Neural mechanisms underlying peak‐dose dyskinesia induced by levodopa and apomorphine are distinct: Evidence from the effects of the alpha₂ adrenoceptor antagonist idazoxan

Abstract

Dyskinesia, secondary to dopamine replacement therapy, is the major complication of currently available therapies for Parkinson's disease. Alpha(2) adrenoceptor antagonists, such as idazoxan, can significantly reduce levodopa-induced dyskinesia in the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-lesioned, nonhuman primate model of Parkinson's disease and in human. This action of adrenoceptor antagonists may involve blockade of the actions of noradrenaline synthesised from levodopa. We hypothesise that, because dopamine receptor agonists, such as apomorphine, cannot be metabolised to produce noradrenaline, activation of adrenoceptors may not be involved in dyskinesia produced by such agents. If this were the case, idazoxan would not be expected to reduce apomorphine-induced dyskinesia. MPTP-lesioned marmosets with stable dyskinesia induced by prolonged levodopa therapy were given an acute challenge with apomorphine (0.3 mg/kg subcutaneously) or levodopa (8.0 mg/kg orally), these doses produced equivalent peak-dose dyskinesia. Idazoxan (2.5 mg/kg p.o.), or vehicle, was then administered with either apomorphine or levodopa. Idazoxan abolished levodopa-induced dyskinesia but did not affect apomorphine-induced dyskinesia (P < 0.05 and P > 0.05, respectively, Wilcoxon matched pairs test). Idazoxan also extended the anti-parkinsonian actions of levodopa but did not affect those of apomorphine. The pharmacological characteristics of the neural mechanisms underlying levodopa-induced dyskinesia and apomorphine-induced dyskinesia in parkinsonism thus appear to be distinct, at least with respect to the involvement of alpha(2) adrenoceptors. Specifically, levodopa, but not apomorphine-induced dyskinesia, involves activation of adrenoceptors. This finding may have major implications for understanding dyskinesia and should be borne in mind when designing clinical studies in which levodopa or dopamine receptor agonist challenges are employed to assess potential anti-dyskinetic properties of drugs.

Differential Involvement of D1 and D2 Dopamine Receptors in L-DOPA-Induced Angiogenic Activity in a Rat Model of Parkinson's Disease

“…Accordingly, microvascular responses ought to be considered when evaluating the effects of either anti-or pro-dyskinetic treatments with unknown mechanisms of action. Intriguingly, some vasoactive substances, such as a 2 -adrenergic receptor antagonists (Zou and Cowley, 2000), nicotine (Hawkins et al, 2002), and nitric oxide synthase inhibitors (Faraci and Brian, 1994) exert strong anti-dyskinetic effects in animal models of PD (Fox et al, 2001;Padovan-Neto et al, 2009;Quik et al, 2007Quik et al, , 2008. Elucidating the effects of these treatments on microvascular physiology and angiogenesis in the brain will be an exciting task for future studies.…”

Dissociation of Metabolic and Neurovascular Responses to Levodopa in the Treatment of Parkinson's Disease

“…It is interesting that several agents proposed for the treatment of LID have potent vasoconstrictive features that may be regionally selective. For instance, ␣ 2 adrenoceptor antagonists have been proposed as a means of treating LID by blocking the effects of noradrenaline on striatal output neurons (Fox et al, 2001). These receptors are known to be widely present on blood vessels and can facilitate vasodilation (Zou and Cowley, 2000).…”

Functional Neuroimaging in Parkinson's Disease

“…These include the opioid system, which acts as a modulator of dopamine and a cotransmitter within GABAergic neurons (Fox et al 2006;Hallett and Brotchie 2007), the adenosine system (Calon et al 2004), the serotonergic system (Carta et al 2007;Carlsson et al 2009), and the a2 adrenergic system (Fox et al 2001;Rascol et al 2001). Piccini et al (1997) found reduced binding of [ 11 C]diphrenorphine (a nonselective marker of opioid receptors) in the striatum, thalamus, and anterior cingulate of PD patients with LID compared to without.…”