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1Department of Neurosurgery, University of Tennessee, Neuroscience Institute, Health Science Center, Memphis; and 2Methodist University Hospital, Memphis, Tennessee
Submitted 1 June 2004; accepted in final form 5 October 2004
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ABSTRACT |
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-methyl-5-HT and was partially mimicked by 5-HT2 receptor agonist DOI or 5-HT4 receptor agonist cisapride. The 5-HT action was partially reversed by 5-HT4 receptor antagonist SB 23597-190, 5-HT2 receptor antagonist ketanserin, and 5-HT2C 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-HT4 and 5-HT2C receptors. |
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INTRODUCTION |
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; Kitai and Kita 1987; Robledo and Feger 1990; Smith and Parent 1988) and is involved in motor functions (DeLong 1990; DeLong et al. 1985; Matsumura et al. 1992) as well as movement disorders (Albin et al. 1989; Bergman et al. 1994; Wichmann and DeLong 1996, 2003). Its prominent role in the physiology and pathophysiology of the basal ganglia has been signified by the dramatic therapeutic effects of lesion or high-frequency stimulation of the STN for Parkinson’s disease patients (DeLong and Wichmann 2001; Levy et al. 2000; Obeso et al. 2001; Pollak et al. 2002).
The STN is innervated by rich varicose serotonin (5-HT) fibers (Bobillier et al. 1976; Lavoie and Parent 1990; Moore et al. 1978; Mori et al. 1985; Palkovits et al. 1974; Steinbusch 1981), which originate mainly from the neurons in the dorsal raphe nucleus (Bobillier et al. 1976; Lavoie and Parent 1990). The serotonergic neurons in the dorsal raphe nucleus have been implicated in various aspects of motor control (Steinfels et al. 1983). The action of serotonin is mediated by a variety of 5-HT receptors, including G protein–coupled subtypes (5-HT1, 5-HT2, 5-HT4–7) and a ligand-gated ion channel (5-HT3) (Barnes and Sharp 1999; Derkach et al. 1989; Gerhardt and van Heerikhuizen 1997; Hoyer et al. 1994, 2002). Several subtypes of 5-HT receptors are expressed in the STN. Histochemical studies by in situ hybridization have shown that 5-HT2C and 5-HT4 receptor mRNA is present at very high levels in the STN, whereas 5-HT1A and 5-HT2A receptor mRNA appears to be expressed at lower levels (Pompeiano et al. 1994).
The effects of 5-HT on membrane excitability of hippocampal and cerebral cortical neurons have been studied extensively. For instance, activation of 5-HT2, 5-HT3, or 5-HT4 receptors resulted in depolarization of membrane potential and increased neuronal excitability (Davies et al. 1987; McCormick et al. 1993; McMahon and Kauer 1997; Ropert and Guy 1991; Xiang and Prince 2003), whereas activation of 5-HT1A receptors caused hyperpolarization and decreased excitability (Andrade and Nicoll 1987; Beck et al. 1992; Davies et al. 1987; Tanaka and North 1993; Xiang and Prince 2003). The 5-HT2 or 5-HT4 receptor-mediated excitation is associated with 1) a decrease in potassium conductances (Bockaert et al. 1992; Davies et al. 1987; Zhang 2003), 2) reduction in high-voltage activated (HVA) calcium channel currents (Bayliss et al. 1997; Foehring 1996) and calcium-activated afterhyperpolarization (AHP) (Andrade and Chaput 1991; Bockaert et al. 1992; Torres et al. 1994), and 3) facilitation in hyperpolarization-activated nonselective cation current [IH or hyperpolarization-activated cyclic nucleotide-gated channels (HCN)] (Bickmeyer et al. 2002; Zhang 2003). For 5-HT2 receptor activation, evidence suggests that in some cases the excitatory responses involve the 5-HT2A receptor subtype while others are mediated by the 5-HT2C receptor (Aghajanian 1995). The excitatory responses to 5-HT3 activation, primarily found in interneurons of the cerebral cortex and hippocampus, result from an increase in a mixed cationic conductance (Kawa 1994; McMahon and Kauer 1997; Roerig and Katz 1997; Ropert and Guy 1991; Xiang and Prince 2003; Zhou and Hablitz 1999). On the other hand, neuronal hyperpolarization induced by 5-HT1A activation is due to opening of potassium channels (Andrade and Nicoll 1987; Davies et al. 1987; Xiang and Prince 2003).
Electrophysiological investigation of serotonin in STN neurons is limited to only one extracellular recording study (Flores et al. 1995), which reported an increase in firing by 5-HT. Our study was designed to analyze in detail the effect of 5-HT on firing properties of STN neurons and to determine underlying ionic mechanisms and the receptor subtypes involved.
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METHODS |
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Slice preparation
Sprague-Dawley rats (P16–P23) were deeply anesthetized with pentobarbital sodium and transcardially perfused with 
20 ml of ice-cold oxygenated (95% O2-5% CO2) "cutting solution," which was composed of (in mM) 230 sucrose, 2.5 KCl, 0.5 CaCl2, 10 MgSO4, 1.25 NaH2PO4, 26 NaHCO3, and 10 D-glucose. The brain was rapidly removed from the skull, blocked in the sagittal plane, and glued to the stage of a D.S.K. microslicer (Dosaka EM). Sagittal slices containing the STN were cut at a thickness of 300 µm in ice-cold oxygenated "cutting solution." Slices were incubated in oxygenated artificial cerebrospinal fluid (ACSF) at 32°C for 1 h and maintained at room temperature afterward until transferred to a recording chamber. The recording chamber was continuously perfused with oxygenated ACSF at 32°C. The ACSF contained (in mM) 126 NaCl, 2.5 KCl, 2 CaCl2, 2 MgSO4, 1.25 NaH2PO4, 26 NaHCO3, and 10 D-glucose. In the experiments where CdCl2 or BaCl2 was used, MgSO4 and NaH2PO4 were replaced by MgCl2 and KCl, respectively.
Electrophysiology
Whole cell, cell-attached, or perforated-patch recordings were made from visually identified STN neurons under an Olympus BX50WI upright microscope (Olympus, Lake Success, NY). A low-power objective (4x) was used to identify the STN, and a 40x water immersion objective coupled with Hoffman optics and infrared video was employed to visualize individual STN neurons. An Axopatch 1D amplifier (Axon Instruments, Union City, CA) was used for the recordings. Patch pipettes were prepared from borosilicate glass (Sutter Instruments, Novato, CA) using a Flaming-Brown micropipette puller (Model P-97, Sutter Instruments). The pipette solution contained (in mM) 106 K-MeSO4, 25 KCl, 1 MgCl2, 0.025 CaCl2, 10 HEPES, 0.1 EGTA, 2 ATP, and 0.2 GTP. The pH of the pipette solution was adjusted to 7.3 with 1 M KOH, and osmolarity was adjusted to 290–295 mOsm. For perforated-patch recordings, gramicidin was added to the pipette solution to a final concentration of 18–40 µg/ml immediately before use. When filled with the above solution, patch pipettes had resistances of 2.5–4 M
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Drug application
GABAzine (SR-95531), -methyl-5-hydroxytryptamine (-m-5-HT), and 1-(m-chlorophenyl)-biguanide (mCPBG), RS 23597-190, and cisapride were obtained from Tocris (Ballwin, MO). All the other drugs including 5-HT, ketanserin, 2,5-dimethoxy-4-iodoamphetamine (DOI), DNQX, and APV were obtained from Sigma (St. Louis, MO). They were made up as concentrated stock solutions in water or DMSO and stored at –20°C. Stocks were thawed and diluted to final concentrations in ACSF immediately before use and either bath-applied or applied through a multibarreled microperfusion pipette (inner diameter 200 µm) placed within 0.5 mm from the recorded neuron.
Statistical analysis
Statistical comparison was performed using the nonparametric Wilcoxon’s matched pairs test or Mann-Whitney U test. P value <0.05 was considered to be statistically significant. Data are presented as means ± SE.
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RESULTS |
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Perforated-patch recording technique was used to examine the effect of 5-HT on the firing frequency, firing pattern, and action potential properties of STN neurons. This and the following experiments were carried out in the presence of ionotropic glutamate receptor antagonists, DNQX (20 µM) and APV (50 µM), and GABAA receptor antagonist GABAzine (SR-95531, 10 µM) to rule out a possible presynaptic effect of 5-HT. Subthalamic neurons exhibited spontaneous, rhythmic firing in unstimulated slices. Blockade of glutamatergic and GABAergic synaptic transmission had no significant effect on the mean values of the interspike interval (ISI) and CV of ISI (158.1 ± 20.2 vs. 144.4 ± 18.8 ms for ISI before and after applying the antagonists, respectively, P = 0.08; 0.068 ± 0.004 vs. 0.068 ± 0.006 for CV of ISI, P = 0.5, n = 15). These observations suggest that a rhythmic firing of STN neurons is governed mainly by their intrinsic membrane properties and that spontaneous synaptic activity in slice preparation plays an insignificant role in the firing patterns of STN neurons. These findings are consistent with the previous experiment on firing pattern of STN neurons with ionotropic glutamate receptor antagonists by Bevan and Wilson (Bevan and Wilson 1999).
An application of 5-HT (10 µM) caused a robust increase in firing frequency, evidenced by a reduction in ISI (Fig. 1, A–C). This effect was reversed following washout of 5-HT (Fig. 1, A–C). In eight STN cells, 5-HT decreased ISI by 15–69% with a mean value of 38.5 ± 6.9% (158.6 ± 19.2 ms in control and 94.0 ± 17.6 ms after 5-HT application, P = 0.01; Fig. 1D, left). 5-HT did not alter the pattern of rhythmic firing (Fig. 1B). The ISI of STN neurons exhibited a normal distribution in controls and shifted to the left without changing its "normalness" after application of 5-HT (Fig. 1C). Quantitative analysis revealed that the CV of ISI did not change following 5-HT application (0.061 ± 0.007 in control and 0.065 ± 0.010 in 5-HT, P = 0.4, n = 8; Fig. 1D, right), suggesting that 5-HT did not modulate the firing pattern of STN neurons. A similar result of 5-HT action on firing properties of STN neurons was obtained with cell-attached recording technique, which minimized a possible influence of intracellular dialysis on neuronal firing properties (data not shown).
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; Hallworth et al. 2003) was not affected by 5-HT. 5-HT had no effect on calcium-dependent K+ channel-mediated AHP current, but directly depolarized the membrane potential
It has been reported that HVA calcium channel currents and calcium-dependent potassium currents play important roles in spontaneous rhythmic firing of STN neurons (Bevan and Wilson 1999). To determine whether 5-HT–induced increase in firing frequency of STN neurons is through its action on HVA calcium channel currents and/or calcium-dependent potassium channels, we examined the effect of 5-HT in the presence of HVA calcium channel blocker cadmium to assess if cadmium could occlude the action of 5-HT. As shown in Fig. 2, applying cadmium (600 µM) gave rise to an increase in firing frequency of STN neurons, reflected by a decrease in ISI; adding 5-HT (10 µM) to the cadmium-containing perfusate caused a further increase in firing frequency (Fig. 2, A, B, D, and E). In six STN neurons, cadmium caused a significant decrease in ISI by 12–28%, with a mean value of 22.1 ± 3.0% (141.5 ± 18.2 ms in control and 109.5 ± 13.8 ms in cadmium, P = 0.03, n = 6; Fig. 2E). Adding 5-HT (100 µM) in the presence of cadmium resulted in a further decrease in ISI by 15–69%, with a mean value of 39.0 ± 8.1% (109.5 ± 13.8 ms in cadmium and 65.2 ± 10.2 ms in 5-HT and cadmium, P = 0.03, n = 6; Fig. 2E). It should be noted that the CV of ISI increased following application of cadmium (0.074 ± 0.018 in control and 0.139 ± 0.032 in cadmium, P = 0.03, n = 6) but did not change after adding 5-HT (0.163 ± 0.034 in 5-HT and cadmium compared with 0.139 ± 0.032 in cadmium alone, P = 0.1, n = 6; Fig. 2E). These data indicate that 5-HT action in STN neurons did not involve modulation of HVA calcium channels and calcium-dependent potassium channels. It is interesting to note that applying cadmium also caused a depolarization of the interspike voltage with a decrease in amplitude of AHP (Fig. 2C), similar to the action of 5-HT (cf. Fig. 1E).
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These data indicate that the mechanisms underlying a modulation of firing properties by cadmium and 5-HT were different. That is, 5-HT–induced increase in firing frequency is due to depolarization of membrane potential, which subsequently leads to a reduction of AHP amplitude. In contrast, cadmium-induced increase in firing frequency is likely to be a direct consequence of a decrease in AHP current. We therefore could conclude that HVA calcium channel currents and calcium-dependent potassium channel-mediated AHP were not involved in the serotonergic modulation of firing frequency in STN neurons.
Decrease in potassium conductance underlies 5-HT–induced membrane potential depolarization
To determine the ionic mechanism underlying the 5-HT–induced depolarization, we conducted whole cell voltage-clamp experiments in which 1-s voltage ramp commands from –60 to –120 mV were applied every 10 s. As shown in Fig. 4A, 5-HT–induced inward current was associated with a decrease in the amplitude of current in response to the voltage ramp command, indicating a decrease in membrane conductance. To estimate the reversal potential (Er) of the 5-HT–induced conductance change, we obtained 5-HT–induced current (
I) by subtracting the current in control from the current in the present of 5-HT (I5-HT –Icontrol) and plotted it as a function of the voltage ramp command (Fig. 4B). The linear portion of the current-voltage relationship was fitted with a linear regression line (Fig. 4B). The voltage corresponding to the crossing point of the linear regression line and the voltage abscissa at I = 0 was taken as a measurement of Er (Fig. 4B). The mean value of Er for the 5-HT–induced current was –100.4 ± 4.1 mV (n = 5), which is close to the calculated K+ equilibrium potential of –104 mV. The involvement of K+ conductance in the 5-HT action was further confirmed by using K+ channel blocker barium. Similar to the 5-HT action, the application of BaCl2 (500 µM) caused an inward shift of the holding current, a reduction in membrane conductance, and a suppression of the response of STN neurons to 5-HT (Fig. 4C; n = 5). These results strongly suggest that a reduction of K+ conductance is involved in the 5-HT–induced excitation in STN neurons.
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It is well known that STN neurons express prominent IH current. To determine whether an enhancement or a change in the voltage dependence of IH activation is contributing to 5-HT–induced excitability in STN neurons, we have examined the effect of 5-HT on IH using a whole cell voltage-clamp recording technique. An application of a series of hyperpolarizing voltage steps (0.8–1.5 s) elicited voltage- and time-dependent inward currents that resembled the characteristics of IH. These responses were blocked by IH blocker ZD 7288 (50 µM; Fig. 5A). Figure 5B shows the records of hyperpolarization-activated currents in control and following application of 5-HT (10 µM). An apparent effect of 5-HT was reduction of membrane conductance. This is shown in Fig. 5C1, where current-voltage relationships for instantaneous current (Iinst) and steady-state current (Iss) were plotted. The reduction of membrane conductance was more apparent when the current differences for Iinst and Iss in control and 5-HT were plotted as a function of membrane potential (Fig. 5C2). The reversal potential of the 5-HT–induced conductance change was about –90 mV. This is consistent with the involvement of potassium conductance indicated by the ramp-voltage-clamp experiment (Fig. 4, B and C). The subtraction of the steady-state current and the instantaneous current (IH = Iss – Iinst) was taken as the measurement of IH. As showed in Fig. 5C3, 5-HT did not enhance IH at the membrane potential ranging from –50 to –140 mV. A quantitative analysis on seven STN neurons revealed that 5-HT had no significant effect on IH measured at –60, –80, or –120 mV (0.7 ± 1.7 pA in control and 0.9 ± 1.1 pA in 5-HT at –60 mV, P = 1; 11.3 ± 3.4 pA in control and 8.7 ± 1.7 pA in 5-HT at –80 mV, P = 0.3; 94.9 ± 19.6 pA in control and 83.8 ± 16.6 pA in 5-HT at –120 mV, P = 0.2).
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Effect of 5-HT on the relationship between firing frequency and level of depolarization by current injection
The effects of 5-HT on repetitive firing frequency in response to intracellular injection of depolarizing current pulses were examined in seven STN neurons. As shown in Fig. 6A, a given intensity of depolarization current injection elicited a higher frequency spike train in the presence of 5-HT (10 µM) than the control. Figure 6B shows the relationships between the firing frequencies (f; 1st ISI and average frequency) versus injected current intensities (I). The linear portion of the f-I relationship was fit with a linear regression line. As shown in Fig. 7B, the f-I relationships for both first ISI and average frequency were shifted to the left following the application of 5-HT. A slight increase in the slope of linear regression line for first ISI was observed with 5-HT application (0.529 ± 0.068 Hz/pA in 5-HT compared with 0.483 ± 0.062 Hz/pA in control, P = 0.01, n = 8), whereas the slope for the average frequency was not significantly altered (0.397 ± 0.048 Hz/pA in control and 0.424 ± 0.059 Hz/pA in 5-HT, P = 0.2, n = 8). In contrast, applying cadmium caused a very robust increase in the slope of f-I relationships for both first ISI and average frequency (0.372 ± 0.049 Hz/pA in control vs. 0.723 ± 0.040 Hz/pA in cadmium for the 1st ISI, P = 0.03, n = 6; 0.298 ± 0.029 Hz/pA in control vs. 0.606 ± 0.028 Hz/pA in cadmium for the average frequency, P = 0.03, n = 6; Fig. 6C). These results indicate that 5-HT plays a limited role in modulating input-output function of STN neurons. It also supports the conclusions that 1) different mechanisms underlie 5-HT–induced and cadmium-induced increase in firing frequency, and 2) HVA calcium channel and AHP current are not involved in the serotonergic modulation of STN neurons.
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To determine 5-HT receptor subtypes involved in modulating firing frequency in STN neurons, we examined the effects of various 5-HT receptor agonists and antagonists in STN neurons. Local application of 5-HT3 receptor agonist mCPBG (3 µM) had negligible effect on the ISI in STN neurons (198.7 ± 58.2 ms in control and 177.1 ± 36.5 ms in mCPBG, P = 0.8, n = 10). In contrast, -m-5-HT (20 µM), an agent commonly used as a 5-HT2 receptor agonist, mimicked the action of 5-HT (Fig. 7). It reduced the ISI by 34% on average (165.6 ± 19.8 vs. 109.1 ± 12.1 ms for ISI in control and -m-5-HT, respectively, P = 0.02, n = 7) with no effect on CV of ISI (0.082 ± 0.030 vs. 0.062 ± 0.011 for CV of ISI in control and -m-5-HT, P = 0.5, n = 7; Fig. 7E). The magnitude of increase in firing frequency by -m-5-HT was comparable to 5-HT–induced action (cf. Fig. 1). On the other hand, another 5-HT2 receptor agonist, DOI (10 µM), was less effective in modulating firing frequency in STN neurons (Fig. 8A). DOI reduced the ISI by 18% (129.7 ± 21.3 ms in control and 105.4 ± 16.8 ms in DOI, P = 0.02, n = 7; Fig. 8A2). Furthermore, preperfusion with 5-HT2 receptor antagonist, ketanserin (10 µM), failed to prevent the action of 5-HT (Fig. 8B). In the presence of 10 µM ketanserin, 5-HT decreased the ISI by 31% (151.8 ± 20.8 ms in ketanserin-containing ACSF as control and 101.3 ± 16.5 ms during co-application of 5-HT and ketanserin, P = 0.04, n = 5; Fig. 8B2). These data suggest that receptors other than 5-HT2 subtypes are also engaged in modulating firing in STN neurons.
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-m-5-HT has been shown to have good affinity for 5-HT4 receptor (Bockaert et al. 1992; Gerald et al. 1995), we examined the effect of a selective 5-HT4 agonist cisapride in STN neurons. As shown in Fig. 8C, application of cisapride (1 µM) decreased the ISI by 25% (178.0 ± 30.7 ms in control and 134.1 ± 27.7 ms in cisapride, P = 0.01, n = 8). To further confirm the roles of 5-HT4 and 5-HT2 receptors in serotonergic modulation of STN neurons, we examined the effects of 5-HT4 receptor antagonist RS 23597-190 together with 5-HT2 receptor antagonist ketanserin on 5-HT action. As shown in Fig. 8D1, application of RS 23597-190 (30 µM) reversed a large fraction of the 5-HT–induced decrease in ISI, and the addition of ketanserin (10 µM) completely reversed the action of 5-HT. Figure 8D2 summarizes the effects of RS 23597-190 and ketanserin on the 5-HT–induced decrease of ISI, expressed as a percentage of the control value. RS 23597-190 reversed the 5-HT action by 62% (from 51.3 ± 4.8% in 5-HT to 81.6 ± 5.5% in 5-HT and RS 23597-190, P = 0.03, n = 6), and the addition of ketanserin fully reversed the 5-HT action (from 81.6 ± 5.5% in 5-HT and RS 23597-190 to 107.2 ± 5.8% after the addition of ketanserin, P = 0.03, n = 6).
Because it has been reported that STN neurons express 5-HT2C receptor mRNA at a high level and 5-HT2A receptor mRNA at a low level (Pompeiano et al. 1994), we examined the effect of a selective 5-HT2C receptor antagonist RS 122201 (Bonhaus et al. 1993) on 5-HT–induced increase in firing frequency. As shown in Fig. 9, RS 122201 (1 µM) partially reversed the 5-HT action by 45% (from 66.2 ± 2.7% in 5-HT to 81.5 ± 1.6% in 5-HT and RS 122201, P = 0.03, n = 6). It is interesting to note that the magnitude of the antagonizing effect of RS 122201 on 5-HT action was comparable with that of keranserin (45 vs. 40%, respectively, P = 0.8), which suggested that the 5-HT2 receptor–mediated component was due to activation of 5-HT2C receptors. Taken together, the results indicated that 5-HT–induced increase in firing frequency in STN neurons was mediated by 5-HT4 and 5-HT2C receptor subtypes, with a larger fraction of action attributed to activation of 5-HT4 receptors.
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DISCUSSION |
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Ionic mechanism underlying 5-HT–induced excitation
5-HT–induced depolarization leading to an increase in neuronal excitation has been observed in various neurons in the CNS (Andrade and Nicoll 1987; Bockaert et al. 1992; Davies et al. 1987; Eriksson et al. 2001; Foehring et al. 2002; McCormick and Wang 1991; Zhang 2003). This observation indicates the importance of 5-HT in modulating neuronal excitability across different brain regions.
Several membrane conductances have been reported to be involved in serotonergic modulation of neuronal excitability. 5-HT has been shown to 1) reduce resting potassium conductance and voltage-dependent potassium conductance (Bockaert et al. 1992; Davies et al. 1987; Zhang 2003), 2) decrease amplitude of calcium-dependent potassium current-mediated AHP (Andrade and Chaput 1991; Bockaert et al. 1992; Lorenzon and Foehring 1992; Torres et al. 1994), 3) facilitate IH (McCormick and Pape 1990; Zhang 2003), and 4) inhibit HVA calcium channel currents (Bayliss et al. 1995, 1997; Foehring 1996). Data from this study provided evidence that 5-HT–induced increase in firing frequency in STN neurons was due to depolarization of membrane potential caused by a reduced potassium conductance. HVA calcium channel currents and calcium-dependent potassium currents were not involved in this action, because cadmium failed to occlude the effect of 5-HT, and 5-HT had no effect on AHP current. Although a blockade of IH did not significantly alter the basal firing in STN neurons (Bevan and Wilson 1999), in principle, an increase in IH or positive shift of the IH activation curve could increase the excitability of STN neurons. However, our voltage-clamp analysis on IH showed that 5-HT had no significant effect on IH amplitude and voltage dependence of IH activation. We therefore concluded that IH was not involved in 5-HT modulation on firing of STN neurons.
5-HT modulation of f-I relationship
5-HT application shifted the f-I relationships for both first ISI and average frequency to the left. At the same time, it increased the slopes of the linear portion of f-I relationship for the first ISI but not the average frequency. Such constancy of the f-I slopes for average frequency following 5-HT application was probably due to the insensitivity of AHP current to 5-HT. This notion was supported by the observation that cadmium, which inhibits AHP current, not only caused a shift of the f-I relationships for both first ISI and average frequency to the left but also caused a robust increase in the f-I slope for both first ISI and average frequency (Fig. 6C). The increase in the slope of f-I relationships for both first ISI and steady-state frequency following 5-HT application has been reported in neonatal hypoglossal and trigeminal motoneurons and attributed to 5-HT–induced attenuation of mAHP (Berger et al. 1992; Hsiao et al. 1997; Inoue et al. 1999). In contrast, the left-shifted f-I relationships without change in the f-I slope for the average frequency indicated that serotonergic activation only increased overall firing frequency without changing average input-output gain of STN neurons. The increase in the f-I slope for the first ISI suggested that the small changes in incoming synaptic inputs would produce large alterations in initial firing frequency of STN neurons.
Receptor subtypes involved in 5-HT–induced excitation
Among the 5-HT receptor families, 5-HT2, 5-HT3, and 5-HT4 receptors have been shown to mediate excitatory responses in the brain (Bockaert et al. 1992; Chapin et al. 2002; Davies et al. 1987; McMahon and Kauer 1997; Xiang and Prince 2003; Zhang 2003). The 5-HT2 receptor family consists of three receptor subtypes (5-HT2A, 5-HT2B, and 5-HT2C), which have similar pharmacological profiles, molecular structures, and signal transduction pathways (Barnes and Sharp 1999). The similarity of the pharmacological profiles of 5-HT2 receptor subtypes makes it difficult to characterize each subtype because of a lack of selective agonists or antagonists (Baxter et al. 1995). The 5-HT4 receptor has at least four splice variants: 5-HT4(a), 5-HT4(b), 5-HT4(c), and 5-HT4(d) (Barnes and Sharp 1999; Hoyer and Martin 1997). These splice variants display an identical pharmacological profile and show a similar ability to stimulate adenylate cyclase activity in the presence of 5-HT (Barnes and Sharp 1999; Blondel et al. 1998). 5-HT4(a) and 5-HT4(b) were previously designated as 5-HT4S and 5-HT4L for the short and long form of the receptor, respectively (Hoyer and Martin 1997). 5-HT3 receptors are the only ligand-gated ion channel receptors in the 5-HT receptor family, which are nonselectively permeable to cations such as Na+, Ca2+, and K+ (Barnes and Sharp 1999; Hoyer et al. 2002). It has been shown that mRNA that code 5-HT2 (particularly 5-HT2C) and 5-HT4 (particularly 5-HT4(a)) receptors is highly expressed in the STN (Pompeiano et al. 1994; Vilaro et al. 1996; Wright et al. 1995). However, no studies have reported the presence of 5-HT3 receptors in the STN.
In this study, we used several agonists and antagonists to determine 5-HT receptor subtypes involved in 5-HT action in STN neurons. First, we examined the effect of 5-HT3 receptor agonist mCPBG. Local application of mCPBG had no effect on firing frequency of STN neurons. It is not likely that the failure to obtain the 5-HT3 receptor–mediated action was due to a rapid desensitization of 5-HT3 receptors (Yakel and Jackson 1988; Yang et al. 1992), because the local application technique we used allowed relatively fast solution exchange. In addition, other studies have shown that even with bath application of mCPBG, 5-HT3 responses can still be induced (Koyama et al. 2000; Zhou and Hablitz 1999). Thus we concluded that the 5-HT3 receptor was not involved in 5-HT–mediated excitation in the STN.
We then examined the effect of -m-5-HT on firing of STN neurons. -m-5-HT is usually used as a 5-HT2 receptor agonist, which has higher affinity for 5-HT2B/2C receptors than for 5-HT2A receptors (Barnes and Sharp 1999; Baxter et al., 1995). In addition, -m-5-HT also shows a good affinity for 5-HT4 receptors (Gerald et al. 1995). At the concentration (20 µM) used in this study, -m-5-HT would likely to have acted on all three 5-HT2 receptor subtypes, as well as 5-HT4 receptors. We found that -m-5-HT mimicked the action of 5-HT. Quantitative analysis revealed that the magnitude of increase in firing frequency by -m-5-HT was comparable with that induced by 5-HT, suggesting that 5-HT action was mediated by 5-HT2 and/or 5-HT4 receptors. To further dissect the subtypes involved in this action, we examined the effect of DOI, a 5-HT2 receptor agonist with similar affinity for all three 5-HT2 receptor subtypes (Barnes and Sharp 1999; Baxter et al., 1995). We found that DOI was less effective than 5-HT or -m-5-HT. This observation suggested that the 5-HT action was partially mediated by 5-HT2 receptors. To substantiate this notion, we applied ketanserin, a commonly used 5-HT2 receptor antagonist with about two orders of magnitude more selective for the 5-HT2A receptors than 5-HT2B/2C receptors (Barnes and Sharp 1999; Baxter et al. 1995). At the concentration of 10 µM used in this study, it would block all three subtypes of 5-HT2 receptors. We found that preperfusion with ketanserin failed to prevent the 5-HT action. This result confirmed the idea that activation of 5-HT2 receptors could only account for a part of the 5-HT action.
To determine whether 5-HT4 receptors have also participated in the 5-HT–induced excitation, we examined the effect of a 5-HT4 receptor agonist cisapride (Briejer et al. 1993) and the effect of a 5-HT4 receptor antagonist RS 23597-190 (Eglen et al. 1993, 1995) on the 5-HT action. We found that an application of cisapride caused an increase in firing frequency. However, the action of cisapride was less effective than 5-HT or -m-5-HT. On the other hand, an application of RS 23597-190 partially antagonized the action of 5-HT, and an addition of ketanserin to the RS 23597-190–containing perfusate completely reversed the 5-HT action. These results indicated that both 5-HT2 and 5-HT4 receptors were involved in 5-HT–induced excitation in STN neurons.
Last, we also used a 5-HT2C receptor antagonist RS 102221 to determine the contribution of 5-HT2C receptor subtype in 5-HT action. We found that an application of RS 102221 partially reversed the action of 5-HT and that the magnitude of its antagonizing effect of RS 122201 was comparable with that of keranserin. These results suggested that 5-HT2 receptor–mediated component was due to the action of 5-HT2C receptors.
Based on these pharmacological experiments, we concluded that 5-HT4 and 5-HT2C receptors were involved in the excitatory action of 5-HT in STN neurons and that 5-HT4 and 5-HT2C receptor subtypes may be co-localized in a single STN neuron. Since RS 23597-190 was more effective than ketanserin or RS 122201, we further concluded that most of the 5-HT effect was mediated by 5-HT4 receptors.
5-HT2 receptor–mediated excitation has been reported in a variety of brain regions. Evidence suggests that in some of these cases the excitation is attributed to 5-HT2A receptors in the neurons in the pyriform cortex and neocortex (Araneda and Andrade 1991; Marek and Aghajanian 1994; Sheldon and Aghajanian 1991), whereas others involve 5-HT2C receptors in the neurons in the pyriform cortex, substantia nigra pars reticulate, hypothalamus, and nucleus tractus solitarius (Eriksson et al. 2001; Rick et al. 1995; Sevoz-Couche et al. 2000; Sheldon and Aghajanian 1991). As for the mechanism of the action of these receptors, the 5-HT2A receptor–mediated excitation is mainly associated with a decrease in potassium conductances (Aghajanian 1995; Zhang 2003). There are also reports suggesting that the excitatory responses to 5-HT2C receptor activation are mediated by the closing of potassium channels (Panicker et al. 1991) or by activation of Na+/Ca2+-exchange (Eriksson et al. 2001). Activation of 5-HT4 receptors has also been shown to reduce potassium conductances and to enhance membrane depolarization in CNS neurons (Bockaert et al. 1992; Fagni et al. 1992). Our results agree with the above studies concerning the reduction of potassium conductances underlying 5-HT2C and 5-HT4 receptor–mediated excitation. On the other hand, we failed to detect a 5-HT4 receptor–mediated broadening of action potentials by inhibiting a voltage-gated potassium current reported in mouse colliculi neurons (Ansanay et al. 1995). In contrast, our data indicated that 5-HT4 receptor–mediated action had no effect on repolarization of action potentials in STN neurons. It is interesting to note that an activation of 5-HT4 receptor results in an increase in IH in hippocampal neurons (Bickmeyer et al. 2002), whereas in a similar preparation, 5-HT4 receptor-mediated depolarization was shown to be independent of IH (Chapin et al. 2002). Our results showed that 5-HT did not enhance IH or change the activation curve (Fig. 5). Furthermore, in the presence of the IH blocker ZD 7288, 5-HT4 receptor agonist cisapride was still able to induce an inward current in STN neurons (data not shown). These data suggested that IH was not engaged in 5-HT4 receptor–mediated excitation in STN neurons.
In addition to 5-HT2, 5-HT4, and 5-HT3 receptors, 5-HT7 receptors were recently shown to mediate membrane potential depolarization in thalamic neurons by acting on IH (Chapin and Andrade 2001a, b). However, our preliminary study revealed that 5-HT7 receptor antagonist SB 269970 (10 µM) had no effect on 5-HT–induced increase in firing in STN neurons (data not shown), suggesting that the 5-HT7 receptor was not involved in 5-HT action in STN neurons.
In conclusion, our study showed that 5-HT, acting on 5-HT2C and 5-HT4 receptors, 1) depolarizes membrane potential due to a reduction of potassium conductance and 2) leads to an increase in firing frequency without changing firing pattern of STN neurons. STN is the only nucleus in the basal ganglia whose output neurons are excitatory and plays an important role in motor functions (DeLong 1990; DeLong et al. 1985; Matsumura et al. 1992; Wichmann et al. 1994). It is interesting to note that serotonergic neurons in the dorsal raphe nucleus have also been implicated in various aspects of motor control (Jacobs and Fornal 1993; Steinfels et al. 1983; Trulson et al. 1981). Anatomical studies have shown that the STN receives serotonergic innervations from the dorsal raphe nucleus (Bobillier et al. 1976; Lavoie and Parent 1990) and that both the STN and the dorsal raphe nucleus receive inputs from the prefrontal cortex (Kitai and Deniau 1981). We may therefore speculate that, on the cortical activation for a specific movement, a group of raphe serotonergic neurons that project to the STN might be activated in concert with STN neurons, which would amplify subthalamic activity, and in turn, facilitate the excitation in the output structures in the basal ganglia, which in turn inhibits the thalamic motor area.
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Address for reprint requests and other correspondence: Z. Xiang, Dept. of Neurosurgery, Univ. of Tennessee, Health Science Center, 847 Monroe Ave., Johnson Bldg., Rm. 427, Memphis, TN 38163 (E-mail: zxiang{at}utmem.edu)
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