title: Alpha-1A adrenergic receptor activation increases inhibitory tone in CA1 hippocampus.
abstract: The endogenous catecholamine norepinephrine (NE) exhibits anti-epileptic properties, however it is not well understood which adrenergic receptor (AR) mediates this effect. The aim of this study was to investigate alpha(1)-adrenergic receptor activation in region CA1 of the hippocampus, a subcortical structure often implicated in temporal lobe epilepsies. Using cell-attached and whole-cell recordings in rat hippocampal slices, we confirmed that selective alpha(1)-AR activation increases action potential firing in a subpopulation of CA1 interneurons. We found that this response is mediated via the alpha(1A)-AR subtype, initiated by sodium influx, and appears independent of second messenger signaling. In CA1 pyramidal cells, alpha(1A)-AR activation decreases activity due to increased pre-synaptic GABA and somatostatin release. Examination of post-synaptic receptor involvement revealed that while GABA(A) receptors mediate the majority of alpha(1A)-adrenergic effects on CA1 pyramidal cells, significant contributions are also made by GABA(B) and somatostatin receptors. Finally, to test whether alpha(1A)-AR activation could have potential therapeutic implications, we performed AR agonist challenges using two in vitro epileptiform models. When GABA(A) receptors were available, alpha(1A)-AR activation significantly decreased epileptiform bursting in CA1. Together, our findings directly link stimulation of the alpha(1A)-AR subtype to release of GABA and somatostatin at the single cell level and suggest that alpha(1A)-AR activation may represent one mechanism by which NE exerts anti-epileptic effects within the hippocampus.
authors.affiliation: Department of Pharmacology, Physiology and Therapeutics, University of North Dakota School of Medicine and Health Sciences, 501 North Columbia Road, Grand Forks, ND 58203, United States.
authors.forename: Kristin L
authors.initials: KL
authors.lastname: Hillman
authors.forename: Saobo
authors.initials: S
authors.lastname: Lei
authors.forename: Van A
authors.initials: VA
authors.lastname: Doze
authors.forename: James E
authors.initials: JE
authors.lastname: Porter
mesh_terms: D000200:Action Potentials / Q000187:drug effects / Q000502:physiology; D000316:Adrenergic alpha-Agonists / Q000494:pharmacology; D000317:Adrenergic alpha-Antagonists / Q000494:pharmacology; D000818:Animals; D000831:Animals, Newborn; D004305:Dose-Response Relationship, Drug; D005071:Evoked Potentials / Q000187:drug effects / Q000502:physiology; D018756:GABA Antagonists / Q000494:pharmacology; D006624:Hippocampus / Q000166:cytology* / Q000187:drug effects / Q000502:physiology*; D066298:In Vitro Techniques; D053444:Inhibitory Postsynaptic Potentials / Q000187:drug effects; D008297:Male; D009433:Neural Inhibition / Q000187:drug effects / Q000502:physiology*; D009474:Neurons / Q000187:drug effects / Q000502:physiology*; D009943:Organophosphorus Compounds / Q000494:pharmacology; D018408:Patch-Clamp Techniques; D010656:Phenylephrine / Q000494:pharmacology; D010852:Picrotoxin / Q000494:pharmacology; D010879:Piperazines / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D018340:Receptors, Adrenergic, alpha-1 / Q000378:metabolism*; D026941:Sodium Channel Blockers / Q000494:pharmacology; D013004:Somatostatin / Q000494:pharmacology; D013779:Tetrodotoxin / Q000494:pharmacology; D013997:Time Factors
chemical_list: D000316:Adrenergic alpha-Agonists; D000317:Adrenergic alpha-Antagonists; D018756:GABA Antagonists; D009943:Organophosphorus Compounds; D010656:Phenylephrine; D010852:Picrotoxin; D010879:Piperazines; D018340:Receptors, Adrenergic, alpha-1; D026941:Sodium Channel Blockers; D013004:Somatostatin; D013779:Tetrodotoxin; C547715:Adra1a protein, rat; C057446:5-methylurapidil; C066430:CGP 35348