Colocalization of serotonin receptor subtypes 5-HT2A, 5-HT2C, and 5-HT6 with neuropeptides in rat striatum

Abstract

There are two primary output pathways from the striatum: a projection to the globus pallidus, and projection to the substantia nigra. Certain striatally expressed neuropeptides are differentially distributed between these two pathways. Specifically, enkephalin is expressed in striatopallidal neurons, whereas substance P and dynorphin are expressed in striatonigral neurons. Several serotonin receptors are also prominently expressed in the striatum, but little is known about how they fit into the molecular neuroanatomy described above. We used double-label in situ hybridization to determine the striatal distribution of the mRNAs of the serotonin2A (5-HT2A), serotonin2C (5-HT2C), and serotonin6 (5-HT6) receptors in relation to enkephalin, substance P, and dynorphin expressing output neurons. Rat brain sections were simultaneously hybridized with an 35S riboprobe for one of the serotonin receptors and a digoxygenin labeled riboprobe for one of the neuropeptides. Sections were examined by using brightfield microscopy, and the degree of colocalization of the two mRNAs determined. All the serotonin receptors colocalized extensively with all three of the neuropeptides examined. None of the serotonin receptors showed preferential colocalization in striatopallidal (enkephalin containing), or striatonigral (substance P or dynorphin containing) cells. The 5-HT2A and 5-HT2C mRNAs displayed a differential distribution with regard to the scattered islands of strongly dynorphin mRNA positive cells, which are thought to reside in the striatal patch compartment. Within these islands, 5-HT2C mRNA expression was much higher than in surrounding areas. 5-HT2A mRNA showed the opposite pattern with decreased expression over dynorphin rich cell clusters.

Endogenous Serotonin Excites Striatal Cholinergic Interneurons via the Activation of 5-HT 2C, 5-HT6, and 5-HT7 Serotonin Receptors: Implications for Extrapyramidal Side Effects of Serotonin Reuptake Inhibitors

“…Previous studies have reported the expression of almost all 5-HT receptor subtypes in the striatum (Blandina et al, 1989;Jakeman et al, 1994;Waeber et al, 1994;Bruinvels et al, 1994;Patel et al, 1995;Gerald et al, 1995;Ward and Dorsa, 1996). However, the 5-HT receptors expressed by striatal cholinergic interneurons are unknown.…”

“…Another 5-HT receptor expressed at significant levels in the striatum is the 5-HT6 receptor (Ruat et al, 1993;Ward and Dorsa, 1996;Gerard et al, 1997). The involvement of these receptors was assessed by using the selective antagonist SB 258585.…”

“…Among 5-HT receptors, only 5-HT3 is a ligand-gated ion channel, whereas the other receptors belong to the G-proteincoupled receptor (GPCR) superfamily. The striatum expresses a variety of 5-HT receptors: 5-HT1B and 5-HT1E (Bruinvels et al, 1994), 5-HT2A and 5-HT2C (Ward and Dorsa, 1996), 5-HT3 (Blandina et al, 1989;Rondé and Nichols, 1998), 5-HT4 (Jakeman et al, 1994;Waeber et al, 1994;Gerald et al, 1995;Patel et al, 1995), and 5-HT6 (Ruat et al, 1993;Ward and Dorsa, 1996;Gerard et al, 1997). The striatal expression of 5-HT7 is controversial (Vizuete et al, 1997;Martin-Cora and Pazos, 2004).…”

“…In the basal ganglia, 5-HT receptors belonging to the 5-HT2C or 5-HT4 class have been reported to mediate the 5-HT-induced excitation of subthalamic nucleus and substantia nigra pars reticulata neurons (Rick et al, 1995;Xiang et al, 2005). Several studies have demonstrated, within the striatum, a high level of expression of 5-HT2 receptors (Ward and Dorsa, 1996) and the highest levels of 5-HT6 mRNA (Ruat et al, 1993;Branchek and Blackburn, 2000). Interestingly, a doublelabel in situ hybridization study reported that 5-HT2A, 5-HT2C, and 5-HT6 receptors colocalize within the striatum either in enkephalin-or in substance P-containing spiny neurons (Ward and Dorsa, 1996).…”

“…Several studies have demonstrated, within the striatum, a high level of expression of 5-HT2 receptors (Ward and Dorsa, 1996) and the highest levels of 5-HT6 mRNA (Ruat et al, 1993;Branchek and Blackburn, 2000). Interestingly, a doublelabel in situ hybridization study reported that 5-HT2A, 5-HT2C, and 5-HT6 receptors colocalize within the striatum either in enkephalin-or in substance P-containing spiny neurons (Ward and Dorsa, 1996). Our electrophysiological and PCR data demonstrate the expression of 5-HT2C, 5-HT6, and 5-HT7 receptors in striatal cholinergic interneurons, where each of them contributes to the depolarization/inward current induced by 5-HT.…”