Tandospirone, a 5-HT1A agonist, ameliorates movement disorder via non-dopaminergic systems in rats with unilateral 6-hydroxydopamine-generated lesions.
Serotonin 1A (5-HT1A) receptors are distributed throughout the brain with their highest concentrations in the frontal cortex, subthalamic nucleus and entopeduncular nucleus as well as the dorsal and median raphe nucleus. There is growing evidence that 5-HT1A receptor agonists have an antidepressant effect in individuals with major depressive disorders. Recent clinical studies suggest that tandospirone, a highly potent and selective 5-HT1A receptor agonist used clinically as an antidepressant in Japan and China, may act as an antiparkinsonian drug. In the present study, we investigated the effect of tandospirone on contralateral rotational behavior in a unilateral hemiparkinsonian rat model produced with 6-hydroxydopamine (6-OHDA). Tandospirone, as well as 8-hydroxy-2-(di-n-propylamino) tetralin (8-OHDPAT), significantly increased contralateral turnings in a dose-dependent manner (0.5-10 mg/kg). Tandospirone also remarkably potentiated the contralateral turning induced by 0.025 mg/kg of apomorphine. Pretreatment with WAY-100635, a 5-HT1A receptor antagonist, almost completely blocked the contralateral turning behavior evoked by tandospirone and 8-OHDPAT, but not that by apomorphine. SCH-23390, a selective dopamine D1 receptor antagonist, did not affect on the tandospirone-induced rotational behavior. These results suggested that tandospirone could act on postsynaptic 5-HT1A receptors and modulate excitatory amino acid pathways in the basal ganglia. Thus, tandospirone could have therapeutic potential for the treatment of Parkinson's disease by modulating neuronal activities of non-dopaminergic pathways.
Matsubara
Kazuo
K
Department of Hospital Pharmacy and Pharmacology, Asahikawa Medical College, Asahikawa 078-8510, Japan. kmatsuba@asahikawa-med.ac.jp
Shimizu
Keiko
K
Suno
Manabu
M
Ogawa
Kento
K
Awaya
Toshio
T
Yamada
Takehiro
T
Noda
Toshihiro
T
Satomi
Machiko
M
Ohtaki
Ko-ichi
K
Chiba
Kaoru
K
Tasaki
Yoshikazu
Y
Shiono
Hiroshi
H
D000704:Analysis of Variance; D000818:Animals; D001058:Apomorphine / Q000494:pharmacology; D001522:Behavior, Animal / Q000187:drug effects; D001552:Benzazepines / Q000494:pharmacology; D001930:Brain Injuries / Q000139:chemically induced / Q000150:complications / Q000503:physiopathology; D004298:Dopamine / Q000378:metabolism*; D018491:Dopamine Agonists / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D007839:Functional Laterality / Q000502:physiology; D054833:Isoindoles; D008297:Male; D009069:Movement Disorders / Q000188:drug therapy* / Q000209:etiology; D016627:Oxidopamine; D010879:Piperazines / Q000494:pharmacology / Q000627:therapeutic use*; D011725:Pyridines / Q000494:pharmacology; D011743:Pyrimidines / Q000627:therapeutic use*; D051381:Rats; D017208:Rats, Wistar; D045442:Rotarod Performance Test / Q000379:methods; D012702:Serotonin Antagonists / Q000494:pharmacology; D017366:Serotonin Receptor Agonists / Q000627:therapeutic use*; D013997:Time Factors
D001552:Benzazepines; D018491:Dopamine Agonists; D054833:Isoindoles; D010879:Piperazines; D011725:Pyridines; D011743:Pyrimidines; D012702:Serotonin Antagonists; D017366:Serotonin Receptor Agonists; C055267:tandospirone; C090413:N-(2-(4-(2-methoxyphenyl)-1-piperazinyl)ethyl)-N-(2-pyridinyl)cyclohexanecarboxamide; D016627:Oxidopamine; D001058:Apomorphine; D004298:Dopamine