title: Buspirone requires the intact nigrostriatal pathway to reduce the activity of the subthalamic nucleus via 5-HT1A receptors.
abstract: The most effective treatment for Parkinson's disease (PD), l-DOPA, induces dyskinesia after prolonged use. We have previously shown that in 6-hydroxydopamine (6-OHDA) lesioned rats rendered dyskinetic by prolonged l-DOPA administration, lesion of the subthalamic nucleus (STN) reduces not only dyskinesias but also buspirone antidyskinetic effect. This study examined the effect of buspirone on STN neuron activity. Cell-attached recordings in parasagittal slices from naïve rats showed that whilst serotonin excited the majority of STN neurons, buspirone showed an inhibitory main effect but only in 27% of the studied cells which was prevented by the 5-HT1A receptor selective antagonist WAY-100635. Conversely, single-unit extracellular recordings were performed in vivo on STN neurons from four different groups, i.e., control, chronically treated with l-DOPA, 6-OHDA lesioned and lesioned treated with l-DOPA (dyskinetic) rats. In control animals, systemic-buspirone administration decreased the firing rate in a dose-dependent manner in every cell studied. This effect, prevented by WAY-100635, was absent in 6-OHDA lesioned rats and was not modified by prolonged l-DOPA administration. Altogether, buspirone in vivo reduces consistently the firing rate of the STN neurons through 5-HT1A receptors whereas ex vivo buspirone seems to affect only a small population of STN neurons. Furthermore, the lack of effect of buspirone in 6-OHDA lesioned rats, suggests the requirement of not only the activation of 5-HT1A receptors but also an intact nigrostriatal pathway for buspirone to inhibit the STN activity.
authors.affiliation: Department of Pharmacology, Faculty of Medicine and Dentistry, University of the Basque Country (UPV/EHU), 48940 Leioa, Spain.
authors.forename: A
authors.initials: A
authors.lastname: Sagarduy
authors.affiliation: Department of Pharmacology, Faculty of Medicine and Dentistry, University of the Basque Country (UPV/EHU), 48940 Leioa, Spain.
authors.forename: J
authors.initials: J
authors.lastname: Llorente
authors.affiliation: Department of Pharmacology, Faculty of Medicine and Dentistry, University of the Basque Country (UPV/EHU), 48940 Leioa, Spain; Department of Pharmacology, School of Pharmacy, University of the Basque Country (UPV/EHU), 01006 Vitoria-Gasteiz, Spain.
authors.forename: C
authors.initials: C
authors.lastname: Miguelez
authors.affiliation: Department of Pharmacology, Faculty of Medicine and Dentistry, University of the Basque Country (UPV/EHU), 48940 Leioa, Spain.
authors.forename: T
authors.initials: T
authors.lastname: Morera-Herreras
authors.affiliation: Department of Pharmacology, Faculty of Medicine and Dentistry, University of the Basque Country (UPV/EHU), 48940 Leioa, Spain; Department of Pharmacology, School of Pharmacy, University of the Basque Country (UPV/EHU), 01006 Vitoria-Gasteiz, Spain.
authors.forename: J A
authors.initials: JA
authors.lastname: Ruiz-Ortega
authors.affiliation: Department of Pharmacology, Faculty of Medicine and Dentistry, University of the Basque Country (UPV/EHU), 48940 Leioa, Spain. Electronic address: luisa.ugedo@ehu.eus.
authors.forename: L
authors.initials: L
authors.lastname: Ugedo
mesh_terms: D000200:Action Potentials / Q000187:drug effects; D018663:Adrenergic Agents / Q000633:toxicity; D018759:Adrenergic Uptake Inhibitors / Q000494:pharmacology; D000818:Animals; D002065:Buspirone / Q000494:pharmacology*; D003891:Desipramine / Q000494:pharmacology; D004195:Disease Models, Animal; D015259:Dopamine Agents / Q000009:adverse effects; D004409:Dyskinesia, Drug-Induced / Q000209:etiology / Q000517:prevention & control; D005260:Female; D007980:Levodopa / Q000009:adverse effects; D008297:Male; D009474:Neurons / Q000187:drug effects*; D020258:Neurotoxicity Syndromes / Q000188:drug therapy / Q000209:etiology; D016627:Oxidopamine / Q000633:toxicity; D051381:Rats; D017207:Rats, Sprague-Dawley; D044282:Receptor, Serotonin, 5-HT1A / Q000378:metabolism*; D017366:Serotonin Receptor Agonists / Q000494:pharmacology*; D020531:Subthalamic Nucleus / Q000166:cytology*
chemical_list: D018663:Adrenergic Agents; D018759:Adrenergic Uptake Inhibitors; D015259:Dopamine Agents; D017366:Serotonin Receptor Agonists; D044282:Receptor, Serotonin, 5-HT1A; D007980:Levodopa; D016627:Oxidopamine; D003891:Desipramine; D002065:Buspirone
keywords: 6-Hydroxydopamine (PubChem CID: 4624); 6-OHDA lesion; Basal ganglia; Buspirone hydrochloride (PubChem CID: 36431); D-AP5 (PubChem CID: 135342); DNQX (PubChem CID: 3899541); Dyskinesia; Gabazine (SR95531 hydrobromide, PubChem CID: 107895); Parkinson's disease; Serotonin; Serotonin hydrochloride (PubChem CID: 160436); WAY-100635 maleate salt (PubChem CID: 11957721); l-DOPA; l-DOPA (PubChem CID: 6047)