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_2A Adrenergic Receptor Activation Inhibits Epileptiform Activity in the Rat Hippocampal CA3 Region

Department of Pharmacology, Physiology and Therapeutics, University of North Dakota School of Medicine and Health Sciences, Grand Forks, North Dakota

Norepinephrine has potent antiepileptic properties, the pharmacology of which is unclear. Under conditions in which GABAergic inhibition is blocked, norepinephrine reduces hippocampal cornu ammonis 3 (CA3) epileptiform activity through ₂ adrenergic receptor (AR) activation on pyramidal cells. In this study, we investigated which ₂AR subtype(s) mediates this effect. First, ₂AR genomic expression patterns of 25 rat CA3 pyramidal cells were determined using real-time single-cell reverse transcription-polymerase chain reaction, demonstrating that 12 cells expressed _2AAR transcript; 3 of the 12 cells additionally expressed mRNA for _2CAR subtype and no cells possessing _2BAR mRNA. Hippocampal CA3 epileptiform activity was then examined using field potential recordings in brain slices. The selective AR agonist 6-fluoronorepinephrine caused a reduction of CA3 epileptiform activity, as measured by decreased frequency of spontaneous epileptiform bursts. In the presence of AR blockade, concentration-response curves for AR agonists suggest that an ₂AR mediates this response, as the rank order of potency was 5-bromo-N-(4,5-dihydro-1H-imidazol-2-yl)-6-quinoxalinamine (UK-14304) epinephrine >6-fluoronorepinephrine > norepinephrine phenylephrine. Finally, equilibrium dissociation constants (K_b) of selective AR antagonists were functionally determined to confirm the specific ₂AR subtype inhibiting CA3 epileptiform activity. Apparent K_b values calculated for atipamezole (1.7 nM), MK-912 (4.8 nM), BRL-44408 (15 nM), yohimbine (63 nM), ARC-239 (540 nM), prazosin (4900 nM), and terazosin (5000 nM) correlated best with affinities previously determined for the _2AAR subtype (r = 0.99, slope = 1.0). These results suggest that, under conditions of impaired GABAergic inhibition, activation of _2AARs is primarily responsible for the antiepileptic actions of norepinephrine in the rat hippocampal CA3 region.

Received for publication October 13, 2006.

Accepted for publication March 6, 2007.

Address correspondence to: Van A. Doze, Department of Pharmacology, Physiology and Therapeutics, School of Medicine and Health Sciences, University of North Dakota, 501 North Columbia Road, Stop 9037, Grand Forks, ND 58202-9037. E-mail: vdoze{at}medicine.nodak.edu

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