Parkinson's disease is a progressive neurodegenerative disease characterized by bradykinesia, rigidity, tremor and postural instability Treatment focuses mainly on dopamine replacement with L-Dopa, which requires conversion to dopamine in the brain, or dopamine agonists, which directly stimulate dopamine receptors Of the two families of dopamine receptors, D1-like ( D1, D5) and D2-like (D2, D3, D4) the D2-like dopamine receptors are the targets of agonists currently used to treat Parkinson's disease These dopamine agonists have been tried as monotherapy at the onset of therapy, as substitutes for L-Dopa in patients with advanced Parkinson's disease and as adjuncts to L-Dopa Both L-Dopa and D2 dopamine agonists produce significant side effects which warrant investigation of other dopaminergic compounds for treating the disease Although D1-like and D2 like agonists are effective antiparkinsonian agents in animal models of Parkinson's disease, the therapeutic eff ectiveness of D1-like agonists as monotherapy in early compared with advanced stages of Parkinson's disease has not been studied To investigate the effects of D1 agonists in mild and advanced parkinsonism in monkeys, we produced two different models of the disease with two dosing regimens of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) mild (2 doses of 0 6 mg/kg MPTP, 1 month apart) or advanced (3 doses of 0 6 mg/kg MPTP within 10 days) These models were distinguishable on a rating scale The therapeutic and undesirable side effects of the two full D1 agonists SKF 81297 (300-fold D1/D2 selective) and dihydrexidine (3-fold D1/D2 selective), and two very selective D2 agonists, quinelorane and (+)PHNO were compared in these two models of the disease In normal monkeys (n=3), SKF 81297 did not promote increased motor activity In advanced parkinsonism (n=4), SKF 81297 (0 01 to 3 0 mg/kg) effectively reversed parkinsonian motor deficits In mild parkinsonian monkeys (n=4) , SKF 81297 was relatively ineffective in relieving motor dysfunction Similarly, dihydrexidine (0 1 to 3 0 mg/kg) almost completely reversed advanced parkinsonism and partially improved parkinsonian signs in mild Parkinsonism Although the selective D2-type agonists quinelorane (0 001 to 3 0 mg/kg) or (+)PHNO (0 0001 to 0 1 mg/kg) had little effects in normal monkeys, in mild parkinsonian monkeys, quinelorane improved and (+)PHNO effectively reversed the motor deficits In contrast to the D1 agonists, quinelorane and (+)PHNO induced marked imbalance and dyskinesias in mild parkinsonian monkeys These data demonstrate that 1 the effectiveness of a selective D1 agonist (SKF-81297) depends on the degree of parkinsonism, with promising results in advanced parkinsonism, but poor results in mild parkinsonism; 2 D1 dopamine receptor response may change in the course of neuronal degeneration; 3 D1 agonists are less prone to producing side effects than D2 agonists in mild parkinsonis m 4 D2 agonists are more effective in mild parkinsonism than D1 agonists These findings are relevant for the development of D1 anti-parkinsonian medications and support the need to further investigate receptor response at different stages of Parkinson's disease PUBLICATIONS Goulet M, Madras BK Efficacy of a dopamine D1 receptor agonist depends on severity of Parkinsonism Soc Neurosci Abstr 24 762, 1998
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