Chronic high-frequency stimulation of the subthalamic nucleus and L-DOPA treatment in experimental parkinsonism: effects on motor behaviour and striatal glutamate transmission.
Hyperactivity of striatal glutamatergic synaptic transmission in response to dopamine depletion plays a major role in the pathogenesis of parkinsonian motor symptoms. In the present study we investigated the impact, on this hyperactivity, of chronic dyskinesiogenic L-DOPA treatment, combined or not with high-frequency stimulation (HFS) of the subthalamic nucleus (STN). In vitro patch-clamp recordings were performed from striatal spiny neurons of hemiparkinsonian rats (intranigral 6-OHDA injection). Here we show that dyskinesiogenic L-DOPA treatment exacerbated striatal glutamatergic hyperactivity induced by 6-OHDA lesion. Chronic 5-day STN HFS had the opposite effect, reducing striatal glutamatergic transmission in both parkinsonian and dyskinetic animals. Consistently, chronic HFS stimulation could progressively ameliorate motor parkinsonian signs (akinesia) but, conversely, did not improve L-DOPA-induced dyskinesia (LID). Thus, the effects of L-DOPA and HFS on corticostriatal transmission seem to be dissociated. These data show for the first time that dyskinesiogenic L-DOPA treatment and chronic STN HFS with antiakinetic effects induce opposite plastic rearrangements in the striatum. The interaction between these two treatments provides further evidence that striatal glutamatergic hyperactivity is a pathophysiological correlate of akinesia rather than LID.
Gubellini
Paolo
P
Equipe IC2N, Institut de Biologie du Développement de Marseille-Luminy (IBDML), UMR6216, 31, Chemin Joseph Aiguier CNRS-Université de la Méditerranée, 13402 Marseille, CEDEX 20, France. paolo.gubellini@ibdml.univ-mrs.fr
Eusebio
Alexandre
A
Oueslati
Abid
A
Melon
Christophe
C
Kerkerian-Le Goff
Lydia
L
Salin
Pascal
P
D000818:Animals; D000978:Antiparkinson Agents / Q000627:therapeutic use*; D001522:Behavior, Animal / Q000187:drug effects; D004195:Disease Models, Animal; D004307:Dose-Response Relationship, Radiation; D004347:Drug Interactions; D020820:Dyskinesias / Q000209:etiology / Q000503:physiopathology; D004558:Electric Stimulation / Q000379:methods*; D018690:Excitatory Amino Acid Agonists / Q000494:pharmacology; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D007839:Functional Laterality / Q000502:physiology; D007980:Levodopa / Q000627:therapeutic use*; D008297:Male; D008564:Membrane Potentials / Q000187:drug effects / Q000502:physiology / Q000528:radiation effects; D016627:Oxidopamine; D020734:Parkinsonian Disorders / Q000139:chemically induced / Q000473:pathology* / Q000628:therapy*; D051381:Rats; D017208:Rats, Wistar; D020531:Subthalamic Nucleus / Q000187:drug effects / Q000503:physiopathology / Q000528:radiation effects; D013997:Time Factors
D000978:Antiparkinson Agents; D018690:Excitatory Amino Acid Agonists; D018691:Excitatory Amino Acid Antagonists; D007980:Levodopa; D016627:Oxidopamine