title: Activation of 5-HT2A receptors upregulates the function of the neuronal K-Cl cotransporter KCC2.
abstract: In healthy adults, activation of γ-aminobutyric acid (GABA)(A) and glycine receptors inhibits neurons as a result of low intracellular chloride concentration ([Cl(-)](i)), which is maintained by the potassium-chloride cotransporter KCC2. A reduction of KCC2 expression or function is implicated in the pathogenesis of several neurological disorders, including spasticity and chronic pain following spinal cord injury (SCI). Given the critical role of KCC2 in regulating the strength and robustness of inhibition, identifying tools that may increase KCC2 function and, hence, restore endogenous inhibition in pathological conditions is of particular importance. We show that activation of 5-hydroxytryptamine (5-HT) type 2A receptors to serotonin hyperpolarizes the reversal potential of inhibitory postsynaptic potentials (IPSPs), E(IPSP), in spinal motoneurons, increases the cell membrane expression of KCC2 and both restores endogenous inhibition and reduces spasticity after SCI in rats. Up-regulation of KCC2 function by targeting 5-HT(2A) receptors, therefore, has therapeutic potential in the treatment of neurological disorders involving altered chloride homeostasis. However, these receptors have been implicated in several psychiatric disorders, and their effects on pain processing are controversial, highlighting the need to further investigate the potential systemic effects of specific 5-HT(2A)R agonists, such as (4-bromo-3,6-dimethoxybenzocyclobuten-1-yl)methylamine hydrobromide (TCB-2).
authors.affiliation: Institut de Neurosciences de la Timone, Unité Mixte de Recherche 7289, Centre National de la Recherche Scientifique,  Aix-Marseille Université, F-13385 cx5 Marseille,  France.
authors.forename: Rémi
authors.initials: R
authors.lastname: Bos
authors.forename: Karina
authors.initials: K
authors.lastname: Sadlaoud
authors.forename: Pascale
authors.initials: P
authors.lastname: Boulenguez
authors.forename: Dorothée
authors.initials: D
authors.lastname: Buttigieg
authors.forename: Sylvie
authors.initials: S
authors.lastname: Liabeuf
authors.forename: Cécile
authors.initials: C
authors.lastname: Brocard
authors.forename: Georg
authors.initials: G
authors.lastname: Haase
authors.forename: Hélène
authors.initials: H
authors.lastname: Bras
authors.forename: Laurent
authors.initials: L
authors.lastname: Vinay
mesh_terms: D000818:Animals; D015153:Blotting, Western; D001643:Bridged Bicyclo Compounds / Q000494:pharmacology; D002712:Chlorides / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects*; D006181:H-Reflex; D007150:Immunohistochemistry; D053444:Inhibitory Postsynaptic Potentials / Q000502:physiology*; D008744:Methylamines / Q000494:pharmacology; D009046:Motor Neurons / Q000378:metabolism*; D009128:Muscle Spasticity / Q000188:drug therapy* / Q000209:etiology; D051381:Rats; D044402:Receptor, Serotonin, 5-HT2A / Q000378:metabolism*; D012701:Serotonin / Q000378:metabolism / Q000494:pharmacology*; D058826:Serotonin 5-HT2 Receptor Agonists / Q000494:pharmacology; D013119:Spinal Cord Injuries / Q000150:complications*; D027981:Symporters / Q000378:metabolism*; D000096922:K Cl- Cotransporters
chemical_list: D001643:Bridged Bicyclo Compounds; D002712:Chlorides; D008744:Methylamines; D044402:Receptor, Serotonin, 5-HT2A; D012701:Serotonin; D058826:Serotonin 5-HT2 Receptor Agonists; D027981:Symporters; D000096922:K Cl- Cotransporters; C514172:(4-bromo-3,6-dimethoxybenzocyclobuten-1-yl)methylamine