Abstract
Recent studies have demonstrated that activation of the β-adrenergic receptor (AR) using the selective β-AR agonist isoproterenol (ISO) facilitates pyramidal cell long-term potentiation in the cornu ammonis 1 (CA1) region of the rat hippocampus. We have previously analyzed β-AR genomic expression patterns of 17 CA1 pyramidal cells using single cell reverse transcription-polymerase chain reaction, demonstrating that all samples expressed the β2-AR transcript, with four of the 17 cells additionally expressing mRNA for the β1-AR subtype. However, it has not been determined which β-AR subtypes are functionally expressed in CA1 for these same pyramidal neurons. Using cell-attached recordings, we tested the ability of ISO to increase pyramidal cell action potential (AP) frequency in the presence of subtype-selective β-AR antagonists. ICI-118,551 [(±)-1-[2,3-(dihydro-7-methyl-1H-inden-4-yl)oxy]-3-[(1-methylethyl)amino]-2-butanol] and butoxamine [α-[1-(t-butylamino)ethyl]-2,5-dimethoxybenzyl alcohol) hydrochloride], agents that selectively block the β2-AR, produced significant parallel rightward shifts in the concentration-response curves for ISO. From these curves, apparent equilibrium dissociation constant (Kb) values of 0.3 nM for ICI-118,551 and 355 nM for butoxamine were calculated using Schild regression analysis. Conversely, effective concentrations of the selective β1-AR antagonists CGP 20712A [(±)-2-hydroxy-5-[2-([2-hydroxy-3-(4-[1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl]phenoxy)propyl]amino)ethoxy]-benzamide methanesulfonate] and atenolol [4-[2′-hydroxy-3′-(isopropyl-amino)propoxy]phenylacetamide] did not significantly affect the pyramidal cell response to ISO. However, at higher concentrations, atenolol significantly decreased the potency for ISO-mediated AP frequencies. From these curves, an apparent atenolol Kb value of 3162 nM was calculated. This pharmacological profile for subtype-selective β-AR antagonists indicates that β2-AR activation is mediating the increased AP frequency. Knowledge of functional AR expression in CA1 pyramidal neurons will aid future long-term potentiation studies by allowing selective manipulation of specific β-AR subtypes.
Footnotes
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This study was supported in part by North Dakota Experimental Program to Stimulate Competitive Research (EPSCoR) through National Science Foundation Grant EPS-0132289 (to V.A.D.), National Science Foundation CAREER Grant 0347259 (to V.A.D.), National Institutes of Health Grant 2P20RR016471 from the Biomedical Research Infrastructure Networks program and National Institutes of Health Grant 5P20RR017699 from the Centers of Biomedical Research Excellence program (to V.A.D. and J.E.P.). A preliminary report of these findings was presented at the 2004 annual meeting of the American Society for Pharmacology and Experimental Therapeutics, Neuropharmacology Session, Apr 2–6, San Diego, CA.
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doi:10.1124/jpet.105.084947.
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ABBREVIATIONS: CA1, cornu ammonis 1; LTP, long-term potentiation; AR, adrenergic receptor; ISO, isoproterenol; APV, d-(–)-2-amino-5-phosphonopentanoic acid; CGP 20712A, (±)-2-hydroxy-5-[2-([2-hydroxy-3-(4-[1-methyl-4-(trifluoromethyl)-1H-imidazol-2-yl]phenoxy)propyl]amino)ethoxy]-benzamide methanesulfonate; DNQX, 6,7-dinitroquinoxaline-2,3-dione; ICI-118,551 hydrochloride, (±)-1-[2,3-(dihydro-7-methyl-1H-inden-4-yl)oxy]-3-[(1-methylethyl)amino]-2-butanol; aCSF, artificial cerebral spinal fluid; BAPTAK4, 1,2-bis(2-aminophenoxy)ethane-N,N,N′,N′-tetraacetic acid, tetrapotassium salt; AP, action potential; RT-PCR, reverse transcription-polymerase chain reaction.
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↵1 These authors contributed equally to this work.
- Received February 22, 2005.
- Accepted May 18, 2005.
- The American Society for Pharmacology and Experimental Therapeutics
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