Modulation of 5-HT1A receptor mediated response by fluoxetine in rat brain.
Radioligand binding studies were done to investigate the effect of chronic administration of fluoxetine on 5-HT1 receptor mediated response to adenylate cyclase (AC) in rat brain. Our studies revealed a significant decrease in the densities of 5-HT1 and 5-HT1A receptor sites in cortex and hippocampus of rat brain after chronic administration of fluoxetine (10 mg/Kg body wt.). However there was no significant change in the affinity of [3H]5-HT and [3H]DPAT for 5-HT1 and 5-HT1A receptor sites, respectively. However, in striatum, along with a significant (75%) downregulation of 5-HT1 sites, the affinity of [3H]5-HT to these sites was increased, as revealed by decrease in Kd (0.50 +/- 0.08 nM). Displacement studies showed that fluoxetine has higher affinity for 5-HT1A receptors with a Ki value of 14.0 +/- 2.8 nM, than 5-HT1 sites. No significant change was observed in basal AC activity in any region after fluoxetine exposure. However, in cortex of experimental rats the 5-HT stimulated AC activity was significantly increased (16.03 +/- 0.97 pmoles/mg protein; p < 0.01), when compared to 5-HT stimulated AC activity (12.98 +/- 0.78 pmoles/mg protein) in control rats. The increase in 5-HT stimulated AC activity in cortex may be due to the significant downregulation of 5-HT1A sites in cortex after fluoxetine exposure as these sites are negatively coupled to AC. The observed significant decrease in 5-HT1 sites with concomitant increase in 5-HT stimulated AC activity, after fluoxetine treatment, suggests that fluoxetine, which has high affinity for these sites, acts by modulating the 5-HT1A receptor mediated response in brain.
Subhash
M N
MN
Department of Neurochemistry, National Institute of Mental Health and Neurosciences, Bangalore, India. subhash@nimhans.kar.nic.in
Srinivas
B N
BN
Vinod
K Y
KY
Jagadeesh
S
S
D017371:8-Hydroxy-2-(di-n-propylamino)tetralin / Q000378:metabolism / Q000494:pharmacology; D000262:Adenylyl Cyclases / Q000032:analysis; D000818:Animals; D001923:Brain Chemistry / Q000187:drug effects* / Q000502:physiology; D005473:Fluoxetine / Q000494:pharmacology*; D008297:Male; D009474:Neurons / Q000187:drug effects / Q000201:enzymology; D011869:Radioligand Assay; D051381:Rats; D017207:Rats, Sprague-Dawley; D011985:Receptors, Serotonin / Q000378:metabolism*; D044263:Receptors, Serotonin, 5-HT1; D015290:Second Messenger Systems / Q000187:drug effects; D017366:Serotonin Receptor Agonists / Q000378:metabolism / Q000494:pharmacology; D017367:Selective Serotonin Reuptake Inhibitors / Q000494:pharmacology*; D014316:Tritium
D017371:8-Hydroxy-2-(di-n-propylamino)tetralin; D000262:Adenylyl Cyclases; D005473:Fluoxetine; D011985:Receptors, Serotonin; D044263:Receptors, Serotonin, 5-HT1; D017366:Serotonin Receptor Agonists; D017367:Selective Serotonin Reuptake Inhibitors; D014316:Tritium