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NEUROPHARMACOLOGY

1A-Adrenergic Receptors Are Functionally Expressed by a Subpopulation of Cornu Ammonis 1 Interneurons in Rat Hippocampus

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

The importance of adrenergic receptors (ARs) in the hippocampus has generally focused on ARs; however, interest is growing in hippocampal ARs given their purported neuroprotective role. We have previously reported ₁AR transcripts in a subpopulation of cornu ammonis 1 (CA1) interneurons. The goal of this study was to identify the specific ₁AR subtype (_1A, _1B, _1D) functionally expressed by these cells. Using cell-attached recordings to measure action potential frequency changes, concentration-response curves for the selective ₁AR agonist phenylephrine (PE) were generated in the presence of competitive subtype-selective ₁AR antagonists. Schild regression analysis was then used to estimate equilibrium dissociation constants (K_b) for each receptor antagonist in our system. The selective _1AAR antagonists, 5-methylurapidil and WB-4101 [2-[(2,6-dimethoxyphenoxyethyl)aminomethyl]-1,4-benzodioxane hydrochloride], produced consecutive rightward shifts in the concentration-response curve for PE when used at discriminating, nanomolar concentrations. Calculated K_b values for 5-methylurapidil (10 nM) and WB-4101 (5 nM) correlate to previously published affinity values for these antagonists at the _1AAR. The selective _1BAR antagonist L-765,314 [(2S)-4-(4-amino-6,7-dimethoxy-2-quinazolinyl)-2-[[(1,1-dimethylethyl)amino]carbonyl]-1-piperazinecarboxylic acid], as well as the selective _1DAR antagonist BMY7378 [8-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]-8-azaspiro[4.5]decane-7,9-dione dihydrochloride], produced significant rightward shifts in the concentration-response curve for PE only when used at nondistinguishing, micromolar concentrations. Calculated K_b values for L-765,314 (794 nM) and BMY7378 (316 nM) do not agree with affinity values for these antagonists at the _1B or _1DAR, respectively. Rather, these K_b values more closely match equilibrium dissociation constants estimated for these compounds when used to identify _1AAR subtypes. Together, our results provide strong evidence to support functional expression of _1AARs in a subpopulation of CA1 interneurons.

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

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