The rationale for the use of dopamine agonists in Parkinson's disease.
Experimental and clinical studies indicate that both dopamine D2-like and D1-like receptors are important in reversing the motor symptoms of Parkinson's disease, and therefore stimulation of both D1 and D2 receptors may be advantageous in its treatment. At present, the role of other receptor subtypes, such as the D3 receptor, remains unknown, although in primates the D3 receptor might be of importance because it exists in significant amounts within the caudate-putamen. Both D1 and D2 agonists induce dyskinesias in drug-naive, MPTP-treated primates and provoke dyskinesias in levodopa-primed animals. D1 agonists in low doses, however, might have antiparkinsonian effects without inducing dyskinesias, and on repeated administration perhaps can diminish the intensity of dyskinesias in levodopa-primed, MPTP-treated primates. The production of dyskinesias in Parkinson's disease might reflect an imbalance in the D1-direct and D2-indirect GABAergic output pathways from the caudate-putamen, which colocalize tachykinins and enkephalins, respectively. Destruction of the nigrostriatal pathway decreases the mRNA for substance P but elevates the mRNA for enkephalin. Treatment with levodopa reverses the decrease in substance P mRNA but has either a partial or no effect on mRNA for enkephalin. This suggests that levodopa treatment leads to a new imbalance between output from the striatum through the direct and indirect pathways. In contrast, dopamine agonists appear less able than levodopa to manipulate basal ganglia outflow. This might reflect their decreased ability to reverse parkinsonian motor deficits or the greater ability of levodopa to provoke dyskinesias. Dopamine agonist drugs also might exert neuroprotective actions.(ABSTRACT TRUNCATED AT 250 WORDS)
Jenner
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Neurodegenerative Diseases Research Centre, King's College London, England, UK.
D018491:Dopamine Agonists / Q000627:therapeutic use*; D006801:Humans; D018696:Neuroprotective Agents / Q000627:therapeutic use; D010300:Parkinson Disease / Q000188:drug therapy*; D011954:Receptors, Dopamine / Q000187:drug effects
D018491:Dopamine Agonists; D018696:Neuroprotective Agents; D011954:Receptors, Dopamine