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.