Antagonist properties of (−)‐pindolol and WAY 100635 at somatodendritic and postsynaptic 5‐HT1A receptors in the rat brain
Authors: Corradetti Renato , Laaris Nora , Hanoun Naima , Laporte Anne‐Marie , Le Poul Emmanuel , Hamon Michel , Lanfumey Laurence 
Published: January 2005

The aim of the present work was to characterize the 5‐hydroxytryptamine1A (5‐HT1A) antagonistic actions of (−)‐pindolol and WAY 100635 (N‐(2‐(4‐(2‐methoxyphenyl)‐1‐piperazinyl)ethyl)‐N‐(2‐pyridinyl) cyclohexane carboxamide). Studies were performed on 5‐HT1A receptors located on 5‐hydroxytryptaminergic neurones in the dorsal raphe nucleus (DRN) and on pyramidal cells in the CA1 and CA3 regions of the hippocampus in rat brain slices.
Intracellular electrophysiological recording of CA1 pyramidal cells and 5‐hydroxytryptaminergic DRN neurones showed that the 5‐HT1A receptor agonist 5‐carboxamidotryptamine (5‐CT) evoked in both cell types a concentration‐dependent cell membrane hyperpolarization and a decrease in cell input resistance. On its own, (−)‐pindolol did not modify the cell membrane potential and resistance at concentrations up to 10 μM, but it antagonized the 5‐CT effects in a concentration‐dependent manner. Similar antagonism of 5‐CT effects was observed in the CA3 hippocampal region. (−)‐Pindolol also prevented the 5‐HT1A receptor‐mediated hyperpolarization of CA1 pyramidal cells due to 5‐HT (15 μM). In contrast, the 5‐HT‐induced depolarization mediated by presumed 5‐HT4 receptors persisted in the presence of 3 μM (−)‐pindolol.
In the hippocampus, (−)‐pindolol completely prevented the hyperpolarization of CA1 pyramidal cells by 100 nM 5‐CT (IC50=92 nM; apparent KB=20.1 nM), and of CA3 neurones by 300 nM 5‐CT (IC50=522 nM; apparent KB=115.1 nM). The block by (−)‐pindolol was surmounted by increasing the concentration of 5‐CT, indicating a reversible and competitive antagonistic action.
Extracellular recording of the firing rate of 5‐hydroxytryptaminergic neurones in the DRN showed that (−)‐pindolol blocked, in a concentration‐dependent manner, the decrease in firing elicited by 100 nM 5‐CT (IC50=598 nM; apparent KB=131.7 nM) or 100 nM ipsapirone (IC50=132.5 nM; apparent KB=124.9 nM). The effect of (−)‐pindolol was surmountable by increasing the concentration of the agonist. Intracellular recording experiments showed that 10 μM (−)‐pindolol were required to antagonize completely the hyperpolarizing effect of 100 nM 5‐CT.
In vivo labelling of brain 5‐HT1A receptors by i.v. administration of [3H]‐WAY 100635 ([O‐methyl‐3H]‐N‐(2‐(4‐(2‐methoxyphenyl)‐1‐piperazinyl)ethyl‐N‐(2‐pyridyl)cyclo‐hexane‐carboxamide) was used to assess their occupancy following in vivo treatment with (−)‐pindolol. (−)‐Pindolol (15 mg kg−1) injected i.p. either subchronically (2 day‐treatment before i.v. injection of [3H]‐WAY 100635) or acutely (20 min before i.v. injection of [3H]‐WAY 100635) markedly reduced [3H]‐WAY 100635 accumulation in all 5‐HT1A receptor‐containing brain areas. In particular, no differences were observed in the capacity of (−)‐pindolol to prevent [3H]‐WAY 100635 accumulation in the DRN and the CA1 and CA3 hippocampal areas.
Intracellular electrophysiological recording of 5‐hydroxytryptaminergic DRN neurones showed that WAY 100635 prevented the hyperpolarizing effect of 100 nM 5‐CT in a concentration‐dependent manner (IC50=4.9 nM, apparent KB=0.25 nM). In CA1 pyramidal cells, hyperpolarization induced by 50 nM 5‐CT was also antagonized by WAY 100635 (IC50=0.80 nM, apparent KB=0.28 nM).

British Journal of Pharmacology (1998) 123, 449–462; doi:10.1038/sj.bjp.0701632