Elsevier

Brain Research

Volume 959, Issue 1, 3 January 2003, Pages 58-67
Brain Research

Research report
The 5-HT1A serotonin receptor is located on calbindin- and parvalbumin-containing neurons in the rat brain

https://doi.org/10.1016/S0006-8993(02)03727-7Get rights and content

Abstract

The 5-HT1A receptor is a well-characterized serotonin receptor playing a role in many central nervous functions and known to be involved in depression and other mental disorders. In situ hybridization, immunocytochemical, and binding studies have shown that the 5-HT1A receptor is widely distributed in the rat brain, with a particularly high density in the limbic system. The receptor’s localization in the different neuronal subtypes, which may be of importance for understanding its role in neuronal circuitries, is, however, unknown. In this study we show by immunocytochemical double-labeling techniques, that the 5-HT1A receptor is present on both pyramidal and principal cells, and calbindin- and parvalbumin-containing neurons, which generally define two different subtypes of interneurons. Moreover, semiquantitative analysis showed that the receptor’s distribution in the different neuronal types varies between brain areas. In cortex, hippocampus, hypothalamus, and amygdala the receptor was located on both principal cells and calbindin- and parvalbumin-containing neurons. In septum and thalamus, the receptor was mostly present on calbindin- and parvalbumin-containing cells. Especially in the medial septum and thalamic reticular nucleus, the receptor highly colocalized with parvalbumin-positive neurons. These results suggest a diverse function of the 5-HT1A receptor in modulating neuronal circuitry in different brain areas, that may depend on the type of neuron the receptor is predominantly located on.

Introduction

The 5-hydroxytryptamine1A (5-HT1A) receptor was one of the first serotonin receptors to be identified and characterized [36]. It belongs to the 5-HT1 receptor family which currently includes five receptor subtypes. The 5-HT1A receptor is involved in various central functions, including control of sexual behavior [27], thermoregulation [17], and feeding [12], and several studies have shown alterations in the binding and distribution of 5-HT1A receptors in depression [32], [38], [44] and Alzheimer’ disease [35].

The 5-HT1A receptor is well characterized; this is due to the availability of a wide range of selective agonists, such as 8-OH-DPAT, and because the 5-HT1A receptor was the first serotonin receptor to be cloned and sequenced [1]. The 5-HT1A receptor is expressed extensively in the brain, especially in the limbic areas. Like most serotonin receptors, 5-HT1A is a G protein coupled receptor [8], and G protein coupling usually indicates that there is a hyperpolarizing effect on the cells. Since most of the serotonin receptors are inhibitory it is usually assumed that the serotonergic fibers projecting to a specific area lead to inhibition of the final electrical output. However, whether activation of the 5-HT1A receptor results in inhibition or excitation of the principal excitatory cells may depend on which type of neurons the receptor is located on and this has not yet been completely clarified. Several studies suggest that the 5-HT1A receptor is localized on pyramidal cells [13], [16], [24]. Others studies have shown that activation of this receptor reduces inhibition of pyramidal cells in CA1 [39] and granule cells [29], suggesting that the 5-HT1A receptor is located on inhibitory interneurons.

In this study we used double immunocytochemical techniques to determine the localization of the 5-HT1A receptor in different neuronal subtypes. We also studied whether distribution of the 5-HT1A receptor in the different neuronal subtypes differs between brain regions. Knowledge of such differences might help explain why specific activation of the 5-HT1A receptor in different brain areas leads to different responses [7], [11]. Two different antibodies recognizing an intracellular segment of the 5-HT1A receptor were used. We looked for the presence of the 5-HT1A receptor in pyramidal and principal cells, and calbindin- and parvalbumin-containing neurons, which generally define different subpopulations of inhibitory interneurons [4].

Section snippets

Materials and methods

All animal experiments were carried out in accordance with the European Communities Council Resolves of 24th November 1986 (86/609/EEC) and approved by the Danish State Research Inspectorate (J. No. 1999-561-25). Effort was made to minimize any suffering of the animal used.

Results

5-HT1A immunopositive cells were found throughout the rat forebrain and especially in frontal cortex, piriform cortex, enthorinal cortex, preoptic areas, olfactory areas, all through hippocampus, lateral septum, medial septum, diagonal band of Broca, rostral thalamic areas, hypothalamic areas and amygdala (Fig. 1, Fig. 2). Many 5-HT1A immunopositive cells were found in raphe nucleus. The staining was especially strong in piriform cortex, olfactory tuberculus, islands of calleja, septal

Discussion

By double immunocytochemical labeling we have shown that the 5-HT1A receptor is localized on principal cells and also on calbindin- and parvalbumin-containing neurons. Furthermore, in different brain areas the receptor colocalizes differently within the three neuronal subtypes. Previous studies that have made use of intrastriatal injections of volkensin, which selectively lesions cortical pyramidal cells by retrograde transport, followed by binding of [3H]8-OH-DPAT, have concluded that the 5-HT

Concluding remarks

Our finding that 5-HT1A receptors are localized on both principal cells and calbindin- and parvalbumin-containing neurons, indicates a diverse function of this receptor in modulating neuronal circuitry. The presence of this receptor in certain groups of parvalbumin-containing neurons that are involved in controlling neuronal firing activity suggests an important role of the 5-HT1A receptor in modulating specific brain functions.

Acknowledgements

Excellent technical assistance was provided by Anja Pedersen and Lene Lyngsie Jensen. This work was supported by research grants from the 1991 Pharmacy Foundation, Health Insurance Fond, the Lundbeck Foundation, the Danish Medical Research Council, Novo Nordisk Foundation and sawmill owner Jeppe Juhl and Ovita Juhl Memorial Foundation.

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