Pharmacological characterization of 5‐HT_1B receptor‐mediated inhibition of local excitatory synaptic transmission in the CA1 region of rat hippocampus

Abstract

1 In the hippocampus, axon collaterals of CA1 pyramidal cells project locally onto neighbouring CA1 pyramidal cells and interneurones, forming a local excitatory network which, in disinhibited conditions, feeds polysynaptic epscs (poly-epscs). 5-hydroxytryptamine (5-HT) has been shown to inhibit poly-epscs through activation of a presynaptic receptor. The aim of the present work was the pharmacological characterization of the 5-HT receptor involved in this 5-HT action. 2 Poly-epscs, evoked by electrical stimulation of the stratum radiatum and recorded in whole-cell voltage-clamp from CA1 pyramidal neurones, were studied in mini-slices of the CA1 region under pharmacological block of GABA A , GABA B , and 5-HT 1A receptors. 3 The 5-HT 1B receptor selective agonist 1,4-dihydro-3-(1,2,3,6-tetrahydro-4-pyridinyl)-5H-pyrrolo[3,2-b]pyridin-5-one dihydrochloride (CP 93129) inhibited poly-epscs (EC 50 =55 nM), an eect mimicked by the 5-HT 1B ligands 5-carboxamidotryptamine (5-CT; EC 50 =14 nM) and methylergometrine (EC 50 =78 nM), but not by 1-(3-chlorophenyl)piperazine dihydrochloride (mCPP; 10 mM) or 7-tri¯uoromethyl-4(4-methyl-1-piperazinyl)-pyrrolo[1,2-a]quinoxaline dimaleate (CGS 12066B; 10 mM). 4 The eects of CP 93129 and 5-CT were blocked by the selective 5-HT 1B receptor antagonist 3-[3-(dimethylamino)propyl]-4-hydroxy-N-[4-(4-pyridinyl)phenyl]benzamide dihydrochloride (GR 55562; K B &100 nM) and by cyanopindolol (K B =6 nM); methiothepin (10 mM) and dihydroergotamine (1 mM). For both GR 55562 and methiothepin, application times of at least two hours were required in order to achieve their full antagonistic eects. 5 Our results demonstrate that 5-HT 1B receptors are responsible for the presynaptic inhibition of neurotransmission at CA1/CA1 local excitatory synapses exerted by 5-HT.

Serotonin as a Modulator of Glutamate- and GABA-Mediated Neurotransmission: Implications in Physiological Functions and in Pathology

“…2), [31,90,97,101,121,130,131,157,162,163,166,179], in frontal cortex [31,192] and in the cerebellum [38,39,75,102]. These data together suggest that, at least in the above mentioned districts, the modulatory action of 5-HT may serve as a "brake" on neuronal excitability.…”

“…At a pre-synaptic level, 5-HT can modulate neurotransmitter release: for example, in various brain regions glutamate release is reduced by 5-HT 1A [162,164,177], 5-HT 1B [13,130,151,167] and 5-HT 6 receptors [31]. Similarly, presynaptic inhibition of GABA release is mediated by 5-HT 1A [90,95,96] and 5-HT 1B receptors [88,117].…”

“…Later, it was reported that 5-HT suppresses long term potentiation (LTP) in hippocampal slices by preventing the activation of NMDA receptors and the enhancement of AMPA-mediated currents that lead to LTP induction [171]. The hippocampus contains several subtypes of serotonin receptors, namely 5-HT 1A [160,174], 5HT 1B [4,130], 5-HT 2 [17,28], 5-HT 3 [116,132], 5-HT 4 [5,160], 5-HT 6 and 5-HT 7 [73], many of which modulate glutamate-mediated transmission acting at different levels. In the CA1 region, pre-synaptic 5-HT 1A receptors reduce glutamate release from Schaffer collaterals to CA1 pyramidal neurons [162] (Fig.…”

“…2 ). 5-HT 1B receptors are instead located on the axons terminals of CA1 pyramidal neurons [4]; their activation inhibits local glutamate release, depressing especially the AMPA/kainate component of excitatory transmission to neighboring CA1 pyramidal neurons and to local interneurons [130,131]. 5-HT 1B receptors also reduce glutamate release from CA1 fibers in the subicular cortex [13].…”

“…In the CA1 region, pre-synaptic 5-HT 1A receptors on Schaffer collaterals reduce glutamate release to pyramidal neurons [162]. 5-HT 1B receptors, located on axon terminals from pyramidal neurons and on their recurrent collaterals, inhibit glutamate release to neighboring pyramidal neurons and to local interneurons [130,131]. The release of GABA from CA1 inhibitory interneurons is stimulated by 5-HT 2 [101,166] and by 5-HT 3 receptors [90,121,157,163,179] and inhibited by 5-HT 1A receptors [90,157,163].…”