Modulation of 5-HT_1A receptor mediated response by fluoxetine in rat brain

Summary.

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-HT_1A 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-HT_1A 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-HT_1A 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-HT_1A 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-HT_1A receptor mediated response in brain.