Serotonin 1B receptor regulation after dorsal subiculum deafferentation

doi:10.1016/0361-9230(95)00066-N

Brain Research Bulletin

Volume 38, Issue 1, 1995, Pages 17-23

https://doi.org/10.1016/0361-9230(95)00066-N Get rights and content

Abstract

The subiculum may be the key structure in the transfer of relevant processed information from the hippocampal formation to cortical areas. We investigated the location of the serotonin 1B receptor (5-HT_1B) in the hippocampus with the specific ligand serotonin-O-carboxymethyl-glycyl[¹²⁵I]tyrosinamide in rat brain sections using in vitro autoradiography. A high density of 5-HT_1B binding sites was found in the dorsal subiculum (DS), in the lacunosum moleculare, and in the most dorsal layer of the stratum oriens of the CAI field. CAI pyramidal neurons that contain 5-HT_1B mRNA project primarily to the DS. We interrupted the pyramidal CA1 axons unilaterally by a stereotaxic knife cut. Histological analysis showed that the lesion was restricted to a trail of cells lost between CA1 and DS. Specific 5-HT_1B binding site density was decreased in the DS on the ipsilateral side of the lesion compared to the contralateral side. We conclude that 5-HT_1B receptors are located on CA1 pyramidal axon terminals in the DS. Serotonin, acting on these receptors, should inhibit CA1 neurotransmitter release and, in this way, modulate subicular functions.

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This effect appears to be signaled by 5-HT4 receptors, but the precise mechanisms by which these receptors gate the plasticity of CA3-CA1 glutamate synapses remain to be determined. Finally, pyramidal neurons of the CA1, but not the CA3 field, express 5-HT1B receptors that are targeted to their axonal projection terminals located principally in the subiculum (Ait Amara, Segu, Naili, & Buhot, 1995). Activation of these receptors inhibits glutamate-mediated synaptic transmission in this region (Boeijinga & Boddeke, 1993) (Fig. 15.1) by reducing the probability of glutamate release at individual synaptic terminals.
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Brain 5-HT1B receptors function as inhibitory autoreceptors on serotonergic neurons and as heteroreceptors on neurons of other neurotransmitters such as ACh and glutamate (Pazos and Palacios, 1985; Olivier and Oorschot, 2005). In the dorsal subiculum, 5-HT1B receptors are located on CA1 pyramidal axon terminals as inhibitory heteroreceptors (Ait et al., 1995), and activation of these receptors attenuates glutamate transmission in the hippocampus (Boeijinga and Boddeke, 1996; Mlinar et al., 2003). Administration of a selective 5-HT1B receptor antagonist NAS-181 caused a dose-dependent increase in ACh levels in the frontal cortex and ventral hippocampus of freely moving rats (Hu et al., 2007).
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This paradox was resolved with the demonstration that the co-activation of 5-HT1A and 5-HT4 receptors resulted in a large change in neuronal gain, a measure of how neurons encode excitatory input into firing output, such that weak excitatory stimuli are suppressed while strong stimuli are facilitated (Andrade and Nicoll, 1987). Finally, pyramidal neurons of the CA1, but not the CA3, field express 5-HT1B receptors that are targeted to their axonal projection terminals located in the subiculum (Ait et al., 1995). Activation of these receptors inhibits glutamate-mediated synaptic transmission in this region (Boeijinga and Boddeke, 1993) by reducing the probability of glutamate release at individual synaptic terminals (Figure 2E).
Serotonergic neurons innervate the entire neuroaxis, thus allowing serotonin to regulate the function of most CNS neurons. Work during the past two decades has made clear that the specific form taken by this regulation is dependent on the complement of serotonin receptors expressed by each cell. This general principle is now being extended to different cell types within defined neuronal networks to understand how serotonin regulates network function. In this chapter we review progress along this front in two intensely studied areas, the hippocampus and the cerebral cortex, and highlight areas of progress while noting outstanding issues that await elucidation.
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The CA1 pyramidal neurons project both to other CA1 pyramidal cells in the stratum radiatum and to the subiculum. Knife-cut lesions disrupting the CA1/subicular synapse and CA1 chemical lesions causing a deafferentation of both the CA1/subicular and the CA1/CA1 synapse decrease 5-HT1B receptor binding (Amara et al., 1995, 2001). Another region with relatively weak 5-HT1B receptor mRNA expression yet strong 5-HT1B receptor binding is the subthalamic nucleus, where both IPSCs and EPSCs are inhibited via activation of 5-HT1B receptors.
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Hippocampal 5-HT1B heteroreceptors are located in positions to control both glutamatergic and cholinergic transmission. Previous studies mainly investigated the location of 5-HT1B receptors on glutamatergic neurons, i.e. terminals of CA1 pyramidal cells in major output projections to the subiculum (Ait Amara et al., 1995, 2001; Boeijinga and Boddeke, 1996; Boschert et al., 1994). The majority of the mRNA-encoding 5-HT1B receptors synthesised in CA1 pyramidal cells migrate to CA1 axon terminals located in the stratum oriens and dorsal subiculum (Boeijinga and Boddeke, 1996).
Serotonergic (5-HT) neurotransmission plays a role in learning and memory processes, but the physiological role of various receptor subtypes is not well characterised. Among these, 5-HT_1B receptors are located as autoreceptors on 5-HT axons and heteroreceptors on non-serotonergic terminals. This study examined the role of the 5-HT_1B receptor in one-trial aversive contextual learning using the passive avoidance (PA) task in NMRI mice. Subcutaneous administration of the 5-HT_1B receptor agonist anpirtoline (0.1–1.0 mg/kg) before PA training impaired retention performance 24 h later. Combined administration of anpirtoline with the selective 5-HT_1B receptor antagonist NAS-181 (0.1–1.0 mg/kg) fully blocked the impairments. Administration of NAS-181 alone dose-dependently improved PA retention performance. This facilitatory effect was blocked by subthreshold doses of both the muscarinic antagonist scopolamine (0.03 mg/kg) and the NMDA receptor antagonist MK-801 (0.03 mg/kg). NAS-181 also fully blocked the PA impairments induced by an amnesic dose of scopolamine (0.1 mg/kg), when administered prior to, but not after, scopolamine. In addition, NAS-181 attenuated PA impairments induced by MK-801 (0.3 mg/kg). These findings indicate that 5-HT_1B receptors are activated at basal levels of 5-HT transmission. The facilitatory effect of NAS-181 involved alleviation of an inhibitory 5-HT tone mediated via 5-HT_1B receptors on cholinergic and glutamatergic transmission. This disinhibition is expected to occur in neuronal circuits involved in contextual learning including the hippocampus and interconnected cortico-limbic regions. Blockade of brain 5-HT_1B heteroreceptors may represent a novel therapeutic strategy for restoration of deficient cholinergic and glutamatergic neurotransmission contributing to memory disorders.
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The purpose of this study was to investigate the effects of the 5-HT_1B receptor antagonist NAS-181 ((R)-(+)-2-(3-morpholinomethyl-2H-chromen-8-yl) oxymethyl-morpholine methanesulfonate) on cholinergic, glutamatergic and GABA-ergic neurotransmission in the rat brain in vivo. Extracellular levels of acetylcholine, glutamate and GABA were monitored by microdialysis in the frontal cortex (FC) and ventral hippocampus (VHipp) in separate groups of freely moving rats. NAS-181 (1, 5 or 10 mg/kg, s.c.) caused a dose-dependent increase in ACh levels, reaching the maximal values of 500% (FC) and 230% (VHipp) of controls at 80 min post-injection. On the contrary, NAS-181 injected at doses of 10 or 20 mg/kg s.c. had no effect on basal extracellular levels of Glu and GABA in these areas. The present data suggest that ACh neurotransmission in the FC and VHipp, the brain structures strongly implicated in cognitive function, is under tonic inhibitory control of 5-HT_1B heteroreceptors localized at the cholinergic terminals in these areas.

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ArticleSerotonin 1B receptor regulation after dorsal subiculum deafferentation

Abstract

Neuroscience

Behav. Brain Res.

Brain Res.

Trends Pharmacol. Sci.

Behav. Neural. Biol.

Eur. J. Pharmacol.

Neurochem. Int.

J. Neurosci. Methods

Brain Res.

Organization of CA1 projections to the subiculum: A Phal-L analysis in the rat

Hippocampus

Acquisition of a complex place task in rats with selective ibotenate lesions of hippocampal formation: Combined lesions of subiculum and entorhinal cortex versus hippocampus

Behav. Neurosci.

Biochemical and pharmacological characterization of serotonin-O-carboxymethylglycyl[125I]iodotyrosinamide, a new radioiodinated probe for 5-HT1B and 5-HT1D binding sites

J. Neurochem.

Effects of retinal deafferentation on serotonin receptor types in the superfical grey layer of the superior colliculus of the rat

J. Chem. Neuroanat.

Autoradiographic characterisation and localisation of 5-HT1D compared to 5-HT1B binding sites in the rat brain

Naunyn Schmiedebergs Arch. Pharmacol.

Polarized sorting of glypiated proteins in hippocampal neurons

Nature

Some intrinsic connections of the hippocampus in the rat: An experimental analysis

J. Comp. Neurol.

Effects of serotonin on retinotectal-, corticotectal-, and glutamate-induced activity in the superior colliculus of the hamster

J. Neurophysiol.

Article
Serotonin 1B receptor regulation after dorsal subiculum deafferentation

Biochemical and pharmacological characterization of serotonin-O-carboxymethylglycyl[¹²⁵I]iodotyrosinamide, a new radioiodinated probe for 5-HT_1B and 5-HT_1D binding sites

Autoradiographic characterisation and localisation of 5-HT_1D compared to 5-HT_1B binding sites in the rat brain