Effects of chronic administration of sibutramine on body weight, food intake and motor activity in neonatally monosodium glutamate-treated obese female rats: relationship of antiobesity effect with monoamines.
When the hypothalamic ventromedial nucleus and arcuate nucleus were destroyed in rats by treatment with monosodium glutamate in the neonatal stage, increase in the Lee index (body weight 1/3/body length) and in retroperitoneal fat as well as decreases in spontaneous motor activity, food consumption and growth hormone secretion function associated with hypothalamic low body length obesity (monosodium glutamate-treated obesity; MSG-OB) were observed as these rats grew. Treatment with sibutramine at 3 and 10 mg/kg p.o. once a day continuously for 14 days improved these parameters, and the degree of improvement was dose related. The plasma lipid values in MSG-OB rats, which were the same as those in normal rats, were decreased by consecutive administration of sibutramine. Levels of hypothalamic monoamines (MAs) such as norepinephrine, 5-HT (serotonin) and dopamine and their metabolites DOPAC, HVA and 5-HIAA were decreased in MSG-OB rats, and further decrease in them, though slight, was observed with consecutive daily administration of sibutramine, probably as a result of the feedback attributable to an increase in MA in synapses caused by inhibition of MA uptake by sibutramine. These results suggest that sibutramine can activate the MA nervous system by MA uptake inhibition in regions of the brain such as the lateral hypothalamic area and the paraventricular nucleus, which control food intake and sympathetic nerve activity, and the nigrostriatal area related to the extrapyramidal motor system, and thereby exhibit anti-obesity effects in the MSG-OB rat.
Nakagawa
T
T
Central Research Institute, Kaken Pharmaceutical Co. Ltd., Kyoto, Japan.
Ukai
K
K
Ohyama
T
T
Gomita
Y
Y
Okamura
H
H
D015102:3,4-Dihydroxyphenylacetic Acid / Q000097:blood; D000273:Adipose Tissue / Q000033:anatomy & histology / Q000187:drug effects; D000818:Animals; D000831:Animals, Newborn; D001067:Appetite Depressants / Q000494:pharmacology*; D001111:Arcuate Nucleus of Hypothalamus / Q000187:drug effects / Q000473:pathology / Q000502:physiology*; D015306:Biogenic Monoamines / Q000097:blood*; D001823:Body Composition / Q000187:drug effects; D001835:Body Weight / Q000187:drug effects; D003503:Cyclobutanes / Q000494:pharmacology*; D004298:Dopamine / Q000097:blood; D002149:Energy Intake / Q000187:drug effects; D005260:Female; D006719:Homovanillic Acid / Q000097:blood; D006897:Hydroxyindoleacetic Acid / Q000097:blood; D008055:Lipids / Q000097:blood; D009043:Motor Activity / Q000187:drug effects / Q000502:physiology*; D009638:Norepinephrine / Q000097:blood; D009765:Obesity / Q000097:blood / Q000188:drug therapy* / Q000503:physiopathology; D051381:Rats; D012701:Serotonin / Q000097:blood; D012970:Sodium Glutamate / Q000633:toxicity*; D014697:Ventromedial Hypothalamic Nucleus / Q000187:drug effects / Q000473:pathology / Q000502:physiology*
D001067:Appetite Depressants; D015306:Biogenic Monoamines; D003503:Cyclobutanes; D008055:Lipids; D015102:3,4-Dihydroxyphenylacetic Acid; D012701:Serotonin; D006897:Hydroxyindoleacetic Acid; D004298:Dopamine; D012970:Sodium Glutamate; C058254:sibutramine; D009638:Norepinephrine; D006719:Homovanillic Acid