title: Excitation of rat hippocampal interneurons via modulation of endogenous agonist activity at the alpha7 nicotinic ACh receptor.
abstract: The alpha7 subtype of the nicotinic acetylcholine receptor (alpha7 nAChR) is prominently expressed in the hippocampus where it is thought to play a role in the regulation of cognitive function. In this study, we have investigated the effects of 5-hydroxyindole (5-HI), a positive modulator of the alpha7 nAChR, on GABAergic activity in hippocampal CA1 stratum radiatum interneurons in acute rat brain slices. Superfusion of 5-HI (100 microM) increased the mean frequency and amplitude of spontaneous IPSCs (sIPSCs). The potentiation was occluded by pretreatment of slices with: (1) a high concentration of the broad-spectrum agonist nicotine to desensitize the alpha7 receptor, (2) an alpha7 nAChR antagonist, and (3) tetrodotoxin to block action potential firing. These results indicate that facilitation by 5-HI was mediated by the alpha7 nAChR and required neuronal excitation. In contrast, 5-HI had no effect on sIPSCs recorded in hippocampal slices from younger animals, even though the expression of functional alpha7 nAChRs was confirmed by agonist application experiments. In these slices, 5-HI only enhanced sIPSCs after pretreatment with the acetylcholinesterase inhibitor Bw284c51. Taken together, our results suggest that 5-HI facilitates GABAergic transmission via excitation of the alpha7 nAChR, and that this effect requires the presence of the endogenous agonist ACh in the extracellular environment of the receptor.
authors.affiliation: Schizophrenia and Bipolar Neurophysiology and Pharmacology, Psychiatry CEDD, GlaxoSmithKline, Harlow, Essex CM19 5AW, UK. selina.m.mok@gsk.com
authors.forename: M H Selina
authors.initials: MH
authors.lastname: Mok
authors.forename: James N C
authors.initials: JN
authors.lastname: Kew
mesh_terms: D000200:Action Potentials / Q000187:drug effects / Q000502:physiology*; D000222:Adaptation, Physiological / Q000187:drug effects / Q000502:physiology; D000818:Animals; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D006624:Hippocampus / Q000187:drug effects / Q000502:physiology*; D007211:Indoles / Q000008:administration & dosage*; D007395:Interneurons / Q000187:drug effects / Q000502:physiology*; D018722:Nicotinic Agonists / Q000008:administration & dosage; D051381:Rats; D011978:Receptors, Nicotinic / Q000187:drug effects / Q000378:metabolism*; D009435:Synaptic Transmission / Q000187:drug effects / Q000502:physiology*; D064569:alpha7 Nicotinic Acetylcholine Receptor; D005680:gamma-Aminobutyric Acid / Q000378:metabolism*
chemical_list: C579165:Chrna7 protein, rat; D007211:Indoles; D018722:Nicotinic Agonists; D011978:Receptors, Nicotinic; D064569:alpha7 Nicotinic Acetylcholine Receptor; C026785:5-hydroxyindole; D005680:gamma-Aminobutyric Acid