title: 5-HT1A agonist alleviates serotonergic potentiation of extrapyramidal disorders via postsynaptic mechanisms.
abstract: We previously demonstrated that 5-HT stimulants, including selective serotonin reuptake inhibitors (SSRIs), potentiated antipsychotic-induced extrapyramidal symptoms (EPS) by stimulating 5-HT2A/2C, 5-HT3 and 5-HT6 receptors. Here, we studied the effects of the 5-HT1A agonist (±)-8-hydroxy-2-(di-n-propylamino) tetralin ((±)-8-OH-DPAT) on the fluoxetine enhancement of EPS (i.e., bradykinesia and catalepsy) to determine if the 5-HT1A agonist can counteract the serotonergic potentiation of EPS. Fluoxetine did not induce EPS signs by itself, but significantly potentiated haloperidol-induced bradykinesia in mice. (±)-8-OH-DPAT (0.1-1mg/kg, i.p.) significantly attenuated the fluoxetine enhancement of haloperidol-induced bradykinesia in a dose-dependent manner. A selective 5-HT1A antagonist (s)-WAY-100135 completely reversed the anti-EPS action of (±)-8-OH-DPAT. Microinjection studies using rats revealed that local application of (±)-8-OH-DPAT into the dorsolateral striatum or the motor cortex significantly diminished fluoxetine-enhanced catalepsy. In contrast, (±)-8-OH-DPAT injected into the medial raphe nucleus failed to affect EPS induction. The present results illustrate that 5-HT1A agonist can alleviate the SSRI enhancement of EPS by activating postsynaptic 5-HT1A receptors in the striatum and cerebral cortex.
authors.affiliation: Laboratory of Pharmacology, Osaka University of Pharmaceutical Sciences, 4-20-1 Nasahara, Takatsuki, Osaka 569-1094, Japan.
authors.forename: Saki
authors.initials: S
authors.lastname: Shimizu
authors.forename: Yuto
authors.initials: Y
authors.lastname: Mizuguchi
authors.forename: Ayaka
authors.initials: A
authors.lastname: Tatara
authors.forename: Tomoya
authors.initials: T
authors.lastname: Kizu
authors.forename: Saki
authors.initials: S
authors.lastname: Andatsu
authors.forename: Akira
authors.initials: A
authors.lastname: Sobue
authors.forename: Mai
authors.initials: M
authors.lastname: Fujiwara
authors.forename: Tomoki
authors.initials: T
authors.lastname: Morimoto
authors.forename: Yukihiro
authors.initials: Y
authors.lastname: Ohno
mesh_terms: D000818:Animals; D001480:Basal Ganglia Diseases / Q000188:drug therapy* / Q000378:metabolism*; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D008297:Male; D051379:Mice; D008845:Microinjections / Q000379:methods; D051381:Rats; D017207:Rats, Sprague-Dawley; D044282:Receptor, Serotonin, 5-HT1A / Q000378:metabolism*; D058825:Serotonin 5-HT1 Receptor Agonists / Q000008:administration & dosage*; D058829:Serotonin 5-HT1 Receptor Antagonists / Q000008:administration & dosage
chemical_list: D058825:Serotonin 5-HT1 Receptor Agonists; D058829:Serotonin 5-HT1 Receptor Antagonists; D044282:Receptor, Serotonin, 5-HT1A
keywords: (±)-8-OH-DPAT; (±)-8-hydroxy-2-(di-n-propylamino) tetralin; 5-HT(1A) agonists; Antidepressants; Antipsychotics; EPS; Extrapyramidal symptoms; MC; MRN; Microinjection; SGA; SSRI; Selective serotonin reuptake inhibitor (SSRI); dlST; dorsolateral striatum; extrapyramidal symptoms; medial raphe nucleus; motor cortex; second generation antipsychotic; selective serotonin reuptake inhibitor