title: SK channel blockade reverses cognitive and motor deficits induced by nigrostriatal dopamine lesions in rats.
abstract: Parkinson's disease has traditionally been viewed as a motor disorder caused by the loss of dopamine (DA) neurons. However, emotional and cognitive syndromes can precede the onset of the motor deficits and provide an opportunity for therapeutic intervention. Potassium channels have recently emerged as potential new targets in the treatment of Parkinson's disease. The selective blockade of small conductance calcium-activated K+ channels (SK channels) by apamin is known to increase burst firing in midbrain DA neurons and therefore DA release. We thus investigated the effects of systemic administration of apamin on the motor, cognitive deficits and anxiety present after bilateral nigrostriatal 6-hydroxydopamine (6-OHDA) lesions in rats. Apamin administration (0.1 or 0.3 mg/kg i.p.) counteracted the depression, anxiety-like behaviors evaluated on sucrose consumption and in the elevated plus maze, social recognition and spatial memory deficits produced by partial 6-OHDA lesions. Apamin also reduced asymmetric motor deficits on circling behavior and postural adjustments in the unilateral extensive 6-OHDA model. The partial 6-OHDA lesions (56% striatal DA depletion) produced 20% decrease of iodinated apamin binding sites in the substantia nigra pars compacta in correlation with the loss of tyrosine hydroxylase positive cells, without modifying apamin binding in brain regions receiving DAergic innervation. Striatal extracellular levels of DA, not detectable after 6-OHDA lesions, were enhanced by apamin treatment as measured by in vivo microdialysis. These results indicate that blocking SK channels may reinstate minimal DA activity in the striatum to alleviate the non-motor symptoms induced by partial striatal DA lesions.
authors.affiliation: Laboratoire de Neurosciences Cognitives (LNC),Aix-Marseille University,CNRS UMR 7291, FR3C 3512, 13331, Marseille,France.
authors.forename: Lin
authors.initials: L
authors.lastname: Chen
authors.affiliation: Laboratoire de Neurosciences Cognitives (LNC),Aix-Marseille University,CNRS UMR 7291, FR3C 3512, 13331, Marseille,France.
authors.forename: Thierry
authors.initials: T
authors.lastname: Deltheil
authors.affiliation: Laboratoire de Neurosciences Cognitives (LNC),Aix-Marseille University,CNRS UMR 7291, FR3C 3512, 13331, Marseille,France.
authors.forename: Nathalie
authors.initials: N
authors.lastname: Turle-Lorenzo
authors.affiliation: Laboratoire de Neurosciences Cognitives (LNC),Aix-Marseille University,CNRS UMR 7291, FR3C 3512, 13331, Marseille,France.
authors.forename: Martine
authors.initials: M
authors.lastname: Liberge
authors.affiliation: Laboratoire de Neurosciences Cognitives (LNC),Aix-Marseille University,CNRS UMR 7291, FR3C 3512, 13331, Marseille,France.
authors.forename: Corinne
authors.initials: C
authors.lastname: Rosier
authors.affiliation: Laboratoire de Neurosciences Intégratives et Adaptatives (NIA),Aix-Marseille University,CNRS UMR 7260, FR3C 3512, 13331, Marseille,France.
authors.forename: Isabelle
authors.initials: I
authors.lastname: Watabe
authors.affiliation: Institut Méditerranéen de Biodiversité et d'Ecologie marine et continentale (IMBE),Aix-Marseille University,CNRS UMR 7263, 13331, Marseille,France.
authors.forename: Leam
authors.initials: L
authors.lastname: Sreng
authors.affiliation: Laboratoire de Neurosciences Cognitives (LNC),Aix-Marseille University,CNRS UMR 7291, FR3C 3512, 13331, Marseille,France.
authors.forename: Marianne
authors.initials: M
authors.lastname: Amalric
authors.affiliation: Laboratoire de Neurosciences Cognitives (LNC),Aix-Marseille University,CNRS UMR 7291, FR3C 3512, 13331, Marseille,France.
authors.forename: Christiane
authors.initials: C
authors.lastname: Mourre
mesh_terms: D000818:Animals; D001030:Apamin / Q000494:pharmacology* / Q000627:therapeutic use; D001522:Behavior, Animal / Q000187:drug effects*; D003071:Cognition / Q000187:drug effects*; D003342:Corpus Striatum / Q000187:drug effects / Q000378:metabolism; D004298:Dopamine / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D008297:Male; D009043:Motor Activity / Q000187:drug effects*; D016627:Oxidopamine / Q000633:toxicity; D010302:Parkinson Disease, Secondary / Q000139:chemically induced / Q000150:complications / Q000188:drug therapy / Q000523:psychology*; D026902:Potassium Channel Blockers / Q000494:pharmacology* / Q000627:therapeutic use; D051381:Rats; D051640:Small-Conductance Calcium-Activated Potassium Channels / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013378:Substantia Nigra / Q000187:drug effects / Q000378:metabolism; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism
chemical_list: D026902:Potassium Channel Blockers; D051640:Small-Conductance Calcium-Activated Potassium Channels; D001030:Apamin; D016627:Oxidopamine; D014446:Tyrosine 3-Monooxygenase; D004298:Dopamine