Electrophysiology of the 5-HT1A ligand MDL 73005EF in the rat hippocampal slice

Hooff, Peter van den; Galvan, M.

doi:10.1016/0014-2999(91)90442-s

Cited by 31 publications

(9 citation statements)

References 37 publications

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“…A contribution of a change in chloride conductance is unlikely since the use of KCl-filled microelectrodes will have shifted the chloride reversal potential to more positive values. This is substantiated by the fact that spontaneous, bicucullinesensitive IPSPs were always depolarizing (Alger & Nicoll, 1980 (Andrade & Nicoll, 1987;van den Hooff & Galvan, 1991). It has been previously demonstrated using autoradiographic methods that 5-HTlA receptors are present in the rat dentate gyrus (Pazos & Palacios, 1985).…”

Section: Discussionmentioning

confidence: 67%

Transient and long‐lasting actions of 5‐HT on rat dentate gyrus neurones in vitro.

Piguet

Galvan

1994

The Journal of Physiology

100

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1. The actions of 5-hydroxytryptamine (5-HT) on rat dentate gyrus neurones were measured with conventional intracellular recording techniques in brain slices maintained in vitro at 32 'C. 2. Bath application of 5-HT (03-100 uM) hyperpolarized the membrane potential and reduced the input resistance; these effects persisted in tetrodotoxin (1 UM) and were abolished by MDL 73,005EF, a 5-HTlA receptor antagonist. 3. Local application of 5-HT via a pressure pipette also elicited a hyperpolarization and a reduction in resistance, and evoked a transient 'burst' of spontaneous inhibitory postsynaptic potentials (IPSPs) which were blocked by tetrodotoxin or bicuculline. 4. The 'burst' of IPSPs was subject to desensitization. It was completely abolished in the presence of the 5-HT3 receptor antagonist dolasetron. 5. In some cells, a longer lasting increase in spontaneous IPSP frequency was observed during application of 5-HT; this effect was blocked by the 5-HT2 receptor antagonist MDL 100,907. 5-Hydroxytryptamine (5-HT) is an important neurotransmitter in the mammalian peripheral and central nervous system. 5-HT-containing neurones are predominantly located in the brainstem raphe nuclei and project to several higher centres, including the hippocampus, the septum and the cerebral and cerebellar cortices. A large number of autonomic functions and behaviours are believed to be mediated via 5-HT-mediated synaptic transmission, including control of blood pressure

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Section: Discussionmentioning

confidence: 67%

Transient and long‐lasting actions of 5‐HT on rat dentate gyrus neurones in vitro.

Piguet

Galvan

1994

The Journal of Physiology

100

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“…Up till now, no direct effect of 5-HT on CA1 pyramidal neurones in hippocampal slices has been ascribed to 5-HT3 receptor stimulation. Activation of 5-HT3 receptors is apparently responsible for the 5-HT-induced increase in spontaneous post-synaptic potentials (s.p.s.ps); this effect has been attributed to enhanced activity of GABAergic interneurones (Ropert & Guy, 1991), although a non-5-HT3 component has also been described (Van den Hooff & Galvan. 1991).…”

Section: Introductionmentioning

confidence: 99%

Effects of DAU 6215, a novel 5‐hydroxytryptamine₃ (5‐HT₃) antagonist on electrophysiological properties of the rat hippocampus

Passani

Pugliese

Azzurrini

et al. 1994

British J Pharmacology

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1 The aim of the present study was to test the effects of DAU 6215 (endo-N-(8-methyl-8-azabicyclo-[3.2.1]-octo-3-yl)-2,3-dihydro-2-oxo-lH-benzimidazole-1-carboxamide hydrochloride), a newly synthesized, selective aminophosphonovaleric acid (APV; 501M) and 6,7-dinitroquinoxaline-2,3-dione (DNQX; 25 tiM), and were elicited by the selective 5-HT3 agonist, 2-methyl-5-HT (2-Me-5-HT, 50 pM).5 The increase in frequency of s.p.s.ps induced by 5-HT was significantly antagonized by DAU 6215 in 70% of the cases, whereas the 5-HT3 antagonist always suppressed the effect of 2-Me-5-HT, at concentrations as low as 60 nM. 6 The antagonistic effect of DAU 6215 was also tested on the 5-HT3-mediated block of induction of long-term potentiation (LTP), elicited by a primed burst (PB) stimulation. Extracellular recordings showed that low concentrations (60 nM) of DAU 6215 suppressed the inhibitory action of 5-HT on PB-induced LTP, without affecting the 5-HTlA-induced reduction in the amplitude of the population spike. 7 These results provide evidence that DAU 6215 is an effective antagonist of the 5-HT3-mediated responses in the central nervous system and may offer a cellular correlate for the pharmacological effects of DAU 6215 as an anxiolytic and cognition enhancer.

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“…We subsequently investigated the agonistic and antagonistic properties of Wf-516, in consideration of the fact that several drugs acting as partial agonists for 5-HT 1A receptor display a high selectivity for presynaptic binding sites relative to postsynaptic components [33]–[35]. In vitro ARG binding of [ 35 S]GTPγS was enhanced by the addition of a 5-HT 1A receptor agonist, 8-OH-DPAT, in the hippocampus and raphe nucleus (Figure 8).…”

Section: Resultsmentioning

confidence: 99%

Presynaptic Selectivity of a Ligand for Serotonin 1A Receptors Revealed by In Vivo PET Assays of Rat Brain

Saijo

Maeda²,

Okauchi³

et al. 2012

PLoS ONE

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A novel investigational antidepressant with high affinity for the serotonin transporter and the serotonin 1A (5-HT1A) receptor, called Wf-516 (structural formula: (2S)-1-[4-(3,4-dichlorophenyl)piperidin-1-yl]-3-[2-(5-methyl-1,3,4-oxadiazol-2-yl)benzo[b]furan-4-yloxy]propan-2-ol monohydrochloride), has been found to exert a rapid therapeutic effect, although the mechanistic basis for this potential advantage remains undetermined. We comparatively investigated the pharmacokinetics and pharmacodynamics of Wf-516 and pindolol by positron emission tomographic (PET) and autoradiographic assays of rat brains in order to elucidate their molecular interactions with presynaptic and postsynaptic 5-HT1A receptors. In contrast to the full receptor occupancy by pindolol in PET measurements, the binding of Wf-516 to 5-HT1A receptors displayed limited capacity, with relatively high receptor occupancy being achieved in regions predominantly containing presynaptic receptors. This selectivity was further proven by PET scans of neurotoxicant-treated rats deficient in presynaptic 5-HT1A receptors. In addition, [35S]guanosine 5′-O-[γ-thio]triphosphate autoradiography indicated a partial agonistic ability of Wf-516 for 5-HT1A receptors. This finding has lent support to reports that diverse partial agonists for 5-HT1A receptors exert high sensitivity for presynaptic components. Thus, the present PET data suggest a relatively high capacity of presynaptic binding sites for partial agonists. Since our in vitro and ex vivo autoradiographies failed to illustrate these distinct features of Wf-516, in vivo PET imaging is considered to be, thus far, the sole method capable of pharmacokinetically demonstrating the unique actions of Wf-516 and similar new-generation antidepressants.

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Electrophysiology of the 5-HT1A ligand MDL 73005EF in the rat hippocampal slice

Cited by 31 publications

References 37 publications

Transient and long‐lasting actions of 5‐HT on rat dentate gyrus neurones in vitro.

Transient and long‐lasting actions of 5‐HT on rat dentate gyrus neurones in vitro.

Effects of DAU 6215, a novel 5‐hydroxytryptamine₃ (5‐HT₃) antagonist on electrophysiological properties of the rat hippocampus

Presynaptic Selectivity of a Ligand for Serotonin 1A Receptors Revealed by In Vivo PET Assays of Rat Brain

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Electrophysiology of the 5-HT1A ligand MDL 73005EF in the rat hippocampal slice

Cited by 31 publications

References 37 publications

Transient and long‐lasting actions of 5‐HT on rat dentate gyrus neurones in vitro.

Transient and long‐lasting actions of 5‐HT on rat dentate gyrus neurones in vitro.

Effects of DAU 6215, a novel 5‐hydroxytryptamine3 (5‐HT3) antagonist on electrophysiological properties of the rat hippocampus

Presynaptic Selectivity of a Ligand for Serotonin 1A Receptors Revealed by In Vivo PET Assays of Rat Brain

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Effects of DAU 6215, a novel 5‐hydroxytryptamine₃ (5‐HT₃) antagonist on electrophysiological properties of the rat hippocampus