlight the need for the development of potent selective D1 agonists for clinical trial in Parkinson's disease. In severe dopamine depletion, D2 stimulation alone appears to be insufficient to restore normal movement. Quinpirole, but not SKF 38393, elicited paroxysmal limb/body jerking in reserpine-AMPT-treated rats, providing further evidence that atypical jerking can be elicited by D2 stimulation in the complete absence of D1 stimulation. This laboratory observation suggests that some jerking dyskinesias seen in treated parkinsonian patients may be mediated by an imbalance in D1-D2 receptor stimulation.
Hubbard
C A
CA
Department of Neurology, University of Virginia Health Sciences Center, Charlottesville 22908.
Trugman
J M
JM
D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D002375:Catalepsy / Q000139:chemically induced* / Q000378:metabolism; D015259:Dopamine Agents / Q000494:pharmacology*; D008124:Locomotion / Q000187:drug effects; D008781:Methyltyrosines / Q000378:metabolism / Q000494:pharmacology*; D011187:Posture; D051381:Rats; D017207:Rats, Sprague-Dawley; D012107:Research Design; D012110:Reserpine / Q000378:metabolism* / Q000494:pharmacology*; D014743:Videotape Recording
D015259:Dopamine Agents; D008781:Methyltyrosines; D012110:Reserpine