Alterations in 5-HT1A receptors and adenylyl cyclase response by trazodone in regions of rat brain

The in vivo effect of trazodone on the density of [H-3]5-HT binding sites and 5-HT1A receptors and adenylyl cyclase (AC) response was studied in regions of rat brain. The chronic administration of trazodone (10 mg/Kg body wt, 40 days) resulted in a significant downregulation of [H-3]5-HT binding sites and 5-HT1A receptors in cortex and hippocampus. Trazodone significantly (p < 0.0001) decreased the density of [H-3]5-HT binding sites in cortex (42.6 ± 3.6 fmol/mg protein, 65%) and hippocampus (12.6 ± 1.6 fmol/mg protein, 87%) when compared to control values of 121.9 ± 5.4 and 99.3 ± 7.5 fmol/mg protein in these regions, respectively. Similarly there was a significant (p < 0.0001) decrease in the density of 5-HT1A receptors in both cortex (7.2 +/- 0.5 fmol/mg protein, 70%) and hippocampus (6.3 +/- 1.2 fmol/mg protein, 79%) when compared to control values of 24.2 +/- 2.1 and 30.6 +/- 3,7 fmol/mg protein, in these regions respectively. However, the affinity of [H-3]5-HT to 5-HT binding sites (1.83 +/- 0.26 nM, p < 0.0001) and [H-3]8-OH-DPAT to 5-HT1A receptors (0.60 ± 0.06 nM, p < 0.05) was significantly decreased only in cortex when compared to the control K-d values of 0.88 +/- 0.04 nM and 0.47 +/- 0.02 nM in these regions, respectively. The basal AC activity did not alter in treated rats, where as, the inhibition of forskolin-stimulated AC activity by 5-HT (10 muM) was significantly (p < 0.0001) decreased both in cortex (43%) and hippocampus (40%) when compared to control levels. In conclusion, chronic treatment with trazodone results in downregulation of 5-HT1A receptors in cortex and hippocampus along with concomitant increased AC response, suggesting the involvement of 5-HT1A receptor-mediated AC response in the mechanism of action of trazodone. (C) 2002 Elsevier Science Inc. All rights reserved.