Acute flesinoxan treatment produces a different effect on rat brain serotonin synthesis than chronic treatment: an alpha-methyl-l-tryptophan autoradiographic study.
5-HT(1A) receptor agonists display anxiolytic and anti-depressant properties in clinical studies. In this study, we used the alpha-[(14)C]methyl-l-tryptophan (alpha-MTrp) autoradiographic method to evaluate the effects of the 5-HT(1A) agonist, flesinoxan, on regional 5-HT synthesis in the rat brain, following acute or a 14-day continuous treatment. In the first series of experiments, flesinoxan (5mg/kg; i.p.) was administered 40min before the alpha-MTrp. It resulted in a significant increase of the arterial blood oxygen partial pressure (pO(2)) and a reduction of the regional rate of 5-HT synthesis throughout the brain, with the exception of a few regions (medial geniculate body and thalamus). In the second series of experiments, flesinoxan (5mg/kgday) was administered for 14 days, using an osmotic minipump implanted subcutaneously. When compared to rats treated with saline, there was an overall significant (p<0.05) reduction in the synthesis (one-sample two-tailed t-test). However, there was no significant influence on the 5-HT synthesis rate in the dorsal and median raphe nuclei and the majority of their projection areas. A significant (p<0.05) reduction was observed in the nucleus raphe magnus, medial caudate, ventral thalamus, amygdala, ventral tegmental area, medial forebrain bundle, nucleus accumbens, medial anterior olfactory nucleus and superior olive. The unaltered 5-HT synthesis rates in a large majority of regions following the 14-day treatment of flesinoxan may reflect the normalization (implies to not be different from salne treated control) of synthesis due to a desensitization of 5-HT(1A) autoreceptors on the cell body of 5-HT neurons as well as at postsynaptic sites, which is known to occur following long-term treatment with 5-HT(1A) agonists. It is of some importance to note that the normalization of the synthesis occurred in the majority of the brain limbic structures, the brain areas implicated in affective disorders and the corresponding successful treatments, as well as in the cortical regions, which are implicated in mood. However, there were some terminal regions (e.g., accumbens, anterior olfactory, lateral thalamus, raphe magnus and obscurus) in which the chronic flesinoxan treatment resulted in a significant reduction of synthesis, suggesting that there was not a full desensitization across the brain of the receptors controlling 5-HT synthesis.
Tohyama
Yoshihiro
Y
Cone Neurosurgical Research Laboratory, Department of Neurology and Neurosurgery, Montreal Neurological Institute, McGill University, 3801 University Street, Montreal, Quebec H3A 2B4, Canada.
Mück-Seler
Dorotea
D
Diksic
Mirko
M
D000818:Animals; D001345:Autoradiography; D001921:Brain / Q000033:anatomy & histology / Q000187:drug effects* / Q000378:metabolism*; D001923:Brain Chemistry / Q000187:drug effects / Q000502:physiology; D002250:Carbon Radioisotopes; D004334:Drug Administration Schedule; D015918:Infusion Pumps, Implantable; D008297:Male; D010101:Oxygen Consumption / Q000187:drug effects / Q000502:physiology; D010879:Piperazines / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D044282:Receptor, Serotonin, 5-HT1A / Q000187:drug effects* / Q000378:metabolism; D012701:Serotonin / Q000096:biosynthesis*; D017366:Serotonin Receptor Agonists / Q000494:pharmacology; D009435:Synaptic Transmission / Q000187:drug effects / Q000502:physiology; D014364:Tryptophan / Q000031:analogs & derivatives* / Q000378:metabolism
D002250:Carbon Radioisotopes; D010879:Piperazines; D017366:Serotonin Receptor Agonists; D044282:Receptor, Serotonin, 5-HT1A; C020774:alpha-methyltryptophan; D012701:Serotonin; C056895:flesinoxan; D014364:Tryptophan