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Sitnikova, E.;  Rutskova, E.;  Smirnov, K. Alpha2 Adrenoreceptors in Relation to Spike-wave Epileptic Activity. Encyclopedia. Available online: https://encyclopedia.pub/entry/40672 (accessed on 20 November 2024).
Sitnikova E,  Rutskova E,  Smirnov K. Alpha2 Adrenoreceptors in Relation to Spike-wave Epileptic Activity. Encyclopedia. Available at: https://encyclopedia.pub/entry/40672. Accessed November 20, 2024.
Sitnikova, Evgenia, Elizaveta Rutskova, Kirill Smirnov. "Alpha2 Adrenoreceptors in Relation to Spike-wave Epileptic Activity" Encyclopedia, https://encyclopedia.pub/entry/40672 (accessed November 20, 2024).
Sitnikova, E.,  Rutskova, E., & Smirnov, K. (2023, January 31). Alpha2 Adrenoreceptors in Relation to Spike-wave Epileptic Activity. In Encyclopedia. https://encyclopedia.pub/entry/40672
Sitnikova, Evgenia, et al. "Alpha2 Adrenoreceptors in Relation to Spike-wave Epileptic Activity." Encyclopedia. Web. 31 January, 2023.
Alpha2 Adrenoreceptors in Relation to Spike-wave Epileptic Activity
Edit
This entry is adapted from the peer-reviewed paper 10.3390/ijms24021477

Spike-wave discharges are the hallmark of idiopathic generalized epilepsy. They are caused by a disorder in the thalamocortical network. Commercially available anti-epileptic drugs have pronounced side effects (i.e., sedation and gastroenterological concerns), which might result from a low selectivity to molecular targets. We suggest a specific subtype of adrenergic receptors (ARs) as a promising anti-epileptic molecular target. The influence of alpha2 ARs is mainly carried out through Gi/o-proteins although coupling to Gs was also demonstrated. Thus, activation of alpha2 ARs can either inhibit or stimulate different intracellular pathways. Numerous neuronal proteins interacting directly or indirectly with alpha2 ARs have been described. Here we describe some mechanisms of noradrenergic modulation of spike-wave activity via ion channels and integral membrane proteins.

absence epilepsy spike-wave discharges adrenergic receptors alpha2 adrenergic receptors

1. Noradrenergic Regulation of Spike-Wave Activity

To date, a large amount of data has been accumulated on the noradrenergic modulation of spike-wave activity (e.g., [1][2][3][4]). Cortico-thalamo-cortical neural circuitry is known to receive dense innervations from noradrenergic neurons [5][6][7]. Nevertheless, existing anti-absence drugs do not directly affect noradrenaline-related mechanisms or molecular targets of noradrenaline (NA). Mechanisms of noradrenergic regulation of arousal level may play a significant role in the generation of SWDs. By participating in state transitions, the NA system sets favorable conditions at molecular, cellular, and network levels for the appearance of pathological spike-wave activity. We suppose that by separating a contribution of the noradrenergic system into sleep-wake cycling and its modulation of spike-wave activity, novel, more selective pharmacological targets could be identified.

In naturally falling asleep, the NA level gradually decreases [8] and the predominantly alpha1- and beta-AR-mediated excitatory effect of NA switches to an alpha2-mediated inhibitory effect. This state is favorable for triggering spike-wave activity [9][10] (the upper part in Figure 1) Natural awakening provides an almost instant turn to arousal with a very low probability of SWDs occurring [9][11]. Injections of alpha2 ARs agonists might cause an unnaturally rapid increase in activation of alpha2 ARs leading to an artificial predominance of alpha2-mediated effect over the effect of other ARs subtypes (the bottom part of Figure 1). The emergence from sedation is again an extended transition favorable for spike-wave discharges (SWDs) to occur. Future studies of pharmacologically induced absence status epilepticus are required to examine the dose-dependent effects of alpha2 ARs agonists on SWDs. Another intriguing issue regarding the role of each ARs subtypes in the modulation of spike-wave activity and arousal level.

Ijms 24 01477 g002 550
Figure 1. The schema demonstrating adrenergic mechanisms of sleep modulation and spike-wave discharge (SWD) modulation. The upper plot demonstrates the natural drug-free state. The bottom plot—pharmacologically induced condition after administration of agonist of alpha2 adrenoreceptors. Noradrenaline affects alpha1, alpha2 and beta-receptors, and NA concentration during sleep/sedation is lower (blue area) than during wakefulness (rose area). Transient states between wake and sleep/sedation are favorable for SWD to occur.

The influence of alpha2 ARs is mainly carried out through Gi/o-proteins although coupling to Gs was also demonstrated [12]. Thus, activation of alpha2 ARs can either inhibit or stimulate various intracellular pathways. Numerous neuronal proteins interacting directly or indirectly with alpha2 ARs have been described. Here we focus on phenomena related to spike-wave activity, such as interaction with ionic channels.

2. Alpha2-Adrenoreceptors and HCN Channels

HCN channels control neuron excitability and participate in the stabilization of resting potential [13]. Due to their unique ability to open during hyperpolarization creating an inward current named Ih, activation of HCN channels may depolarize the neuron enough to initiate rebound bursting, a form of spiking activity crucial for spike-wave discharges [14]. There are four HCN isoforms (HCN1–4). HCN1 isoform is mainly expressed in the cerebral cortex, and HCN2 is mostly in the thalamus but also in the cortex, and HCN4 in the thalamus (with the exception of the reticular nucleus) but not in the cortex. HCN3 is expressed at a low level in both structures and thus will not be analyzed further [14][15][16][17]. HCN2 channels activate slower and at more negative voltages and have an increased sensitivity to cAMP modulation than HCN1 [18][19]. An increase in cAMP leads to a more pronounced shift in the activation of HCN2 channels into the depolarized direction, which leads to the elimination of differences in the degree of hyperpolarization needed to activate both isoforms. HCN4 has the slowest kinetics and is strongly modulated by cAMP [20][21]. Melis Yavuz and Filiz Onat in 2018 published a comprehensive review about the role of HCN channels in the pathophysiology of absence epilepsy (also in rat models), where they emphasized the involvement of the second messenger system in modulating HCN channels [22].
In different models of absence epilepsy and under different registration conditions, sometimes opposite changes in the HCN channels were found [23][24][25]. However, it can be concluded that blocking the Ih current in the cortex leads to an increase in the excitability of neurons [26]. This effect is based on enhanced temporal summation of the distal dendritic excitatory postsynaptic potentials, which can participate in SWDs generation [27][28]. Conversely, blocking the Ih current in the thalamus suppresses burst firing and SWDs [29]. HCN channels have an increasing distal expression gradient on dendrites (that is, the farther away from the soma, the denser) [30], thus they provide signal filtering by weakening the contribution of remote excitatory postsynaptic potentials, EPSPs [31].
The interaction of alpha2 ARs and HCN channels was studied in the context of epileptogensis [31][32] and pain relief [33]. It has been shown that activation of postsynaptic alpha2 ARs blocks Ih current, which increases input resistance and enhances temporal summation during trains of distally evoked EPSPs making a cell more excitable [34]. Whether this mechanism is sufficient to aggravate spike-wave activity is yet to be investigated. Studies of the combined effects of the local application of substances acting on alpha2 ARs and HCN channels may clarify the role of their interaction in the spike-wave initiating site in the somatosensory cortex.
If alpha2 AR agonists inhibit HCN, then injection of alpha2 AR agonists into the thalamus should have an anti-absence effect, because blockage of the Ih current in thalamic neurons suppresses SWDs [18]. This contradicts the results of Buzsáki et al. (1991) [2]. Therefore, the effect of alpha2 AR agonists on Ih current may differ in the thalamus and in the cortex [26]. Differences in the molecular cascades triggered by the activation of alpha2 AR subtypes are mostly studied in cell expression systems and need to be proved in vivo. Nevertheless, activation of the alpha2B subtype, predominantly expressed in the thalamus, may have a stimulatory effect on cAMP synthesis in contrast to the inhibitory action of alpha2A ARs [35]. Selective coupling of alpha 2-adrenergic receptor subtypes to cyclic AMP-dependent reporter gene expression in transiently transfected JEG-3 cells.
There is contradictory data on whether alpha2 AR agonists affect HCN channels through the modulation of cAMP synthesis or other pathways such as activation of protein kinase C [4] or even by direct binding in an alpha2 AR-independent manner (Figure 2) [4][36][37][38]. The resulting effect seems to be dependent on which subtype of alpha2 and which isoforms of HCN interact. For example, increasing cAMP counteracts the inhibitory effect of ZD7288, a potent blocker of Ih, or dexmedetomidine and guanfacine on HCN channels [37][39][40]. Thus, it may increase or even reverse inhibitory effects in tissues where cAMP-sensitive isoforms of HCN are highly expressed. Another way of alpha2-mediated upregulation of HCN channels is cellular alkalinization [41] which shifts Ih activation potential to more depolarized values [42]. A recent study showed that in rats genetically predisposed to absence epilepsy, spike-wave activity can be triggered by hypoxia-induced blood alkalosis resulting in the activation of neurons in the intralaminar thalamic nuclei [43].
Ijms 24 01477 g004 550
Figure 2. The main effects of alpha2 AR agonists on HCN channels. Red lines—activation. Blue lines—inhibition. Solid lines—effects have strong empirical evidence. Dashed lines—effects have limited evidence.
It should be mentioned that the impact of Ih on neuron excitability is intertwined with currents mediated by other ion channels such as G protein-coupled inwardly rectifying K+ channels [44], which themselves may be influenced by alpha2 AR agonists. Dexmedetomidine activates a G protein-coupled inwardly rectifying K+ current [45] which is suppressed by the first choice anti-absence drug ethosuximide [46]. Considering the impending revision of the mechanism of action of ethosuximide as an anti-absence drug [46], it is interesting to compare its effects on cell currents with the effects of alpha2 AR antagonists.

3. Alpha2-Adrenoreceptors and Calcium Channels

Calcium channels are important regulators of neuronal firing properties (reviewed in [47]). Calcium channels are divided into low-voltage activated (T-type) and high-voltage activated (L-, N-, P/Q-, R-types). The role of calcium channels in the absence epilepsy is confirmed by genetic findings in patients and studies in knockout animal models. Pharmacological modulation of the spike-wave activity using calcium channel blockers and activators has been shown in animals genetically predisposed to absence seizures. In particular, intraperitoneal and intracerebroventricular microinjections of L-type blockers resulted in an increase in the number and duration of SWDs, but intracortical microinjections suppressed SWDs [48][49].
Systemic administration of L-current activator BAY K8644 decreased the number and duration of spike-wave discharges, regardless of the method of administration. L-type calcium channel blockers are known to modulate the sedative effects of alpha-2 AR agonists. Local administration of nifedipine into LC and a subhypnotic dose of dexmedetomidine led to the loss of righting reflex [50]; intraperitoneal injection of a low dose of nifedipine (2 mg/kg) blocked the sedative effect of clonidine [51], and the high dose (20 mg/kg) enhanced dexmedetomidine-induced sleep time [52]. Nevertheless, the sedative effects of alpha2 AR agonists were at least partially mediated by the blocking of L-type calcium channels, since the injection of nifedipine restored the hypnotic ability of dexmedetomidine in rats who developed tolerance after chronic administration [52]. Noteworthy, the method of administration determined how an L-current blocker would affect a decrease in blood pressure induced by clonidine. Intravenous injection of nifedipine induced an increase in blood pressure in rabbits, but intravenous administration prevented the hypotensive action of clonidine [53]. Since L-type blockers are used as antihypertensive drugs, their action on spike-wave activity and locomotion after systemic administration might be accounted for a decrease in blood pressure. Indeed, SWDs in humans and animals are known to be linked with a reduction in blood pressure [54]. Identification of the contribution of L-current into pro-absence and sedative effects of alpha2 AR activation is possible with the local co-administration of substances into the central nervous system.
Alpha2 agonists reduce N- and P/Q-type currents [12][55][56]. There is only limited evidence of the effects of N- or P/Q blockers on spike-wave activity, but they were either indistinguishable from the general detrimental influence of N-blockers or minor, as in the case of P/Q blockers [48]. However, since mutations in high-voltage gated calcium channels lead to the development of absence epilepsy phenotypes in animal models [57][58], the study of alpha2 ARs activation or inhibition in these models may indicate other ways to modulate spike-wave activity.
Altogether, T-type calcium channels play a crucial role in the generation of SWDs [59][60], and interactions between alpha2 ARs and T-type calcium channels need to be further investigated. An increase in thalamic burst firing mediated by T-type channels might not be as significant in the generation of SWDs as previously assumed [61][62]. Therefore, future studies are required to examine the relationship between the burst firing of thalamic cells and the SWD-promoting effects of alpha2 AR agonists.

4. Astrocytic Alpha2-Adrenoreceptors

More and more evidence has been obtained in favor of the fact that astrocytes can play an important role in the pathogenesis of epilepsy [63][64]. Most studies have demonstrated the involvement of astrocytes in the pathogenesis of focal epilepsies [63][64][65][66], but recently the role of astrocytes in the pathogenesis of absence epilepsy has been disclosed. Optogenetic excitation of astrocytes in the ventrobasal thalamus caused a pro-absence effect in GAERS and WAG/Rij rats [67].
Astrocytes might be a promising target for the therapy of absence epilepsy. Alpha2A ARs are highly expressed in astrocytes, where they potentiate glutamate synthesis [68] and stimulate GABA release [69]. Although the general increase in GABA mediates the therapeutic effects of valproate, the administration of GABAa or GABAb agonists into the ventrobasal thalamus leads to an increase in spike-wave activity [70][71]. Given the special role of astrocytes in controlling the level of GABA in the thalamus, where they provide the main contribution to the reuptake of this neurotransmitter [72], they can be suggested as a target for novel drugs. It can be assumed that blocking thalamic alpha2 ARs with the selective antagonist to subtype B can reduce the level of GABA and prevent hyperpolarization of relay neurons, which creates a predisposition for burst firing.

References

  1. Micheletti, G.; Warter, J.-M.; Marescaux, C.; Depaulis, A.; Tranchant, C.; Rumbach, L.; Vergnes, M. Effects of Drugs Affecting Noradrenergic Neurotransmission in Rats with Spontaneous Petit Mal-like Seizures. Eur. J. Pharmacol. 1987, 135, 397–402.
  2. Buzsáki, G.; Kennedy, B.; Solt, V.B.; Ziegler, M. Noradrenergic Control of Thalamic Oscillation: The Role of Alpha-2 Receptors. Eur. J. Neurosci. 1991, 3, 222–229.
  3. Sitnikova, E.; Luijtelaar, G. van Reduction of Adrenergic Neurotransmission with Clonidine Aggravates Spike-Wave Seizures and Alters Activity in the Cortex and the Thalamus in WAG/Rij Rats. Brain Res. Bull. 2005, 64, 533–540.
  4. Yavuz, M.; Aydın, B.; Çarçak, N.; Akman, Ö.; Raci Yananlı, H.; Onat, F. Atipamezole, a Specific A2A Antagonist, Suppresses Spike-and-Wave Discharges and Alters Ca2+ /Calmodulin-Dependent Protein Kinase II in the Thalamus of Genetic Absence Epilepsy Rats. Epilepsia 2020, 61, 2825–2835.
  5. Pérez-Santos, I.; Palomero-Gallagher, N.; Zilles, K.; Cavada, C. Distribution of the Noradrenaline Innervation and Adrenoceptors in the Macaque Monkey Thalamus. Cereb. Cortex 2021, 31, 4115–4139.
  6. Zhang, Y.; Fu, B.; Liu, C.; Yu, S.; Luo, T.; Zhang, L.; Zhou, W.; Yu, T. Activation of Noradrenergic Terminals in the Reticular Thalamus Delays Arousal from Propofol Anesthesia in Mice. FASEB J. 2019, 33, 7252–7260.
  7. Rho, H.-J.; Kim, J.-H.; Lee, S.-H. Function of Selective Neuromodulatory Projections in the Mammalian Cerebral Cortex: Comparison Between Cholinergic and Noradrenergic Systems. Front. Neural Circuits 2018, 12, 47.
  8. Kjaerby, C.; Andersen, M.; Hauglund, N.; Untiet, V.; Dall, C.; Sigurdsson, B.; Ding, F.; Feng, J.; Li, Y.; Weikop, P.; et al. Memory-enhancing properties of sleep depend on the oscillatory amplitude of norepinephrine. Nat Neurosci. 2022, 25, 1059–1070.
  9. Coenen, A.M.L.; Van Luijtelaar, E.L.J.M. Genetic Animal Models for Absence Epilepsy: A Review of the WAG/Rij Strain of Rats. Behav. Genet. 2003, 33, 635–655.
  10. Riekkinen, P.; Sirviö, J.; Jäkälä, P.; Lammintausta, R.; Riekkinen, P. Interaction between the Alpha 2-Noradrenergic and Muscarinic Systems in the Regulation of Neocortical High Voltage Spindles. Brain Res. Bull. 1990, 25, 147–149.
  11. Smyk, M.K.; van Luijtelaar, G. Circadian Rhythms and Epilepsy: A Suitable Case for Absence Epilepsy. Front. Neurol. 2020, 11, 245.
  12. Timmons, S.D.; Geisert, E.; Stewart, A.E.; Lorenzon, N.M.; Foehring, R.C. Alpha2-Adrenergic Receptor-Mediated Modulation of Calcium Current in Neocortical Pyramidal Neurons. Brain Res. 2004, 1014, 184–196.
  13. He, C.; Chen, F.; Li, B.; Hu, Z. Neurophysiology of HCN Channels: From Cellular Functions to Multiple Regulations. Prog. Neurobiol. 2014, 112, 1–23.
  14. Pape, H.C. Queer Current and Pacemaker: The Hyperpolarization-Activated Cation Current in Neurons. Annu. Rev. Physiol. 1996, 58, 299–327.
  15. Moosmang, S.; Biel, M.; Hofmann, F.; Ludwig, A. Differential Distribution of Four Hyperpolarization-Activated Cation Channels in Mouse Brain. Biol. Chem. 1999, 380, 975–980.
  16. Santoro, B.; Chen, S.; Luthi, A.; Pavlidis, P.; Shumyatsky, G.P.; Tibbs, G.R.; Siegelbaum, S.A. Molecular and Functional Heterogeneity of Hyperpolarization-Activated Pacemaker Channels in the Mouse CNS. J. Neurosci. 2000, 20, 5264–5275.
  17. Notomi, T.; Shigemoto, R. Immunohistochemical Localization of Ih Channel Subunits, HCN1-4, in the Rat Brain. J. Comp. Neurol. 2004, 471, 241–276.
  18. Wainger, B.J.; DeGennaro, M.; Santoro, B.; Siegelbaum, S.A.; Tibbs, G.R. Molecular Mechanism of CAMP Modulation of HCN Pacemaker Channels. Nature 2001, 411, 805–810.
  19. Chen, S.; Wang, J.; Siegelbaum, S.A. Properties of Hyperpolarization-Activated Pacemaker Current Defined by Coassembly of HCN1 and HCN2 Subunits and Basal Modulation by Cyclic Nucleotide. J. Gen. Physiol. 2001, 117, 491–504.
  20. Seifert, R.; Scholten, A.; Gauss, R.; Mincheva, A.; Lichter, P.; Kaupp, U.B. Molecular Characterization of a Slowly Gating Human Hyperpolarization-Activated Channel Predominantly Expressed in Thalamus, Heart, and Testis. Proc. Natl. Acad. Sci. USA 1999, 96, 9391–9396.
  21. Ishii, T.M.; Takano, M.; Xie, L.H.; Noma, A.; Ohmori, H. Molecular Characterization of the Hyperpolarization-Activated Cation Channel in Rabbit Heart Sinoatrial Node. J. Biol. Chem. 1999, 274, 12835–12839.
  22. Yavuz, M.; Onat, F. The Role of Hyperpolarization-Activated Cyclic Nucleotide-Gated Channels in the Pathophysiology of Absence Epilepsy. J. Turkish Epilepsi Soc. 2018, 24, 41–50.
  23. Kuisle, M.; Wanaverbecq, N.; Brewster, A.L.; Frère, S.G.A.; Pinault, D.; Baram, T.Z.; Lüthi, A. Functional Stabilization of Weakened Thalamic Pacemaker Channel Regulation in Rat Absence Epilepsy. J. Physiol. 2006, 575, 83–100.
  24. Cain, S.M.; Tyson, J.R.; Jones, K.L.; Snutch, T.P. Thalamocortical Neurons Display Suppressed Burst-Firing Due to an Enhanced Ih Current in a Genetic Model of Absence Epilepsy. Pflügers Arch.–Eur. J. Physiol. 2015, 467, 1367–1382.
  25. David, F.; Çarçak, N.; Furdan, S.; Onat, F.; Gould, T.; Mészáros, Á.; Di Giovanni, G.; Hernández, V.M.; Chan, C.S.; Lőrincz, M.L.; et al. Suppression of Hyperpolarization-Activated Cyclic Nucleotide-Gated Channel Function in Thalamocortical Neurons Prevents Genetically Determined and Pharmacologically Induced Absence Seizures. J. Neurosci. 2018, 38, 6615–6627.
  26. Yavuz, M.; Aydın, B.; Çarçak, N.; Onat, F. Decreased Hyperpolarization-Activated Cyclic Nucleotide-Gated Channel 2 Activity in a Rat Model of Absence Epilepsy and the Effect of ZD7288, an Ih Inhibitor, on the Spike-and-Wave Discharges. Pharmacology 2022, 107, 227–234.
  27. Strauss, U.; Kole, M.H.P.; Bräuer, A.U.; Pahnke, J.; Bajorat, R.; Rolfs, A.; Nitsch, R.; Deisz, R.A. An Impaired Neocortical Ih Is Associated with Enhanced Excitability and Absence Epilepsy. Eur. J. Neurosci. 2004, 19, 3048–3058.
  28. Kole, M.H.P.; Bräuer, A.U.; Stuart, G.J. Inherited Cortical HCN1 Channel Loss Amplifies Dendritic Calcium Electrogenesis and Burst Firing in a Rat Absence Epilepsy Model. J. Physiol. 2007, 578, 507–525.
  29. Zobeiri, M.; Chaudhary, R.; Blaich, A.; Rottmann, M.; Herrmann, S.; Meuth, P.; Bista, P.; Kanyshkova, T.; Lüttjohann, A.; Narayanan, V.; et al. The Hyperpolarization-Activated HCN4 Channel Is Important for Proper Maintenance of Oscillatory Activity in the Thalamocortical System. Cereb. Cortex 2019, 29, 2291–2304.
  30. Lörincz, A.; Notomi, T.; Tamás, G.; Shigemoto, R.; Nusser, Z. Polarized and Compartment-Dependent Distribution of HCN1 in Pyramidal Cell Dendrites. Nat. Neurosci. 2002, 5, 1185–1193.
  31. Huang, Z.; Walker, M.C.; Shah, M.M. Loss of Dendritic HCN1 Subunits Enhances Cortical Excitability and Epileptogenesis. J. Neurosci. 2009, 29, 10979–10988.
  32. Blumenfeld, H.; Klein, J.P.; Schridde, U.; Vestal, M.; Rice, T.; Khera, D.S.; Bashyal, C.; Giblin, K.; Paul-Laughinghouse, C.; Wang, F.; et al. Early Treatment Suppresses the Development of Spike-Wave Epilepsy in a Rat Model. Epilepsia 2008, 49, 400–409.
  33. Yang, Y.; Meng, Q.; Pan, X.; Xia, Z.; Chen, X. Dexmedetomidine Produced Analgesic Effect via Inhibition of HCN Currents. Eur. J. Pharmacol. 2014, 740, 560–564.
  34. Carr, D.B.; Andrews, G.D.; Glen, W.B.; Lavin, A. Alpha2-Noradrenergic Receptors Activation Enhances Excitability and Synaptic Integration in Rat Prefrontal Cortex Pyramidal Neurons via Inhibition of HCN Currents. J. Physiol. 2007, 584, 437–450.
  35. Näsman, J.; Jansson, C.C.; Akerman, K.E. The Second Intracellular Loop of the Alpha2-Adrenergic Receptors Determines Subtype-Specific Coupling to CAMP Production. J. Biol. Chem. 1997, 272, 9703–9708.
  36. Won, J.; Lee, P.R.; Oh, S.B. Alpha 2 Adrenoceptor Agonist Guanabenz Directly Inhibits Hyperpolarization-Activated, Cyclic Nucleotide-Modulated (HCN) Channels in Mesencephalic Trigeminal Nucleus Neurons. Eur. J. Pharmacol. 2019, 854, 320–327.
  37. Wang, M.; Ramos, B.P.; Paspalas, C.D.; Shu, Y.; Simen, A.; Duque, A.; Vijayraghavan, S.; Brennan, A.; Dudley, A.; Nou, E.; et al. Alpha2A-Adrenoceptors Strengthen Working Memory Networks by Inhibiting CAMP-HCN Channel Signaling in Prefrontal Cortex. Cell 2007, 129, 397–410.
  38. Parkis, M.A.; Berger, A.J. Clonidine Reduces Hyperpolarization-Activated Inward Current (Ih) in Rat Hypoglossal Motoneurons. Brain Res. 1997, 769, 108–118.
  39. Brummett, C.M.; Hong, E.K.; Janda, A.M.; Amodeo, F.S.; Lydic, R. Perineural Dexmedetomidine Added to Ropivacaine for Sciatic Nerve Block in Rats Prolongs the Duration of Analgesia by Blocking the Hyperpolarization-Activated Cation Current. Anesthesiology 2011, 115, 836–843.
  40. Ramos, B.P.; Stark, D.; Verduzco, L.; van Dyck, C.H.; Arnsten, A.F.T. A2A-Adrenoceptor Stimulation Improves Prefrontal Cortical Regulation of Behavior through Inhibition of CAMP Signaling in Aging Animals. Learn. Mem. 2006, 13, 770–776.
  41. Isom, L.L.; Cragoe, E.J.; Limbird, L.E. Alpha 2-Adrenergic Receptors Accelerate Na+/H+ Exchange in Neuroblastoma X Glioma Cells. J. Biol. Chem. 1987, 262, 6750–6757.
  42. Munsch, T.; Pape, H.C. Modulation of the Hyperpolarization-Activated Cation Current of Rat Thalamic Relay Neurones by Intracellular PH. J. Physiol. 1999, 519 Pt 2, 493–504.
  43. Salvati, K.A.; Souza, G.M.P.R.; Lu, A.C.; Ritger, M.L.; Guyenet, P.; Abbott, S.B.; Beenhakker, M.P. Respiratory Alkalosis Provokes Spike-Wave Discharges in Seizure-Prone Rats. Elife 2022, 11, e72898.
  44. Lüscher, C.; Slesinger, P.A. Emerging Roles for G Protein-Gated Inwardly Rectifying Potassium (GIRK) Channels in Health and Disease. Nat. Rev. Neurosci. 2010, 11, 301–315.
  45. Shirasaka, T.; Kannan, H.; Takasaki, M. Activation of a G Protein–Coupled Inwardly Rectifying K+Current and Suppression of I HContribute to Dexmedetomidine-Induced Inhibition of Rat Hypothalamic Paraventricular Nucleus Neurons. Anesthesiology 2007, 107, 605–615.
  46. Kobayashi, T.; Hirai, H.; Iino, M.; Fuse, I.; Mitsumura, K.; Washiyama, K.; Kasai, S.; Ikeda, K. Inhibitory Effects of the Antiepileptic Drug Ethosuximide on G Protein-Activated Inwardly Rectifying K+ Channels. Neuropharmacology 2009, 56, 499–506.
  47. Simms, B.A.; Zamponi, G.W. Neuronal Voltage-Gated Calcium Channels: Structure, Function, and Dysfunction. Neuron 2014, 82, 24–45.
  48. Van Luijtelaar, G.; Wiaderna, D.; Elants, C.; Scheenen, W. Opposite Effects of T- and L-Type Ca2+ Channels Blockers in Generalized Absence Epilepsy. Eur. J. Pharmacol. 2000, 406, 381–389.
  49. Sadighi, M.; Shahabi, P.; Gorji, A.; Pakdel, F.G.; Nejad, G.G.; Ghorbanzade, A. Role of L- and T-Type Calcium Channels in Regulation of Absence Seizures in Wag/Rij Rats. Neurophysiology 2013, 45, 312–318.
  50. Nacif-Coelho, C.; Correa-Sales, C.; Chang, L.L.; Maze, M. Perturbation of Ion Channel Conductance Alters the Hypnotic Response to the A2-Adrenergic Agonist Dexmedetomidine in the Locus Coeruleus of the Rat. Anesthesiology 1994, 81, 1527–1534.
  51. Desai, M.K.; Dikshit, R.K.; Mansuri, S.M.; Shah, U.H. Effect of Nifedipine, a Calcium Channel Inhibitor, on Sedation Produced by Reserpine, Clonidine and Propranolol in Mice. Indian J. Exp. Biol. 1994, 32, 314–317.
  52. Reid, K.; Guo, T.Z.; Davies, M.F.; Maze, M. Nifedipine, an L-Type Calcium Channel Blocker, Restores the Hypnotic Response in Rats Made Tolerant to the Alpha-2 Adrenergic Agonist Dexmedetomidine. J. Pharmacol. Exp. Ther. 1997, 283, 993–999.
  53. Czarnecka, E.; Tymczyszyn, W.; Pietrzak, B. Effect of Nifedipine and Verapamil on Hypotensive Action of Clonidine in Rabbits. Pol. J. Pharmacol. 1998, 50, 193–201.
  54. Nehlig, A.; Vergnes, M.; Waydelich, R.; Hirsch, E.; Charbonne, R.; Marescaux, C.; Seylaz, J. Absence Seizures Induce a Decrease in Cerebral Blood Flow: Human and Animal Data. J. Cereb. Blood Flow Metab. 1996, 16, 147–155.
  55. Kolaj, M.; Renaud, L. Norepinephrine Acts via A2 Adrenergic Receptors to Suppress N-Type Calcium Channels in Dissociated Rat Median Preoptic Nucleus Neurons. Neuropharmacology 2001, 41, 472–480.
  56. Hara, M.; Zhou, Z.Y.; Hemmings, H.C. A2-Adrenergic Receptor and Isoflurane Modulation of Presynaptic Ca2+ Influx and Exocytosis in Hippocampal Neurons. Anesthesiology 2016, 125, 535–546.
  57. Tokuda, S.; Kuramoto, T.; Tanaka, K.; Kaneko, S.; Takeuchi, I.K.; Sasa, M.; Serikawa, T. The Ataxic Groggy Rat Has a Missense Mutation in the P/Q-Type Voltage-Gated Ca2+ Channel A1A Subunit Gene and Exhibits Absence Seizures. Brain Res. 2007, 1133, 168–177.
  58. Bomben, V.C.; Aiba, I.; Qian, J.; Mark, M.D.; Herlitze, S.; Noebels, J.L. Isolated P/Q Calcium Channel Deletion in Layer VI Corticothalamic Neurons Generates Absence Epilepsy. J. Neurosci. 2016, 36, 405–418.
  59. McCormick, D.A.; Connors, B.W.; Lighthall, J.W.; Prince, D.A. Comparative Electrophysiology of Pyramidal and Sparsely Spiny Stellate Neurons of the Neocortex. J. Neurophysiol. 1985, 54, 782–806.
  60. Llinás, R.; Jahnsen, H. Electrophysiology of Mammalian Thalamic Neurones in Vitro. Nature 1982, 297, 406–408.
  61. Lee, S.E.; Lee, J.; Latchoumane, C.; Lee, B.; Oh, S.-J.; Saud, Z.A.; Park, C.; Sun, N.; Cheong, E.; Chen, C.-C.; et al. Rebound Burst Firing in the Reticular Thalamus Is Not Essential for Pharmacological Absence Seizures in Mice. Proc. Natl. Acad. Sci. USA 2014, 111, 11828–11833.
  62. McCafferty, C.; David, F.; Venzi, M.; Lőrincz, M.L.; Delicata, F.; Atherton, Z.; Recchia, G.; Orban, G.; Lambert, R.C.; Di Giovanni, G.; et al. Cortical Drive and Thalamic Feed-Forward Inhibition Control Thalamic Output Synchrony during Absence Seizures. Nat. Neurosci. 2018, 21, 744–756.
  63. Coulter, D.A.; Steinhauser, C. Role of Astrocytes in Epilepsy. Cold Spring Harb. Perspect. Med. 2015, 5, a022434.
  64. Verhoog, Q.P.; Holtman, L.; Aronica, E.; van Vliet, E.A. Astrocytes as Guardians of Neuronal Excitability: Mechanisms Underlying Epileptogenesis. Front. Neurol. 2020, 11, 1541.
  65. Devinsky, O.; Vezzani, A.; Najjar, S.; De Lanerolle, N.C.; Rogawski, M.A. Glia and Epilepsy: Excitability and Inflammation. Trends Neurosci. 2013, 36, 174–184.
  66. Binder, D.K.; Steinhäuser, C. Functional Changes in Astroglial Cells in Epilepsy. Glia 2006, 54, 358–368.
  67. Ozgur, M.; Özyurt, M.G.; Arkan, S.; Cavdar, S. The Effects of Optogenetic Activation of Astrocytes on Spike-and-Wave Discharges in Genetic Absence Epileptic Rats. Ann. Neurosci. 2022, 29, 53–61.
  68. Hertz, L.; Lovatt, D.; Goldman, S.A.; Nedergaard, M. Adrenoceptors in Brain: Cellular Gene Expression and Effects on Astrocytic Metabolism and I. Neurochem. Int. 2010, 57, 411–420.
  69. Gaidin, S.G.; Zinchenko, V.P.; Sergeev, A.I.; Teplov, I.Y.; Mal’tseva, V.N.; Kosenkov, A.M. Activation of Alpha-2 Adrenergic Receptors Stimulates GABA Release by Astrocytes. Glia 2020, 68, 1114–1130.
  70. Liu, Z.; Vergnes, M.; Depaulis, A.; Marescaux, C. Evidence for a Critical Role of GABAergic Transmission within the Thalamus in the Genesis and Control of Absence Seizures in the Rat. Brain Res. 1991, 545, 1–7.
  71. Liu, Z.; Vergnes, M.; Depaulis, A.; Marescaux, C. Involvement of Intrathalamic GABAb Neurotransmission in the Control of Absence Seizures in the Rat. Neuroscience 1992, 48, 87–93.
  72. Vitellaro-Zuccarello, L.; Calvaresi, N.; De Biasi, S. Expression of GABA Transporters, GAT-1 and GAT-3, in the Cerebral Cortex and Thalamus of the Rat during Postnatal Development. Cell Tissue Res. 2003, 313, 245–257.
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Subjects: Neurosciences
Contributors MDPI registered users' name will be linked to their SciProfiles pages. To register with us, please refer to https://encyclopedia.pub/register :
Evgenia Sitnikova
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Elizaveta Rutskova
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Kirill Smirnov
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Update Date: 01 Feb 2023
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