1. Altered motor responses complicating L-Dopa therapy of Parkinson's disease initially arise as a consequence of the loss of striatal dopamine storage due to dopaminergic terminal degeneration, but later secondarily reflect postjunctional alterations. In Parkinsonian rats, postsynaptic changes, leading to increased responsivity of D2 dopamine receptor-mediated striatal efferents and diminished responsivity of D1 mediated projections, occur with intermittent, but not continuous, dopaminomimetic administration. Since striatal D2 receptor binding remains essentially unchanged and there is only mild up-regulation of D1 receptors, alterations in dopaminoceptive peptidergic and downstream glutamatergic systems are presumably responsible. Blockade of the NMDA subtype of glutamate receptors exerted differential effects on dopamine agonist-induced rotational behavior that depend on which dopamine receptor subtype is activated and the previous exposure to dopamine agonists. NMDA antagonists might thus be expected to influence dopaminomimetic responses clinically and counter certain of the motor complications associated with chronic L-Dopa treatment. 2. Earlier studies suggested that drugs acting to extend the biologic half-life of L-Dopa and dopamine will confer prophylactic as well as palliative benefit to Parkinsonian patients. Now we find that coadministration of a novel inhibitor of catechol-O-methyltransferase substantially prolongs the response to L-Dopa-carbidopa without significantly affecting the type or severity of adverse effects. The addition of talcapone to the therapeutic regimen of Parkinsonian patients should thus prove useful in controlling wearing-off fluctuations and other motor response complications. 3. The glycine prodrug, milacemide, which positively modulates NMDA receptor-mediated glutamatergic transmission, transiently increased overall symptom severity in Parkinsonian patients, lending further support to our view that pharmaceuticals that block certain glutamate receptor subtypes may assist in the treatment of this disease. The selective kappa receptor agonist, spiradoline, given to evaluate the clinical effects of the enhanced dynorphinergic transmission attending chronic levodopa administration to parkinsonian rats, produced dose limiting adverse effects that precluded attainment of dose levels approximating those affecting rodent motor performance.

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