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. 2023 Jul 27;15:17590914231191016. doi: 10.1177/17590914231191016

The α2 Adrenoceptor Agonist and Sedative/Anaesthetic Dexmedetomidine Excites Diverse Neuronal Types in the Ventrolateral Preoptic Area of Male Mice

Sumei Fan 1,2, Xinqi Cheng 3,✉, Pingping Zhang 2, Yuanyin Wang 4, Liecheng Wang 1,2,5,✉, Juan Cheng 2,✉
PMCID: PMC10388635  PMID: 37499170

Abstract

The unique sedative activities with rapid arousal of dexmedetomidine (Dex) are not fully understood. Growing evidence suggests the involvement of the ventrolateral preoptic area (VLPO) in sleep–wake cycle. The major type in the VLPO is sleep-active neurons, inhibited by noradrenaline (NA(−) neurons). The other type of neurons is activated by NA (NA(+) neurons), which are wake-active. Previous research showed that Dex-induced sedation and sleep homeostasis likely share common mechanisms. To explore the underlying mechanisms of Dex in the VLPO, in vivo polysomnography recording and in vitro electrophysiological recording were used in our study. Bath application of Dex (2 μM) increased the firing rate of both VLPO NA(−) and NA(+) neurons. Compared to the control group, there was no difference in the firing rate of both VLPO NA(−) and NA(+) neurons after Dex (2 μM) and RS79948 (1 mM) administration, an α2 receptor antagonist. No difference was detected regarding resting membrane potential (RMP) amplitude of both VLPO NA (−) and NA(+) neurons after application of Dex (2 μM). Moreover, Dex (2 μM) significantly reduced the frequency of miniature inhibitory postsynaptic currents (mIPSCs) in both VLPO NA(−) and NA(+) neurons. These electrophysiology results were consistent with behavioral sedation, with increased nonrapid eye movement sleep (NREM sleep) and increased expression of c-Fos in the VLPO during the dark phase after intraperitoneal injection with Dex (80 μg/kg). In conclusion, Dex activates NA(−) and NA(+) neurons in the VLPO via presynaptic α2 receptors. This mechanism may explain the unique sedative properties with rapid arousal.

Summary Statement

Dexmedetomidine is an important ICU sedative. The mechanism of dexmedetomidine is not fully understood. Activating NA(−) and NA(+) neurons in the VLPO by dexmedetomidine using polysomnography and electrophysiological recording, this may explain the unique sedative properties with rapid arousal.

Keywords: dexmedetomidine, sedation, the ventrolateral preoptic area, sleep, NA(−) neurons, NA(+) neurons

Introduction

Dexmedetomidine (Dex), an α2 adrenoceptor agonist, induces unique sedative activities with rapid arousal (Lee, 2019; Mei et al., 2021; Qiu et al., 2020; Sha et al., 2019; Wang et al., 2020; Weerink et al., 2017). The unique sedative effect of Dex is widely used in intensive care unit (ICU) sedation, and patients are arousable to communicate their needs (Mantz et al., 2011). This mechanism of rapid arousability upon Dex sedation is unclear, but the ventral tegmental (VTA) dopaminergic neurons are possibly involved (Qiu et al., 2020). It is generally believed that Dex induces sedative activities by activating presynaptic α2 receptors on noradrenaline (NA) neurons in the locus coeruleus (LC), thereby reducing NA release through a Gi-coupled mechanism (Lakhlani et al., 1997; Nelson et al., 2003). In addition, a study has shown that α2A receptors can signal via both Gi-coupled and Gs-coupled mechanisms (Proudman et al., 2022). However, sedation is a complex process involving multiple brain nuclei and circuits (Franks, 2008; Yu et al., 2018). In addition to the known LC and VTA, there may be other brain nuclei involved in the sedation process of Dex, which remains to be studied. For example, Zhang et al. suggested neurons in the mouse lateral preoptic (LPO) hypothalamic area were sufficient for Dex-induced sedation, as these neurons became active during Dex-induced sedation and reactivating them using c-Fos activity tagging produced nonrapid eye movement (NREM)-like sedation (Zhang et al., 2015). Similarly deleting the vesicular γ-aminobutyric acid (GABA) transporter gene from the LPO area abolished Dex's ability to induce immediate sedation (Zhang et al., 2015). Furthermore, within the LPO area, genetically lesioning galanin neurons substantially reduced Dex's ability to induce sedation (Ma et al., 2019).

The ventrolateral preoptic (VLPO) area is an important sleep-promoting nucleus that plays an irreplaceable role in the sleep–wake process, regulating sleep and arousal (Kim et al., 2020; Kroeger et al., 2018; Lombardi et al., 2020; Saito et al., 2018). There are two major types of VLPO neurons. The major type is sleep-active neurons, inhibited by NA (NA(−) neurons) (Cheng et al., 2020; Liang et al., 2021; Liu et al., 2010; Saito et al., 2018). On the contrary, the other type of neurons is activated by NA (NA(+) neurons) (Gallopin et al., 2000), which are wake-active (Liang et al., 2021; Liu et al., 2010). Previous studies have shown that Dex-induced sedation and sleep homeostasis likely share common mechanisms (Ma et al., 2019; Zhang et al., 2015). The sedative effects induced by dexmedetomidine resemble deep restorative sleep after sleep deprivation (Ye et al., 2019). Although the key site of hypnotic actions of Dex has been thought to be the LC, there is evidence that this is not the case, as in the case of VLPO lesioned in rats, Dex is not able to induce sedation (Nelson et al., 2003). Although the exact adrenoceptors that mediate NA hyperpolarization in the VLPO remain unknown, this is related to presynaptic α2 receptors adjacent to putative sleep-promoting VLPO neurons (Matsuo et al., 2003). However, it is unclear how Dex acts on VLPO neurons.

We hypothesized that the VLPO may be an important region regulated by Dex to induce unique sedative activities with rapid arousal. In our study, we studied the effects of Dex in the VLPO on NA(−) neurons and NA(+) neurons by using polysomnography recordings and electrophysiological approaches.

Materials and Methods

Animals

Male SPF C57BL/6J mice aged between 6 and 8 weeks were used. The mice were housed in a room kept at 22 ± 2°C with an automated 12-h dark/light (D/L) cycle (light off at 08:00 am). Water and food were available. In this study, all animal experimental procedures were approved by the Laboratory Animal Management Office of Laboratory Animals of Anhui Medical University and complied with all relevant ethical guidelines of the Institutional Animal Care Unit Committee of Anhui Medical University, with project number LLSC20190763.

Chemicals

Synaptic Systems provided a rabbit anti-c-Fos antibody (226 003, Synaptic Systems). Alexa Fluor 488-conjugated donkey anti-rabbit secondary antibodies were purchased from Jackson (711-545-152). Jiangsu Heng Rui Pharmaceutical Co. Ltd. Provided dexmedetomidine (Jiangsu, China). Noradrenaline was purchased from Acmec (69815-49-2). TOCRIS provided RS79948 (0987). Tetrodotoxin (TTX) was purchased from Bailingwei J&K (608506). CNQX was purchased from abcam (ab120017). D-AP5 was purchased from abcam (ab144482).

Polysomnographic Recordings

The mice were anesthetized with intraperitoneal pentobarbital (50 mg/kg) and electroencephalography/electromyogram (EEG/EMG) electrodes were slowly implanted on the mice skull to record polysomnographic (Huang et al., 2005). EEG and EMG electrodes were welded to a mini-connector and implanted in the skull. EEG electrodes contained two stainless steel screws, which were placed over the cortical surface through the skull and connected to the mini-connector by insulated stainless steel wires. EMG electrodes consisted of two insulated stainless steel wires. One end was connected to the mini-connector, and the other end was placed on both sides of the trapezius muscle. After a week from surgery, mice were placed in transparent barrels. The mini-connector was connected to the recording instrument by a slip ring, ensuring the free movement of mice.

Cortical EEG and EMG signals were registered with Acqknowledge (USA) as previously described (Huang et al., 2005). After the experiment, the sleep Sign software was used to automatically classify the EEG/EMG data offline. Check these manually and correct if necessary.

Drug-delivery way

Dexmedetomidine was administered by intraperitoneal injection (80 μg/kg) in a volume of 10 ml/kg with sterile saline. To assess hypnotic effects or sleepiness during the dark period, we consecutively recorded EEG/EMG signals for 48 h starting at 08:00 am. Intraperitoneal injection of sterile saline at 10:00 am was administered on the first day, as a self-control, while intraperitoneal injection of dexmedetomidine (80 μg/kg) was executed at 10:00 am on the following day.

c-Fos Immunofluorescence Labeling

We divided the mice into two groups to evaluate the effects of dexmedetomidine on VLPO. Both groups received intraperitoneal injection of saline or dexmedetomidine at 10:00 am and sacrificed for immunofluorescence staining 120 min later. After intraperitoneal anesthesia with pentobarbital (50 mg/kg), mice were first administered with normal saline, then with 4% paraformaldehyde (PFA), and finally the brains were collected and fixed in 4% paraformaldehyde for approximately 12 h. The brains were moved in a 20% sucrose solution. The brains were moved in a 30% sucrose solution when they were sunk to the bottom. When the brains were sunk to the bottom again, a freezing microtome (CM3050S, Leica, Germany) cut the brains in coronal planes about 20 μm thickness. The slices were then moved in phosphate-buffered saline (PBS). For immunofluorescence staining, the brain slices were washed 5 times with PBS, then blocked with blocking solution (1% normal BSA, 0.2% Triton X-100, and 6% donkey serum in 0.01 M PBS) for 2 h at room temperature, then washed again with PBS 5 times, and incubated with rabbit antibodies against c-Fos (1:1,000; no. 226 003, Synaptic Systems) overnight in blocking solution at 4°C. The next day, the brain slices were washed 5 times with PBS and then incubated with Alexa Fluor 488-conjugated donkey anti-rabbit secondary antibodies (1:100; 711-545-152, Jackson) in the dark for 2 h at room temperature. Again, the slices were washed 5 times with PBS and incubated with 4,6-diamidino-2-phenylindole (DAPI, 1:5,000; D8417, Sigma) at room temperature for 5 min. Finally, the brain slices were washed 5 times with PBS and placed on glass slides.

For quantification of c-Fos positive neurons, we used an Olympus slide scanner (VS120-S6-W, Olympus) with a 10x objective to capture images of the VLPO.

Preparation of Brain Slices

Male mice (6–8 weeks) were deeply anesthetized with 0.04% isoflurane and later sacrificed during the dark phase under dim red light. The brains were quickly extracted and moved in ice-cold N-methyl-D-glucamine (NMDG) cutting solution, which contained (in mM) 92 NMDG, 30 NaHCO3, 1.2 KCl, 25 D-glucose, 1.2 KH2PO4, 5 L-ascorbic acid, 20 HEPES, 2 thiourea, 3 Na-pyruvate, 0.5 CaCl2, and 1 MgSO4 (pH: 7.2 ± 0.1; osmolarity: 310 ± 5 mOsm kg−1). The solution was filled with 95% O2/5% CO2 for about 10 min, and then placed in a refrigerator to freeze into ice-cold compound prior to use. We used a vibrating microtome (VT1200 s, Leica) to cut the brains in coronal planes about 300 μm thickness at 0.18 mm s−1 and then bred in artificial cerebrospinal fluid (aCSF) bubbled with 95% O2/5% CO2 for 30–45 min at 37 °C before recording. The aCSF contained (in mM) 1.25 KCl, 125 NaCl, 1.25 KH2PO4, 25 NaHCO3, 25 D-glucose, 1 MgCl2 and 2 CaCl2 supplemented with 0.4 L-ascorbic acid and 2 Na-pyruvate. The chemicals were purchased from Sigma.

Whole-cell Patch-Clamp Recordings

The recordings were executed in oxygenated aCSF solution at room temperature. Neurons were observed by an upright microscope using a × 40 water-immersion objective (FN26.5, Olympus, Japan). Neurons in the VLPO were selected for electrophysiological evaluation. Patch pipettes (5–7 MΩ) were retrieved from borosilicate glass capillaries using a horizontal pipette puller (P-97, Sutter Instruments, USA). The recordings were obtained by using a Multiclamp 700B amplifier and analyzed with the Clampfit 10.6 software (Molecular Devices). The aCSF was flushed at a specific rate (2 ml/min).

Drugs dissolved at given concentrations in aCSF were applied locally by a pressure puff (MPS-4, China). We used puff administration when recording action potentials. The MPS-4 series multichannel rapid micro dosing system has eight separate dosing pipes, which were applied to the cells through the same dosing tip, with a tip diameter of 150 μm, and controlled by an electronic switch. The dosing power of the system is provided by gravity hydrostatic pressure. This allowed the almost instantaneous application of drugs. Dexmedetomidine (2 μM), RS79948 (1 mM), and noradrenaline (100 μM) were placed in three dosing pipes.

Synaptic Transmission

Neurons at −60 mV were used to record action potentials using the current-clamp mode. For active potentials recording, a potassium-based internal solution containing (in mM) 135 potassium gluconate, 0.1 EGTA, 10 HEPES, 10 KCl, 0.5 Na-GTP, and 5 Mg-ATP was used in patch pipettes. The pH was adjusted to 7.2 with KOH. The osmolarity was set to 310 ± 5 mOsm kg−1. Neurons at −60 mV were used to record spontaneous inhibitory postsynaptic currents (sIPSCs) and miniature inhibitory postsynaptic currents (mIPSCs) using the voltage-clamp mode (Figures 1 and 2). For sIPSCs and mIPSCs recordings (Figures 1 and 2), a high-chloride cesium-based internal solution containing (in mM) 140 CsCl, 10 HEPES, 5 Mg-ATP, 0.5 Na-GTP, and 1 EGTA was used in patch pipettes. The pH was adjusted to 7.2 with CsOH. The osmolarity was set to 310 ± 5 mOsm kg−1 with CsCl. Neurons at −35 mV were used to record mIPSCs using the voltage-clamp mode (Figure 3), a potassium-based internal solution filled in patch pipettes, which were manifested as outward currents. The bath solution plus 20 μM CNQX, 20 μM D-AP5 was used to record sIPSCs. The bath solution plus 20 μM CNQX, 20 μM D-AP5, and 400 nM TTX was used to record mIPSCs. Baseline recordings were obtained at least 5 min before drug use. Data were sampled at 20 kHz and filtered at 10 kHz.

Figure 1.

Figure 1.

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NA increases the frequency and amplitude of sIPSCs in VLPO NA(−) neurons. (A) Experimental procedure of electrophysiological experiments. We recorded sIPSCs for 18 min on a NA(−) neuron. 5–7 min of control and 10–12 min of NA (100 μM) were selected for statistical analysis. (B) Representative sIPSCs traces of a NA(−) neuron of the VLPO after NA (100 μM) perfusion. (C) Cumulative probability of inter-event interval from a NA(−) neuron. (D) Statistical results for frequency of sIPSCs after NA (100 μM) administration in VLPO NA(−) neurons (paired t test; n = 7 neurons; **p < .01). (E) Statistical results for relative frequency of sIPSCs after NA (100 μM) administration in VLPO NA(−) neurons (paired t test; n = 7 neurons; *p < .05). Error bars indicate the SEM. (F) Normalized probability of amplitude of sIPSCs from a NA(−) neuron. (G) Statistical results for amplitude of sIPSCs after NA (100 μM) administration in VLPO NA(−) neurons (paired t test; n = 7 neurons; *p < .05). (H) Statistical results for relative amplitude of sIPSCs after NA (100 μM) administration in VLPO NA(−) neurons (paired t test; n = 7 neurons; **p < .01). Error bars indicate the SEM.

Figure 2.

Figure 2.

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Dex potentiates mIPSCs of VLPO NA(-) neurons. (A) Experimental procedure of electrophysiological experiments. We recorded mIPSCs for 18 min on a NA(−) neuron. 5–7 min of control and 10–12 min of Dex (2 μM) were selected for statistical analysis. (B) Representative mIPSCs traces of a NA(−) neuron of the VLPO after Dex (2 μM) perfusion. (C) Cumulative probability of inter-event interval from a NA(−) neuron. (D) Statistical results for frequency of mIPSCs after Dex (2 μM) administration in VLPO NA(−) neurons (paired t test; n = 7 neurons; **p < .01). (E) Statistical results for relative frequency of mIPSCs after Dex (2 μM) administration in VLPO NA(−) neurons (paired t test; n = 7 neurons; **p < .01). Error bars indicate the SEM. (F) Normalized probability of amplitude of mIPSCs from a NA(−) neuron. (G) Statistical results for amplitude of mIPSCs after Dex (2 μM) administration in VLPO NA(−) neurons (paired t test; n = 7 neurons; p = .623). (H) Statistical results for relative amplitude of mIPSCs after Dex (2 μM) administration in VLPO NA(−) neurons (paired t test; n = 7 neurons; p = .459). Error bars indicate the SEM.

Figure 3.

Figure 3.

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Dex potentiates mIPSCs of VLPO NA(+) neurons. (A) Experimental procedure of electrophysiological experiments. We recorded mIPSCs for 18 min on a NA(+) neuron. 5–7 min of control and 10–12 min of Dex (2 μM) were selected for statistical analysis. (B) Representative mIPSCs traces of a NA(+) neuron of the VLPO after Dex (2 μM) perfusion. (C) Cumulative probability of inter-event interval from a NA(+) neuron. (D) Statistical results for frequency of mIPSCs after Dex (2 μM) administration in VLPO NA(+) neurons (paired t test; n = 8 neurons; *p < .05). (E) Statistical results for relative frequency of mIPSCs after Dex (2 μM) administration in VLPO NA(+) neurons (paired t test; n = 8 neurons; ****p < .0001). Error bars indicate the SEM. (F) Normalized probability of amplitude of mIPSCs from a NA(+) neuron. (G) Statistical results for amplitude of mIPSCs after Dex (2 μM) administration in VLPO NA(+) neurons (paired t test; n = 8 neurons; p = .565). (H) Statistical results for relative amplitude of mIPSCs after Dex (2 μM) administration in VLPO NA(+) neurons (paired t test; n = 8 neurons; p = .767). Error bars indicate the SEM.

Statistical Analysis

p values were computed using paired and unpaired t tests. ANOVA followed by Bonferroni correction was used to calculate p values with multiple conditions. All of the data are represented as mean ± standard error of the mean (SEM). p < .05 was considered to be statistically significant. All data were analyzed with GraphPad Prism 7.0. The data obtained from whole-cell recordings were analyzed using Clampfit software v.10.6 and Igor Pro 6.37.

Results

Dexmedetomidine Decreases Wakefulness and Increases NREM Sleep

A set of representative EEG-EMG recording traces and hypnograms at 8 h after saline or Dex (80 μg/kg) administration were displayed in Supplemental Figure S1A. Mice treated with Dex fell asleep and experienced more NREM sleep than the self-control. As displayed in Supplemental Figure S1B, the time spent in each stage revealed that Dex increased NREM sleep (F(23, 138) = 10.93, p < .0001) in the first 4 h after administration. The changes during NREM sleep agreed with a reduction in wakefulness (F(23, 138) = 12.14, p < .0001) compared with the self-controls. Dex increased the NREM sleep (t(2, 6) = 8.11, p = .0002), reduced rapid eye movement sleep (REM sleep) by 96% (t(2, 6) = 3.66, p = .0106), and reduced the wakefulness by 67% (t(2, 6) = 7.09, p = .0004), compared with the self-controls in each group (Supplemental Figure S1C).

Furthermore, Dex reduced the episodes of REM sleep (t(2, 12) = 2.61, p = .005; Supplemental Figure S2A). However, the duration of NREM sleep augmented by 78% (t(2, 12) = 3.48, p = .023; Supplemental Figure S2B), with a consensual 73% reduction in wakefulness (t(2, 12) = 3.86, p = .002; Supplemental Figure S2B). In addition, Dex increased the state transitions from NREM sleep to wakefulness (t(2, 12) = 3.07, p = .010; Supplemental Figure S2C) and the bouts of NREM sleep with durations of 32–64 (t(2, 12) = 3.73, p = .003; Supplemental Figure S2D) and > 2048s (t(2, 12) = 6, p < .0001; Supplemental Figure S2D). At the same time, Dex especially decreased the bouts of wakefulness with durations of > 2048s (t(2, 12) = 4.08, p = .002; Supplemental Figure S2D). Compared with the self-controls, Dex increased the delta power of approximately 1.31-fold (t(2, 4) = 3.50, p = .025; Supplemental Figure S2E). These findings indicated that Dex extended the overall duration of NREM sleep and augmented the depth of sleep.

Effects of Dex on c-Fos Expression

The number of c-Fos-positive neurons during the dark phase in the VLPO and LPO was counted after saline or Dex treatment. Dex (80 μg/kg) was administered at 10:00 am, when mice were awake and active. As shown in Figure 4(A), Dex significantly augmented the expression of c-Fos in the VLPO and LPO compared to the saline control. Analysis showed that Dex increased the c-Fos-immunoreactive nuclei in the VLPO by approximately 4.14-fold (t(2, 4) = 3.21, p = .033; Figure 4(B)) and in the LPO by approximately 2.17-fold (t(2, 4) = 3.55, p = .024; Figure 4(C)).

Figure 4.

Figure 4.

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VLPO and LPO neurons are positive to c-Fos during the dark phase following treatment with Dex. (A) Sample photomicrographs describing the expression of c-Fos in the VLPO and LPO following saline or Dex. (B) Quantification of c-Fos-positive neurons in the VLPO at 120 min, following treatment with saline or Dex (80 μg/kg). Error bars indicate the SEM. Unpaired t test: *p < .05; n = 3 mice. (C) Quantification of c-Fos-positive neurons in the LPO at 120 min, following treatment with saline or Dex (80 μg/kg). Error bars indicate the SEM. Unpaired t test: *p < .05; n = 3 mice.

Dexmedetomidine Excites VLPO NA(-) Neurons via α2 Receptors

We identified two mayor types of VLPO neurons to be given Dex. The majority were NA(−) neurons with triangular and multipolar shapes (Figure 5A) and were inhibited by NA (100 μM, for 15 s) (Figure 5B). Conversely, the minority were NA(+) neurons with fusiform and bipolar shapes (Figure 6A) and were excited by NA (100 μM, for 15 s) (Figure 6B).

Figure 5.

Figure 5.

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Dexmedetomidine excites NA(−) neurons in the VLPO. (A) A triangular VLPO neuron with a whole-cell recording electrode in place. Scale bar: 100 μm. (B) Hyperpolarization induced by a brief (15 s) puff application of NA (100 μM). (C) Experimental procedure of electrophysiological experiments. We recorded action potentials for 570 s on a NA(−) neuron. 305–315 s of control and 320–330 s of Dex/(Dex + RS79948) (Dex (2 μM) and RS79948 (1 mM)) were selected for statistical analysis. (D) Sample traces of action potential of a NA(−) neuron in the VLPO after Dex (2 μM) perfusion. (E) Statistical results for firing rate after Dex (2 μM) administration in VLPO NA(−) neurons (paired t test; n = 7 neurons; **p < .01). (F) Statistical results for relative firing rate after Dex (2 μM) administration in VLPO NA(−) neurons (paired t test; n = 6 neurons; *p < .05). Error bars indicate the SEM. (G) Representation traces of action potential of a NA(−) neuron in the VLPO after Dex (2 μM) and RS79948 (1 mM) perfusion. (H) Statistical results for firing rate after Dex (2 μM) and RS79948 (1 mM) administration in VLPO NA(−) neurons (paired t test; n = 7 neurons; p = .396). (I) Statistical results for relative firing rate after Dex (2 μM) and RS79948 (1 mM) administration in VLPO NA(-) neurons (paired t test; n = 6 neurons; p = .752). Error bars indicate the SEM.

Figure 6.

Figure 6.

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Dexmedetomidine increases the excitability of NA(+) neurons in the VLPO. (A) A typical bipolar VLPO neuron displays a fusiform aspect. Scale bar: 100 μm. (B) Depolarization induced by a brief (15 s) puff application of NA (100 μM). (C) Experimental procedure of electrophysiological experiments. We recorded action potentials for 570 s on a NA(+) neuron. 305–315 s of control and 320–330 s of Dex/(Dex + RS79948) (Dex (2 μM) and RS79948 (1 mM)) were selected for statistical analysis. (D) Sample traces of action potential of a NA(+) neuron in the VLPO after Dex (2 μM) perfusion. (E) Statistical results for firing rate after Dex (2 μM) administration in VLPO NA(+) neurons (paired t test; n = 7 neurons; **p < .01). (F) Statistical results for relative firing rate after Dex (2 μM) administration in VLPO NA(+) neurons (paired t test; n = 7 neurons; **p < .01). Error bars indicate the SEM. (G) Representation traces of action potential of a NA(+) neuron in the VLPO after Dex (2 μM) and RS79948 (1 mM) perfusion. (H) Statistical results for firing rate after Dex (2 μM) and RS79948 (1 mM) administration in VLPO NA(+) neurons (paired t test; n = 6 neurons; p = .358). (I) Statistical results for relative firing rate after Dex (2 μM) and RS79948 (1 mM) administration in VLPO NA(+) neurons (paired t test; n = 6 neurons; p = .972). Error bars indicate the SEM.

We used the current clamp to investigate the activities of Dex on the spontaneous firing of VLPO NA(−) neurons (Figure 5C). Whole-cell recordings indicated a significant increase in the action potentials firing rate of VLPO NA(−) neurons after Dex (2 μM) perfusion (Figure 5D). Dex (2 μM) transiently augmented the firing rate of VLPO NA(−) neurons from 1.60 ± 0.45 to 2.30 ± 0.56 Hz (p = .007; n = 7 neurons; Figure 5E), which was corresponding to 151.40 ± 13.24% of the control level (p = .012; n = 6 neurons; Figure 5F). In addition, we investigated the receptor through which Dex excites the NA(-) neurons of the VLPO, as shown in Figure 5G.To block the effect of Dex activation of VLPO NA(−) neurons, a selective α2 receptors antagonist (RS79948) was used. Compared to the control group, there was no difference in the firing rate of VLPO NA(−) neurons after Dex (2 μM) and RS79948 (1 mM) administration (control: 0.62 ± 0.16 Hz and Dex + RS79948: 0.73 ± 0.18 Hz, p = .396; n = 7 neurons; Figure 5H), corresponding to 107.50 ± 22.53% of the control level (p = .752; n = 6 neurons; Figure 5I). No difference was detected regarding resting membrane potential (RMP) amplitude of VLPO NA (−) neurons after application of Dex (2 μM) (n = 4 neurons; Supplemental Figure S3). Our results indicate that Dex excites VLPO NA(−) neurons which is via α2 receptors.

Dexmedetomidine Increases the Excitability of NA(+) Neurons in the VLPO via α2 Receptors

We explored the role of Dex in NA(+) neurons in the VLPO firing using electrophysiological techniques, as depicted in Figure 6C. Whole-cell recordings indicated a significant increase in the action potentials firing rate of VLPO NA(+) neurons after Dex (2 μM) perfusion (Figure 6D). Statistical analysis showed that Dex (2 μM) significantly augmented the firing rate of VLPO NA(+) neurons from 3.65 ± 0.91 to 5.63 ± 1.12 Hz (p = .005; n = 7 neurons; Figure 6E), which was corresponding to 167.10 ± 18.08% of the control level (p = .010; n = 7 neurons; Figure 6F). We further evaluated the receptor through which Dex increases the excitability of the NA(+) neurons in the VLPO, as shown in Figure 6G. Compared to the control group, there was no difference in the firing rate of VLPO NA(+) neurons after Dex (2 μM) and RS79948 (1 mM) administration (control: 4.81 ± 1.26 Hz and Dex + RS79948: 5.03 ± 1.45 Hz, p = .358; n = 6 neurons; Figure 6H), corresponding to 100.50 ± 5.08% of the control level (p = .927; n = 6 neurons; Figure 6I). No difference was detected regarding RMP amplitude of VLPO NA(+) neurons after application of Dex (2 μM) (n = 6 neurons; Supplemental Figure S4). These data suggest that Dexmedetomidine increases the excitability of NA(+) neurons in the VLPO via α2 receptors.

NA Increases the Frequency and Amplitude of sIPSCs of NA(−) Neurons in the VLPO

Previous reports (Liang et al., 2021) have suggested that NA inhibited multipolar neurons (low-threshold spike (LTS) cells) and the perfusion of NA also increased the frequency and amplitude of sIPSCs in VLPO LTS cells. This is consistent with previous studies showing that NA administration inhibits NA(−) neurons. Thus, these provide a new method for identifying the characteristics of VLPO NA(-) neurons in the voltage-clamp mode. We applied NA in voltage-clamp mode to identify the type of VLPO neurons, as depicted in Figure 1(A). Figure 1(B) showed the effect of NA (100 μM) on VLPO NA(−) neurons. In the cumulative probability plot, NA (100 μM) shifts the distribution of the inter-event interval to the left (Figure 1C). The statistical results showed that the frequency of sIPSCs after NA (100 μM) administration was significantly increased than that from the control group (control: 2.20 ± 0.65 Hz and NA: 3.21 ± 0.73 Hz, p = .006; n = 7 neurons; Figure 1D), accompanied by 176.40 ± 25.03% of the control level (p = .023; n = 7 neurons; Figure 1E). At the same time, in the normalized probability plot, the amplitude distribution of sIPSCs between the control and NA (100 μM) was different (Figure 1F). There was a statistically significant increase in the amplitude of sIPSCs after NA (100 μM) administration compared to the control group (control: 76.33 ± 32.68 pA and NA: 105.20 ± 43.11 pA, p = .046; n = 7 neurons; Figure 1G), which was corresponding to 140.10 ± 10.64% of the control level (p = .009; n = 7 neurons; Figure 1H).

Dex Reduces mIPSCs of VLPO NA(−) Neurons

To check whether the receptor of Dex acting on VLPO NA(−) neurons is located presynaptic or postsynaptic, we perfused TTX (0.4 μM) in the aCSF to eliminate spontaneous action potentials during voltage-clamp recording of postsynaptic currents, and CNQX (20 μM) and D-AP5 (20 μM) to block glutamate receptors, as shown in Figure 2A. The effect of Dex (2 μM) on VLPO NA(−) neurons was shown in Figure 2B. In the cumulative probability plot, Dex (2 μM) caused the distribution of the inter-event interval to shift to the right (Figure 2C). The statistical analysis showed that the frequency of mIPSCs after Dex (2 μM) application was significantly lower than that from the control group (control: 1.98 ± 0.46 Hz and Dex: 1.57 ± 0.38 Hz, p = .010; n = 7 neurons; Figure 2D), corresponding to 78.07 ± 4.28% of the control level (p = .002; n = 7 neurons; Figure 2E). Meanwhile, in the normalized probability plot, no difference in the amplitude distribution of mIPSCs between the control and Dex (2 μM) was observed (Figure 2F). The statistical results showed that the amplitude of mIPSCs after Dex (2 μM) perfusion was the same as that from the control group (control: 42.89 ± 4.06 pA and Dex: 41.67 ± 5.69 pA, p = .623; n = 7 neurons; Figure 2G), accompanied by 94.71 ± 6.69% of the control level (p = .459; n = 7 neurons; Figure 2H). Therefore, our results reveal that Dex excites the NA(−) neurons of the VLPO through presynaptic mechanisms.

Dex Reduces mIPSCs of VLPO NA(+) Neurons

We identified NA(+) neurons in the VLPO with the same method as in Figure 6(A) and (B). To check whether the receptor of Dex acting on VLPO NA(+) neurons is located presynaptic or postsynaptic, we perfused TTX (0.4 μM) in the aCSF to eliminate spontaneous action potentials during voltage-clamp recording of postsynaptic currents, as shown in Figure 3(A). The effect of Dex (2 μM) on VLPO NA(+) neurons was shown in Figure 3(B). In the cumulative probability plot, Dex (2 μM) caused the distribution of the inter-event interval to shift to the right (Figure 3C). The statistical analysis showed that the frequency of mIPSCs after Dex (2 μM) application was significantly lower than that from the control group (control: 0.15 ± 0.04 Hz and Dex: 0.03 ± 0.01 Hz, p = .010; n = 8 neurons; Figure 3D), corresponding to 26.79 ± 6.93% of the control level (p < .0001; n = 8 neurons; Figure 3E). Meanwhile, in the normalized probability plot, no difference in the amplitude distribution of mIPSCs between the control and Dex (2 μM) was observed (Figure 3F). The statistical results showed that the amplitude of mIPSCs after Dex (2 μM) perfusion was the same as that from the control group (control: 10.94 ± 1.18 pA and Dex: 9.61 ± 1.69 pA, p = .565; n = 8 neurons; Figure 3G), accompanied by 95.31 ± 15.25% of the control level (p = .767; n = 8 neurons; Figure 3H). Therefore, our results reveal that Dex excites the NA(+) neurons of the VLPO through presynaptic mechanisms.

Discussion

This study aimed to explore the mechanism underlying sedation with rapid arousal of Dex using polysomnography recording, immunofluorescent staining, and whole-cell patch clamp. Our findings showed that Dex extended the overall duration of NREM sleep and augmented the depth of sleep and increased the c-Fos-immunoreactive nuclei in the VLPO. Patch-clamp recording results indicated that Dex excited both VLPO NA(−) and NA(+) neurons via presynaptic α2 receptors.

VLPO is located in zona rostral caudalis hypothalamus, which innervated with arousal-associated nucleus, such as the tuberomammillary nucleus (TMN) in the caudal hypothalamus (Cheng et al., 2020). The presence of θ-δ coupling indicates that VLPO might be involved in both sleep and arousal (Lombardi et al., 2020). The relationship between anesthetics and sleep is increasingly studied. Dex is an important drug in clinical anesthesia and ICU sedation, it has its anesthesia characteristics (sedation with rapid arousal) and Dex-induced sedation and sleep homeostasis may share a common mechanism (Gallopin et al., 2000). In our study, we found that Dex increased NREM sleep in the first 4 h after administration and increased the c-Fos-immunoreactive nuclei in the VLPO by approximately 4.14-fold. However, Dex increased the state transitions from NREM sleep to wakefulness. These results may explain the unique sedative properties with rapid arousal.

The VLPO is involved in maintaining natural sleep, and two-thirds of the VLPO is comprised of NA(−) neurons, which are believed to be sleep-promoting. The majority of NA(−) neurons release GABA, some also release galanin (Huang et al., 2005). Previous studies have shown that Dex-induced sedation and sleep homeostasis likely share common mechanisms (Ma et al., 2019; Zhang et al., 2015). The sedative effects induced by Dex resemble deep restorative sleep after sleep deprivation (Ye et al., 2019). In addition, a study has shown that α2A receptors can signal via both Gi-coupled and Gs-coupled mechanisms (Proudman et al., 2022). In this study, Dex increased NREM sleep in the first 4 h after administration and transiently augmented the firing rate of VLPO NA(-) neurons from 1.60 ± 0.45 to 2.30 ± 0.56 Hz, which might be the sedative effect of Dex. Compared to the control group, there was no difference in the firing rate of VLPO NA(−) neurons after Dex and RS79948 administration, indicating that α2 receptors mediated the effects of Dex. In addition, the statistical analysis showed that the frequency of mIPSCs after Dex application was significantly lower than that from the control group, suggesting a Dex-induced excitation effect through presynaptic mechanisms in NA(−) neurons. Study has shown that activating NAergic LC-VLPO pathways promotes arousal through inhibiting NA(−) neurons via α2A receptors (Liang et al., 2021). The lateral hypothalamus contains abundant α1, α2, and β adrenergic receptors (Burnham et al., 2021). Studies have shown that acutely activated wake-promoting GABAergic neurons in the lateral hypothalamus, the galaninergic neurons in the VLPO are inhibited, resulting in arousal (Arrigoni and Fuller, 2022; Venner et al., 2016, 2019). Moreover, previous evidences have verified that presynaptic α2 receptors can modulate the release of GABA (Wang et al., 1998). No difference was detected regarding RMP amplitude after the application of Dex (2 μM) alone. These results reveal that Dex excites the NA(−) neurons of the VLPO via presynaptic α2 receptors probably through a Gi-coupled mechanism, which may induce sedation.

The rapid arousal function of Dex is widely used to awaken patients for communicating their needs (Mantz et al., 2011). The low percentage of NA(+) neurons exhibited higher activity during wakefulness in vivo (Liang et al., 2021). Although the VLPO is believed to be a sleep-promoting brain region, Dex injection into the VLPO directly causes behavioral arousal and increases movement (McCarren et al., 2014), strongly implicating VLPO signaling in the modulation of the arousal state. In addition, a study has shown that α2A receptors can signal via both Gi-coupled and Gs-coupled mechanisms (Proudman et al., 2022). Statistical analysis showed that Dex significantly augmented the firing rate of VLPO NA(+) neurons from 3.65 ± 0.91 to 5.63 ± 1.12 Hz. And our results showed that Dex increased the state transitions from NREM sleep to wakefulness, which indicated that the VLPO NA(+) neurons may mediate rapid arousal during Dex sedation Compared to the control group, there was no difference in the firing rate of VLPO NA(+) neurons after Dex and RS79948 administration, which indicated that α2 receptors mediate the effects of Dex on the action potentials of VLPO NA(+) neurons. In addition, the statistical analysis showed that the frequency of mIPSCs after Dex application was significantly lower than that from the control group, suggesting a Dex-induced excitation effect through presynaptic mechanisms in NA(+) neurons. Previous evidences have verified that presynaptic α2 receptors of the supraoptic neurons can modulate the release of GABA (Wang et al., 1998). No difference was detected regarding RMP amplitude after the application of Dex (2 μM) alone. These results reveal that Dex excites the NA(+) neurons of the VLPO via presynaptic α2 receptors probably through a Gi-coupled mechanism, which may induce rapid arousal.

Many studies have shown that there may be some differences in sleep between the sexes. Boys had shorter time awake after sleep onset than girls on Friday nights. Boys fell asleep later on Friday and Saturday nights. Boys had longer sleep latency, and worse sleep efficiency than girls on Saturday nights (Hrozanova et al., 2023). In exploring the effects of pituitary adenylate cyclase-activating polypeptide (PACAP) and corticotropin-releasing factor (CRF) on sleep structure, the researchers found that at baseline, male mice spent more time in NREM sleep and less time in wake than female mice (Foilb et al., 2023). Only male mice were used in our experiment. The experiments with female mice will be done and compare with the experiments with male mice.

In summary, Dex activates NA(−) and NA(+) neurons in the VLPO via presynaptic α2 receptors. This mechanism may explain the unique sedative properties with rapid arousal.

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Abbreviations

Dex

dexmedetomidine

VLPO

Ventrolateral preoptic area

LPO

Lateral preoptic area

RMP

Resting membrane potential

NA

Noradrenalin

mIPSCs

Miniature inhibitory postsynaptic currents

NREM

sleep Nonrapid eye movement sleep

ICU

Intensive care unit

VTA

Ventral tegmental

LC

Locus coeruleus

EEG/EMG

Electroencephalography/electromyogram

PFA

Paraformaldehyde

PBS

Phosphate-buffered saline

DAPI

4,6-diamidino-2-phenylindole

NMDG

N-methyl-D-glucamine

aCSF

Artificial cerebrospinal fluid

sIPSCs

Spontaneous inhibitory postsynaptic currents

TTX

Tetrodotoxin

GABA

γ-aminobutyric acid

SEM

Standard error of the mean

REM

sleep Rapid eye movement sleep

LTS

Low-threshold spike

TMN

Tuberomammillary nucleus

PACAP

Pituitary adenylate cyclase-activating polypeptide

CRF

Corticotropin-releasing factor

Footnotes

The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding: The authors disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This work was supported by the National Natural Science Foundation of China, Scientific Research Platform and Base Upgrading Plan of Anhui Medical University, National College Students Innovation and Entrepreneurship Training Program, Natural Science Foundation of Universities of Anhui Province, Postgraduate Innovation Research and Practice Program of Anhui Medical University (grant number 31800997, 81971236, 81571293, 2021xkjT048, S202110366009, 2022AH050783, kj2021A0278, YJS20230035).

Supplemental Material: Supplemental material for this article is available online.

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sj-tif-3-asn-10.1177_17590914231191016 - Supplemental material for The α2 Adrenoceptor Agonist and Sedative/Anaesthetic Dexmedetomidine Excites Diverse Neuronal Types in the Ventrolateral Preoptic Area of Male Mice
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Supplemental material, sj-tif-3-asn-10.1177_17590914231191016 for The α2 Adrenoceptor Agonist and Sedative/Anaesthetic Dexmedetomidine Excites Diverse Neuronal Types in the Ventrolateral Preoptic Area of Male Mice by Sumei Fan, Xinqi Cheng, Pingping Zhang, Yuanyin Wang, Liecheng Wang and Juan Cheng in ASN Neuro

sj-tif-4-asn-10.1177_17590914231191016 - Supplemental material for The α2 Adrenoceptor Agonist and Sedative/Anaesthetic Dexmedetomidine Excites Diverse Neuronal Types in the Ventrolateral Preoptic Area of Male Mice
Click here for additional data file. (1,008KB, tif)

Supplemental material, sj-tif-4-asn-10.1177_17590914231191016 for The α2 Adrenoceptor Agonist and Sedative/Anaesthetic Dexmedetomidine Excites Diverse Neuronal Types in the Ventrolateral Preoptic Area of Male Mice by Sumei Fan, Xinqi Cheng, Pingping Zhang, Yuanyin Wang, Liecheng Wang and Juan Cheng in ASN Neuro

sj-tif-5-asn-10.1177_17590914231191016 - Supplemental material for The α2 Adrenoceptor Agonist and Sedative/Anaesthetic Dexmedetomidine Excites Diverse Neuronal Types in the Ventrolateral Preoptic Area of Male Mice
Click here for additional data file. (1,008KB, tif)

Supplemental material, sj-tif-5-asn-10.1177_17590914231191016 for The α2 Adrenoceptor Agonist and Sedative/Anaesthetic Dexmedetomidine Excites Diverse Neuronal Types in the Ventrolateral Preoptic Area of Male Mice by Sumei Fan, Xinqi Cheng, Pingping Zhang, Yuanyin Wang, Liecheng Wang and Juan Cheng in ASN Neuro

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