Amantadine attenuates levodopa‐induced dyskinesia in mice and rats preventing the accompanying rise in nigral GABA levels

Abstract

J. Neurochem. (2011) 118, 1043–1055. Abstract Amantadine is the only drug marketed for treating levodopa‐induced dyskinesia. However, its impact on basal ganglia circuitry in the dyskinetic brain, particularly on the activity of striatofugal pathways, has not been evaluated. We therefore used dual probe microdialysis to investigate the effect of amantadine on behavioral and neurochemical changes in the globus pallidus and substantia nigra reticulata of 6‐hydroxydopamine hemi‐lesioned dyskinetic mice and rats. Levodopa evoked abnormal involuntary movements (AIMs) in dyskinetic mice, and simultaneously elevated GABA release in substantia nigra reticulata (∼3‐fold) but not globus pallidus. Glutamate levels were unaffected in both areas. Amantadine (40 mg/kg, i.p.), ineffective alone, attenuated (∼50%) AIMs expression and prevented the GABA rise. Moreover, it unraveled a facilitatory effect of levodopa on pallidal glutamate levels. Levodopa also evoked AIMs expression and a GABA surge (∼2‐fold) selectively in the substantia nigra of dyskinetic rats. However, different from mice, glutamate levels rose simultaneously. Amantadine, ineffective alone, attenuated (∼50%) AIMs expression preventing amino acid increase and leaving unaffected pallidal glutamate. Overall, the data provide neurochemical evidence that levodopa‐induced dyskinesia is accompanied by activation of the striato‐nigral pathway in both mice and rats, and that the anti‐dyskinetic effect of amantadine partly relies on the modulation of this pathway.

Levodopa-induced dyskinesias are associated with transient down-regulation of cAMP and cGMP in the caudate-putamen of hemiparkinsonian rats: Reduced synthesis or increased catabolism?

“…Co-treatment salinelevodopa, or amantadine-levodopa was performed daily for three days, and the differences between groups in the severity of dyskinesia were assessed after the last daily injection of levodopa + carbidopa. In agreement with previous reports (Bido et al, 2011), dyskinetic animals pretreated with amantadine showed attenuated severity of all types of dyskinesias, reduced by about 60% along the time course after levodopa injection compared with dyskinetic animals pretreated with saline, demonstrating highly significant differences between the two groups ( Fig. 1a, b).…”

“…or subcutaneously 1 h before (Antonioli et al, 2007); PDE2 inhibitor BAY60-7550 by gavage 3 mg/kg 30 min before (van Donkelaar et al, 2008); PDE10A inhibitor papaverine 3 mg/kg i.p. 20 min before (such low dose of papaverine was chosen because it can inhibit phencyclidinestimulated locomotor activity avoiding inhibition of spontaneous locomotor activity; Siuciak et al, 2006); PDE1A inhibitor and NMDA receptor antagonist amantadine 40 mg/kg s.c. 1 h before (Bido et al, 2011;Kakkar et al, 1997). Moreover, to test the specific antidyskinetic effect of amantadine we used also memantine, dimethyl derivative of amantadine, known only as NMDA receptor antagonist (2 mg/kg s.c. 1 h before) (Beconi et al, 2011).…”

“…Moreover, we evaluated whether in rat with levodopa-induced dyskinesias a possible down-regulation of the cAMP and cGMP levels could be associated with changes of their catabolism by total PDE activities, and/ or with altered expressions and activities of phosphodiesterase-1B and -10A isozymes highly and specifically located in the basal ganglia. Finally, we evaluated whether amantadine, a drug widely used to attenuate levodopa dyskinesias both in parkinsonian patients and in rat and monkey models of Parkinson's disease (see Bido et al, 2011), could also prevent eventual changes of cAMP and cGMP levels and of cAMP-PDE and cGMP-PDE activities in dyskinetic rats.…”

The Kinase Fyn As a Novel Intermediate in l-DOPA-Induced Dyskinesia in Parkinson’s Disease

“…However, the development of a selective Fyn antagonist is desirable. Mice responding to saracatinib show a reduction of LID scores and FosB/∆FosB staining in the order of 30% compared to controls, which is comparable to what has been reported with other drugs that have previously shown efficacy against LID in the same animal model, such as amantadine or riluzole [6,28]. We may conclude that, in agreement with our findings in Fyn-KO mice, there seems to be a plateau of therapeutic effect with every drug that has been tested, giving further support to the hypothesis that several mechanisms are involved in the development of LID.…”

“…In this scenario, the greatest clinical challenge is to reduce the development of LID without affecting the positive restorative effect of DA stimulation, and the NMDAR is a desired target to achieve such a goal as amantadine alleviates LID by reducing glutamate signaling [6], without affecting DA response [5,7]. In addition to the classical signaling downstream of the dopamine receptors, which likely participate in both the therapeutic and side effects of dopamine stimulation, the postsynaptic density (PSD) zone is determinant of plastic rearrangements and a candidate area aiming at dissecting both effects.…”