Differential expression of serotonin2B receptors in GABAergic and serotoninergic neurons of the rat and mouse dorsal raphe nucleus.
Molecular and Cellular Neuroscience. 2022-07-01; 121: 103750
DOI: 10.1016/j.mcn.2022.103750
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Cathala A(1), Lucas G(2), López-Terrones E(3), Revest JM(4), Artigas F(5), Spampinato U(6).
Author information:
(1)Inserm U1215, Neurocentre Magendie, Physiopathology and therapeutic
approaches of stress-related diseases, Bordeaux F-33000, France; Université de
Bordeaux, Bordeaux F-33000, France. Electronic address:
.
(2)Université de Bordeaux, Bordeaux F-33000, France; CNRS UMR 5287, INCIA, P3TN,
Bordeaux F-33000, France. Electronic address: .
(3)Depart. de Neurociències i Terapèutica Experimental, Institut
d’Investigacions Biomèdiques de Barcelona, IIBB-CSIC, Barcelona, Spain; Institut
d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain;
Centro de Investigación Biomédica en Red de Salud Mental (CIBERSAM), Instituto
de Salud Carlos III, Madrid, Spain. Electronic address:
.
(4)Inserm U1215, Neurocentre Magendie, Physiopathology and therapeutic
approaches of stress-related diseases, Bordeaux F-33000, France; Université de
Bordeaux, Bordeaux F-33000, France. Electronic address:
.
(5)Depart. de Neurociències i Terapèutica Experimental, Institut
d’Investigacions Biomèdiques de Barcelona, IIBB-CSIC, Barcelona, Spain; Institut
d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain;
Centro de Investigación Biomédica en Red de Salud Mental (CIBERSAM), Instituto
de Salud Carlos III, Madrid, Spain. Electronic address:
.
(6)Inserm U1215, Neurocentre Magendie, Physiopathology and therapeutic
approaches of stress-related diseases, Bordeaux F-33000, France; Université de
Bordeaux, Bordeaux F-33000, France. Electronic address:
.
The central serotonin2B receptor (5-HT2BR) modulates 5-HT and dopamine (DA)
neuronal function in the mammalian brain and has been suggested as a potential
target for the treatment of neuropsychiatric disorders involving derangements of
these monoamine systems, such as schizophrenia, cocaine abuse and dependence and
major depressive disorder. Studies in rats and mice yielded contrasting results
on the control of 5-HT/DA networks by 5-HT2BRs, thereby leading to opposite
views on the therapeutic potential of 5-HT2BR agents for treating the above
disorders. These discrepancies may result from anatomo-functional differences
related to a different cellular location of 5-HT2BRs in rat and mouse brain.
Using immunohistochemistry, we assessed this hypothesis by examining the
expression of 5-HT2BRs in 5-HT and GABAergic neurons of rats and mice within
different subregions of the dorsal raphe nucleus (DRN), currently considered as
the main site of action of 5-HT2B agents. Likewise, using in vivo microdialysis,
we examined their functional relevance in the control of DRN 5-HT outflow, a
surrogate index of 5-HT neuronal activity. In the DRN of both species, 5-HT2BRs
are expressed in 5-HT cells expressing tryptophan hydroxylase 2 (TPH2), in
GABAergic cells expressing glutamic acid decarboxylase 67 (GAD67), and in cells
expressing both markers (GAD67 & TPH2; i.e., GABA-expressing 5-HT neurons). The
proportion of 5-HT2BR-positive cells expressing only TPH2 was significantly
larger in mouse than in rat DRN, whereas the opposite holds true for the
expression in cells expressing GAD67 & TPH2. No major species differences were
found in the dorsal and ventral subregions. In contrast, the lateral subregion
exhibited large differences, with a predominant expression of 5-HT2BRs in
TPH2-positive cells in mice (67.2 vs 19.9 % in rats), associated with a lower
expression in GAD67 & TPH2 cells (7.9 % in mice vs 41.5 % in rats). Intra-DRN
(0.1 μM) administration of the preferential 5-HT2BR agonist BW 723C86 decreased
and increased DRN 5-HT outflow in rats and mice respectively, both effects being
prevented by the intra-DRN perfusion of the selective 5-HT2BR antagonist RS
127445 (0.1 μM). Altogether, these results show the existence of anatomical
differences in the cellular expression of 5-HT2BRs in the rat and mouse DRN,
which translate into an opposite control of 5-HT outflow. Also, they highlight
the relevance of the subset of GAD67-positive 5-HT neurons as a key factor
responsible for the functional differences between rats and mice in terms of
5-HT neuronal activity modulation.