Modulation of Spontaneous Firing in Rat Subthalamic Neurons by 5-HT Receptor Subtypes

Abstract

Xiang, Zixiu, Lie Wang, and Stephen T. Kitai. Modulation of spontaneous firing in rat subthalamic neurons by 5-HT receptor subtypes. J Neurophysiol 93: 1145-1157, 2005 doi:10.1152/jn.00561. 2004. The subthalamic nucleus (STN) is considered to be one of the driving forces in the basal ganglia circuit. The STN is innervated by serotonergic afferents from the raphe nucleus and expresses a variety of 5-HT receptor subtypes. We investigated the effects of 5-HT and 5-HT receptor subtype agonists and antagonists on the firing properties of STN neurons in rat brain slices. We used cell-attached, perforated-patch, and whole cell recording techniques to detect changes in firing frequency and pattern and electrical membrane properties. Due to the depolarization of membrane potential caused by reduced potassium conductance, 5-HT (10 M) increased the firing frequency of STN neurons without changing their firing pattern. Cadmium failed to occlude the effect of 5-HT on firing frequency. 5-HT had no effect on afterhyperpolarization current. These results indicated that the 5-HT action was not mediated by high-voltageactivated calcium channel currents and calcium-dependent potassium currents. 5-HT had no effect on hyperpolarization-activated cation current (I H ) amplitude and voltage-dependence of I H activation, suggesting that I H was not involved in 5-HT-induced excitation. The increased firing by 5-HT was mimicked by 5-HT 2/4 receptor agonist ␣-methyl-5-HT and was partially mimicked by 5-HT 2 receptor agonist DOI or 5-HT 4 receptor agonist cisapride. The 5-HT action was partially reversed by 5-HT 4 receptor antagonist SB 23597-190, 5-HT 2 receptor antagonist ketanserin, and 5-HT 2C receptor antagonist RS 102221. Our data indicate that 5-HT has significant ability to modulate membrane excitability in STN neurons; modulation is accomplished by decreasing potassium conductance by activating 5-HT 4 and 5-HT 2C receptors.

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

“…In particular, in agreement with our data on striatal cholinergic interneurons, in other neuronal populations the excitatory responses to 5-HT2C receptor activation have been reported to be mediated by the closing of K + channels (Hsiao et al, 1997;Xiang et al, 2005).…”

“…Of note, 5-HT has already been reported to exert an excitatory effect by suppressing K + conductances in other striatal neuronal subtypes (Stefani et al, 1990), as well as in nucleus accumbens neurons, subthalamic nucleus neurons, and cortical pyramidal neurons (North and Uchimura, 1989;Zhang, 2003;Xiang et al, 2005). In particular, in agreement with our data on striatal cholinergic interneurons, in other neuronal populations the excitatory responses to 5-HT2C receptor activation have been reported to be mediated by the closing of K + channels (Hsiao et al, 1997;Xiang et al, 2005).…”

“…The depolarizing response induced by DOI (20 mM, 3 min) was prevented by pretreatment with ketanserin (10 mM, 10-15 min preincubation; Figure 3b 2 ; 9.170.5% of control; n ¼ 6; po0.01). In order to discriminate between 5-HT2 receptor subtypes, the effect of the selective 5-HT2C antagonist RS 102221 was tested on the 5-HT-induced response (Xiang et al, 2005). Pretreatment with RS 102221 (1-3 mM, 10-15 min) caused a significant reduction in the depolarization produced by 50 mM 5-HT ( Figure 3c, Table 1; 3 mM: 66.971.3% of control; n ¼ 4; po0.05); addition of 10 mM ketanserin did not cause further inhibitory effect ( Figure 3c 4 ; n ¼ 3; p40.05).…”

“…A 5-HT-dependent membrane depolarization has been observed in a variety of neuronal subtypes in different brain regions, involving various ionic mechanisms (Chapin and Andrade, 2001;Chapin et al, 2002;Xiang et al, 2005; for a review, see Hoyer et al, 2002). This observation suggests an important role for 5-HT in modulating neuronal excitability in several brain areas.…”

“…The diversity of receptor subtypes matches the complexity of effects exerted by 5-HT on its target cells. 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).…”