Inhibition of the firing of midbrain 5-HT neurones by acute administration of selective serotonin reuptake inhibitors (SSRIs) may contribute to their delayed onset of antidepressant effect. It is generally thought that this inhibition is mediated by indirect activation of somatodendritic 5-HT_1A autoreceptors (Gartside et al., 1995). However, recent studies indicate that activation of 5-HT₂ receptors also inhibits the firing of 5-HT neurones (Boothman et al., 2003). The present study tested whether 5-HT₂ receptors contribute to the inhibition of 5‑HT cell firing induced by the SSRI, fluoxetine.

Male Sprague-Dawley rats (240-320 g) were anaesthetised by chloral hydrate and a tail vein was cannulated for drug administration. Single-barrel glass electrodes were stereotaxically lowered into the dorsal raphe nucleus (DRN) and extracellular recordings of identified 5-HT neurones were carried out as described previously (Hajós et al., 1995). Fluoxetine was given in increasing doses (0.3-10.0 mg kg^-1) at 120 s intervals to groups of rats (n=5-8) pre-treated for 300 s with vehicle or one of the following antagonists: ritanserin (5-HT₂ 1 mg kg^-1), MDL 100907 (5-HT_2A; 0.2 mg kg^-1), SB 206553 (5-HT _2B/2C; 0.5 or 2.5 mg kg^-1), SB 242084 (5-HT_2C; 0.5 mg kg^-1) or WAY 100635 (5-HT_1A; 0.1 mg kg^-1). A separate vehicle/fluoxetine group was run with each antagonist. Firing rates were measured in the final 60 s of each drug interval. Data were analysed using one- or two-way ANOVA with appropriate post hoc tests.

Fluoxetine (0.3-10.0 mg kg^-1 i.v.) caused a dose-related inhibition of 5-HT cell firing with 10 mg kg^-1 reducing firing by 97 % of pre-drug values (P<0.0001). Ritanserin caused a statistically significant (P<0.01) rightward shift in the fluoxetine dose-response curve. The fluoxetine dose-response curve was also slightly shifted to the right by the low but not high dose of SB 206553. Although there was a statistically significant difference between these groups overall (P=0.048), further analysis did not identify a statistical difference between individual groups. Both MDL 100907 and SB 242084 caused a slight rightward shift in the fluoxetine dose-response curve but this effect was not statistically significant. In comparison, WAY 100635 markedly attenuated the effect of fluoxetine (P<0.0001).

In summary, the present findings indicate that 5-HT₂ receptors may play a role in the inhibitory effect of fluoxetine on the firing of 5-HT neurones in vivo. However, the data suggest that this contribution appears small in comparison to that of 5-HT_1A receptors. Since there are data suggesting that fluoxetine has moderate affinity for 5-HT₂ receptors (Palvimaki et al., 1999), the contribution of 5-HT₂ receptors to the inhibitory effect of other SSRIs on 5-HT cell firing should be tested.

Boothman L., et al. (2003) Br J Pharmacol 139 (5), 998-1004.
Gartside S.E. et al., (1995) Br J Pharmacol 115 (6), 1064-1070.
Hajós M. et al. (1995) N S Arch Pharmacol 351, 624-629.
Palvimaki E. et al., (1999) Int J Neuropsychopharmacol 2, 95-99.

LJB was supported by a MRC Industrial Collaborative Studentship with Eli Lilly & Co.