Enhanced head-twitch response to 5-HT-related agonists in thiamine-deficient mice.
While many studies suggest an involvement of brain serotonergic systems in neuro-psychiatric disorders such as schizophrenia and depression, their role in Wernicke-Korsakoff syndrome (WKS) remains unclear. Since dietary thiamine deficiency (TD) in mice is considered as a putative model of WKS, it was used in the present study to investigate the function of serotonergic neurons in this disorder. After 20 days of TD feeding, the intensity of tryptophan hydroxylase immunofluorescence was found to be significantly decreased in the dorsal and medial raphe nuclei. In addition, the head-twitch response (HTR) elicited by the intracerebroventricular administration of the 5-HT(2A) agonist 2,5-dimethoxy-4-iodoamphetamine hydrochloride (DOI) was significantly increased in TD versus control mice, whereas the injection of ketanserin, a 5-HT(2A) receptor antagonist, prevented this enhancement. A single injection of thiamine HCl on the 19th day of TD feeding did not reduce the enhanced DOI-induced HTR. On the other hand, the administration of d-fenfluramine, a 5-HT releaser, did not enhance the HTR in TD mice. Together, our results indicate that TD causes a super-sensitivity of 5-HT(2A) receptors by reducing presynaptic 5-HT synthesis derived from degenerating neurons projecting from the raphe nucleus.
Nakagawasai
O
O
Department of Pharmacology, Tohoku Pharmaceutical University, Sendai, Japan. osamun@tohoku-pharm.ac.jp
Murata
A
A
Arai
Y
Y
Ohba
A
A
Wakui
K
K
Mitazaki
S
S
Niijima
F
F
Tan-No
K
K
Tadano
T
T
D000662:Amphetamines / Q000009:adverse effects; D000818:Animals; D001921:Brain / Q000187:drug effects / Q000378:metabolism / Q000503:physiopathology*; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004361:Drug Tolerance / Q000502:physiology; D005277:Fenfluramine / Q000494:pharmacology; D019416:Head Movements / Q000187:drug effects / Q000502:physiology; D007650:Ketanserin / Q000494:pharmacology; D020915:Korsakoff Syndrome / Q000378:metabolism / Q000503:physiopathology; D008297:Male; D051379:Mice; D009069:Movement Disorders / Q000378:metabolism / Q000503:physiopathology*; D011903:Raphe Nuclei / Q000187:drug effects / Q000378:metabolism / Q000503:physiopathology; D044402:Receptor, Serotonin, 5-HT2A / Q000187:drug effects / Q000378:metabolism*; D012701:Serotonin / Q000378:metabolism*; D012702:Serotonin Antagonists / Q000494:pharmacology; D017366:Serotonin Receptor Agonists / Q000009:adverse effects*; D017367:Selective Serotonin Reuptake Inhibitors / Q000494:pharmacology; D009435:Synaptic Transmission / Q000187:drug effects / Q000502:physiology; D013831:Thiamine / Q000378:metabolism / Q000494:pharmacology; D013832:Thiamine Deficiency / Q000378:metabolism / Q000503:physiopathology*; D014365:Tryptophan Hydroxylase / Q000378:metabolism
D000662:Amphetamines; D005277:Fenfluramine; D007650:Ketanserin; D044402:Receptor, Serotonin, 5-HT2A; D012701:Serotonin; D012702:Serotonin Antagonists; D017366:Serotonin Receptor Agonists; D017367:Selective Serotonin Reuptake Inhibitors; D013831:Thiamine; D014365:Tryptophan Hydroxylase; C015952:4-iodo-2,5-dimethoxyphenylisopropylamine