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Norepinephrine inhibits a subset of hippocampal interneurons.

Norepinephrine (NE) has potent inhibitory effects in the hippocampus in vivo, consistent with our previous results indicating that NE depolarizes and increases the firing rate of GABAergic interneurons in this structure. However, whole-cell and cell-attached patch recordings from visualized CA1 interneurons in rat hippocampal slices revealed that NE was not uniformly excitatory, as it decreased the firing rate of a subset of hippocampal interneurons located in stratum lacunosum-moleculare. Whole-cell and cell-attached patch recordings were made from visualized CA1 interneurons and pyramidal cells in acute slices of rat hippocampus to investigate the modulatory effects of exogenous NE on GABAergic inhibition. NE at 10 [micro]M reversibly decreased the firing frequency of a subset of hippocampal interneurons whose cell bodies were located primarily in stratum lacunosum-moleculare. This inhibition resulted from a direct hyperpolarization (~8 mV) that was accompanied by a decrease in input resistance. Interneurons that were hyperpolarized by NE had electrophysiological characteristics different from interneurons located in the same region that were depolarized by NE, exhibiting larger amplitude action potentials that were shorter in duration. Camera Lucida reconstruction of the morphology of biocytin-filled cells indicated that these interneurons had axonal arbors that were located primarily in stratum lacunosum-moleculare and stratum radiatum. Axon arborizations were rarely observed in the pyramidal cell layer. Slow voltage ramps (-130 to 20 mV) revealed that the outward current induced by NE reversed at the predicted equilibrium potential for potassium ([K.sup.+]) ions and showed prominent inward rectification, suggesting that NE activates G protein-coupled inwardly rectifying [K.sup.+] channels (GIRK) channels in these interneurons.

The inhibitory effect of NE on these interneurons is mediated by an [alpha] adrenergic receptor (AR), as the effect of NE was mimicked by the [alpha] AR agonist 6-fluoronorepinephrine, but not the [beta] AR agonist isoproterenol. The AR appears to be an [[alpha].sub.2] subtype, as the selective [[alpha].sub.2] AR agonists, [alpha]-methylnorepinephrine and oxymetazoline, similarly hyperpolarized these cells. In addition, the NE-induced hyperpolarization was inhibited by atipamezole, a selective [[alpha].sub.2] AR antagonist, but not by YM-12617, a selective [[alpha].sub.1] AR antagonist. The amplitude of pharmacologically isolated late inhibitory postsynaptic potentials (IPSPs) evoked in CA 1 pyramidal neurons was reduced by NE. This effect also was blocked by atipamezole, a selective [[alpha].sub.2] AR antagonist. In addition, this effect was occluded by prior application of the opioid, [D-[Ala.sup.2]]-methionine-enkephalinamide (DALA), which hyperpolarizes interneurons, suggesting that the inhibition of the late IPSP by NE may result from the [[alpha].sub.2] AR-mediated hyperpolarization of interneurons located in stratum lacunosummoleculare.

The inhibition of the late IPSP by NE caused a time-dependent increase in the excitability of CA1 pyramidal neurons by reducing the amplitude of the after-hyperpolarization following afferent stimulation.

(1) Dwight E. Bergles and (2) Van A. Doze *

(1) Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, MD 21205, and

(2) Department of Pharmacology, Physiology & Therapeutics, University of North Dakota School of Medicine and Health Sciences, Grand Forks, ND 58202
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Author:Bergles, Dwight E.; Doze, Van A.
Publication:Proceedings of the North Dakota Academy of Science
Geographic Code:1USA
Date:Mar 1, 2003
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