Buspirone requires the intact nigrostriatal pathway to reduce the activity of the subthalamic nucleus via 5-HT1A receptors

• Published in: Experimental neurology Vol. 277; pp. 35 - 45
• Main Authors: Sagarduy, A., Llorente, J., Miguelez, C., Morera-Herreras, T., Ruiz-Ortega, J.A., Ugedo, L.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01-03-2016
• Subjects: 6-OHDA lesion; Action Potentials - drug effects; Adrenergic Agents - toxicity; Adrenergic Uptake Inhibitors - pharmacology; Animals; Basal ganglia; Buspirone - pharmacology; Desipramine - pharmacology; Disease Models, Animal; Dopamine Agents - adverse effects; Dyskinesia; Dyskinesia, Drug-Induced - etiology; Dyskinesia, Drug-Induced - prevention & control; Female; l-DOPA; Levodopa - adverse effects; Male; Neurons - drug effects; Neurotoxicity Syndromes - drug therapy; Neurotoxicity Syndromes - etiology; Oxidopamine - toxicity; Parkinson's disease; Rats; Rats, Sprague-Dawley; Receptor, Serotonin, 5-HT1A - metabolism; Serotonin; Serotonin Receptor Agonists - pharmacology; Subthalamic Nucleus - cytology; DRN; Serotonin hydrochloride (PubChem CID: 160436); l-DOPA (PubChem CID: 6047); Basal ganglia; Buspirone hydrochloride (PubChem CID: 36431); Parkinson's disease; Serotonin; LID; 6-OHDA; 6-Hydroxydopamine (PubChem CID: 4624); 6-OHDA lesion; STN; Gabazine (SR95531 hydrobromide, PubChem CID: 107895); PD; TH; DNQX (PubChem CID: 3899541); aCSF; D-AP5 (PubChem CID: 135342); l-DOPA; WAY-100635 maleate salt (PubChem CID: 11957721); 5-HT; Dyskinesia
• ISSN: 0014-4886; 1090-2430
• DOI: 10.1016/j.expneurol.2015.12.005

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.
•Buspirone and 5-HT ex vivo inhibited, by 5-HT1A receptor, few STN neurons.•Buspirone in vivo inhibited, by 5-HT1A receptor, every recorded STN neurons.•In vivo, buspirone-effect in the STN was absent in 6-OHDA lesioned rats.•Prolonged l-DOPA administration did not rescue buspirone-effect.•An intact nigrostriatal pathway is required for buspirone to inhibit the STN activity.