Antagonist properties of (-)-pindolol and WAY 100635 at somatodendritic and postsynaptic 5-HT sub(1A) receptors in the rat brain

The aim of the present work was to characterize the 5-hydroxytryptamine sub(1A) (5-HT sub(1A)) 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-HT sub(1A) 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-HT sub(1A) 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 mu M, 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-HT sub(1A) receptor-mediated hyperpolarization of CA1 pyramidal cells due to 5-HT (15 mu M). In contrast, the 5-HT-induced depolarization mediated by presumed 5-HT sub(4) receptors persisted in the presence of 3 mu M (-)-pindolol. In the hippocampus, (-)-pindolol completely prevented the hyperpolarization of CA1 pyramidal cells by 100 nM 5-CT (IC sub(50)=92 nM; apparent K sub(B)=20.1 nM), and of CA3 neurones by 300 nM 5-CT (IC sub(50)=522 nM; apparent K sub(B)=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 (IC sub(50)=598 nM; apparent K sub(B)=131.7 nM) or 100 nM ipsapirone (IC sub(50)=132.5 nM; apparent K sub(B)=124.9 nM). The effect of (-)-pindolol was surmountable by increasing the concentration of the agonist. Intracellular recording experiments showed that 10 mu M (-)-pindolol were required to antagonize completely the hyperpolarizing effect of 100 nM 5-CT. In vivo labelling of brain 5-HT sub(1A) receptors by i.v. administration of [ super(3)H]-WAY 100635 ([O-methyl- super(3)H]-N-(2-(4-(2-methoxyphenyl)-1-piperazinyl)ethyl-N-(2 -pyridyl)cyclo-hexane-carboxamide) was used to assess their occupancy