Differential expression of serotonin2B receptors in GABAergic and serotoninergic neurons of the rat and mouse dorsal raphe nucleus

Abstract

The central serotonin receptor (5-HTR) 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-HTRs, thereby leading to opposite views on the therapeutic potential of 5-HTR agents for treating the above disorders. These discrepancies may result from anatomo-functional differences related to a different cellular location of 5-HTRs in rat and mouse brain. Using immunohistochemistry, we assessed this hypothesis by examining the expression of 5-HTRs 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-HT 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-HTRs are expressed in 5-HT cells expressing tryptophan hydroxylase 2 (TPH), in GABAergic cells expressing glutamic acid decarboxylase 67 (GAD67), and in cells expressing both markers (GAD67 & TPH; i.e., GABA-expressing 5-HT neurons). The proportion of 5-HTR-positive cells expressing only TPH was significantly larger in mouse than in rat DRN, whereas the opposite holds true for the expression in cells expressing GAD67 & TPH. 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-HTRs in TPH-positive cells in mice (67.2 vs 19.9 % in rats), associated with a lower expression in GAD67 & TPH cells (7.9 % in mice vs 41.5 % in rats). Intra-DRN (0.1 μM) administration of the preferential 5-HTR 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-HTR antagonist RS 127445 (0.1 μM). Altogether, these results show the existence of anatomical differences in the cellular expression of 5-HTRs 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.