Chronic buspirone treatment normalizes regional serotonin synthesis in the olfactory bulbectomized rat brain: an autoradiographic study.
The effects of chronic buspirone treatments, administered by minipump at doses of 10 and 20 mg/(kg day) for 14 days, on brain 5-HT synthesis in olfactory bulbectomized (OBX) rats were evaluated. The alpha-[14C]methyl-L-tryptophan autoradiographic method was used. We compared the synthesis in the buspirone treated OBX rats (administered either 10 mg/(kg day) (OBX-10) or 20 mg/(kg day) (OBX-20)) to that of the saline treated OBX rats (OBX-SAL), and the sham operated rats (SHX) treated with saline. In addition, OBX-10 rats were compared to SHX rats treated with 10 mg/(kg day) (SHX-10) of buspirone. All treatments were carried out for 14 days. Adult Sprague-Dawley rats were used. Two weeks following the OBX or SHX procedures, the rats were assigned to the OBX-10, OBX-20, OBX-SAL, SHX-10, or SHX-SAL groups, respectively. The 5-HT synthesis rates R (pmol/(g/min)) were calculated from the trapping constant of alpha-[14C]MTrp (K*; ml/(g min)) and the plasma concentration of the plasma non-protein-bound tryptophan (Cp; pmol/ml) using the lumped constant (LC) measured previously in the rat brain. There was no significant difference in the plasma free or total tryptophan among these groups. The overall synthesis in the OBX-10 group was not statistically different from the OBX-SAL group, but it was different from the OBX-20 and SHX-SAL groups. The OBX-20 rats had an overall significant reduction in 5-HT synthesis, when compared to the OBX-SAL group, but did not differ from the SHX-SAL group, which did not differ from the SHX-10 group. These results suggest that 10 mg/(kg day) of buspirone for 14 days in the OBX rats did not produce a significant alteration in 5-HT synthesis, but 20 mg/(kg day) for 14 days resulted in an overall significant reduction in brain 5-HT synthesis. The latter treatment brought the synthesis to the level found in the sham operated rats, i.e., a normal level. These results suggest that normalization (reduction to the level found in the SHX-SAL rats) of 5-HT synthesis in the OBX requires a greater dose of buspirone (20 mg/(kg day)) than that needed to produce a desensitization of the 5-HT1A receptors in the sham operated rats (10 mg/(kg day)). This probably indicates that 5-HT1A receptors have different functionality in the OBX rats than that found in the intact or sham operated rats. Furthermore, our results support the hypothesis that 5-HT1A receptors mediate the antidepressant-like effect of 5-HT1A agonists, as the chronic 5-HT1A agonist treatment in the depression model known to be sensitive to antidepressants resulted in the normalization of 5-HT synthesis.
Watanabe
Arata
A
Department of Neurology and Neurosurgery, Montreal Neurological Institute, McGill University, Montreal, Que., H3A 2B4, Canada.
Hasegawa
Shu
S
Nishi
Kyoko
K
Nguyen
Khnah Q
KQ
Diksic
Mirko
M
D000818:Animals; D001345:Autoradiography; D001921:Brain / Q000187:drug effects* / Q000378:metabolism / Q000503:physiopathology; D002065:Buspirone / Q000494:pharmacology*; D002250:Carbon Radioisotopes; D003714:Denervation; D003866:Depressive Disorder / Q000188:drug therapy* / Q000378:metabolism / Q000503:physiopathology; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation / Q000187:drug effects / Q000502:physiology; D004334:Drug Administration Schedule; D008297:Male; D009830:Olfactory Bulb / Q000293:injuries / Q000601:surgery; D051381:Rats; D017207:Rats, Sprague-Dawley; D044282:Receptor, Serotonin, 5-HT1A / Q000187:drug effects / Q000378:metabolism; D012683:Sensory Deprivation / Q000502:physiology; D012701:Serotonin / Q000096:biosynthesis*; D017366:Serotonin Receptor Agonists / Q000494:pharmacology; D014364:Tryptophan / Q000031:analogs & derivatives / Q000097:blood / Q000378:metabolism
D002250:Carbon Radioisotopes; D017366:Serotonin Receptor Agonists; D044282:Receptor, Serotonin, 5-HT1A; C020774:alpha-methyltryptophan; D012701:Serotonin; D014364:Tryptophan; D002065:Buspirone