Nondopaminergic mechanisms in levodopa-induced dyskinesia

被引:162
作者
Brotchie, JA [1 ]
机构
[1] Toronto Western Hosp, Toronto Western Res Inst, Toronto, ON M5T 2S8, Canada
关键词
levodopa-induced dyskinesia; globus pallidus; subthalamic nucleus; postsynaptic signaling; basal ganglia circuitry;
D O I
10.1002/mds.20612
中图分类号
R74 [神经病学与精神病学];
学科分类号
摘要
It has become increasingly apparent that Parkinson's disease involves many transmitter systems other than dopamine. This nondopaminergic involvement impacts on the generation of symptoms, on the neurodegenerative process, but, most tellingly, in the generation of side effects of current treatments, in particular, levodopa-induced dyskinesia (LID). Such mechanisms contribute not only to the expression of LID once it has been established but also to the mechanisms responsible for the development, or priming, of the dyskinetic state and the subsequent maintenance of the brain in that primed state. Within the basal ganglia, abnormalities in different nondopaminergic components of the circuitry have been defined in LID. In particular, a role for enhanced inhibition of basal ganglia outputs by the GABAergic direct pathway has been suggested as a basic mechanism generating LID. We speculate that the external globus pallidus and subthalamic nucleus may play distinct roles in different forms of dyskinesia, e.g., chorea/dystonia; peak/diphasic/off. At the cellular level, an appreciation of abnormal signaling by, among others, glutamatergic (NMDA and AMPA receptors in particular), alpha(2) adrenergic, serotonergic (5HT), cannabinoid and opioid mechanisms in both priming and expression of LID has begun to emerge over the last decade. This is being consolidated, though in many cases questions remain regarding the specific sites of such abnormality within the circuitry. Very recently, at the molecular level, mechanisms controlling neurotransmitter release and impacting on the ability of neurons to maintain particular forms of firing patterning and synchronization, e.g., SV2A, have been identified. This increased understanding has already delivered and will continue to define novel approaches to treatment that target both pre- and postsynaptic signaling molecules throughout the basal ganglia circuitry. (c) 2005 Movement Disorder Society.
引用
收藏
页码:919 / 931
页数:13
相关论文
共 140 条
[71]   AMPA receptor blockade improves levodopa-induced dyskinesia in MPTP monkeys [J].
Konitsiotis, S ;
Blanchet, PJ ;
Verhagen, L ;
Lamers, E ;
Chase, TN .
NEUROLOGY, 2000, 54 (08) :1589-1595
[72]   Challenges in Parkinson's disease: restoration of the nigrostriatal dopamine system is not enough [J].
Lang, AE ;
Obeso, JA .
LANCET NEUROLOGY, 2004, 3 (05) :309-316
[73]   Increased cannabinoid CB1 receptor binding and activation of GTP-binding proteins in the basal ganglia of patients with Parkinson's syndrome and of MPTP-treated marmosets [J].
Lastres-Becker, I ;
Cebeira, M ;
de Ceballos, ML ;
Zeng, BY ;
Jenner, P ;
Ramos, JA ;
Fernández-Ruiz, JJ .
EUROPEAN JOURNAL OF NEUROSCIENCE, 2001, 14 (11) :1827-1832
[74]   Antiparkinsonian activity of Ro 25-6981, a NR2B subunit specific NMDA receptor antagonist, in animal models of Parkinson's disease [J].
Löschmann, PA ;
De Groote, C ;
Smith, L ;
Wüllner, U ;
Fischer, G ;
Kemp, JA ;
Jenner, P ;
Klockgether, T .
EXPERIMENTAL NEUROLOGY, 2004, 187 (01) :86-93
[75]  
Luginger E, 2000, MOVEMENT DISORD, V15, P873, DOI 10.1002/1531-8257(200009)15:5<873::AID-MDS1017>3.0.CO
[76]  
2-I
[77]   Cellular and behavioural effects of the adenosine A2a receptor antagonist KW-6002 in a rat model of L-DOPA-induced dyskinesia [J].
Lundblad, M ;
Vaudano, E ;
Cenci, MA .
JOURNAL OF NEUROCHEMISTRY, 2003, 84 (06) :1398-1410
[78]   Pharmacological validation of behavioural measures of akinesia and dyskinesia in a rat model of Parkinson's disease [J].
Lundblad, M ;
Andersson, M ;
Winkler, C ;
Kirik, D ;
Wierup, N ;
Cenci, MA .
EUROPEAN JOURNAL OF NEUROSCIENCE, 2002, 15 (01) :120-132
[79]   The synaptic vesicle protein SV2A is the binding site for the antiepileptic drug levetiracetam [J].
Lynch, BA ;
Lambeng, N ;
Nocka, K ;
Kensel-Hammes, P ;
Bajjalieh, SM ;
Matagne, A ;
Fuks, B .
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 2004, 101 (26) :9861-9866
[80]   Levodopa treatment reverses endocannabinoid system abnormalities in experimental parkinsonism [J].
Maccarrone, M ;
Gubellini, P ;
Bari, M ;
Picconi, B ;
Battista, N ;
Centonze, D ;
Bernardi, G ;
Finazzi-Agrò, A ;
Calabresi, P .
JOURNAL OF NEUROCHEMISTRY, 2003, 85 (04) :1018-1025