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NEUROPHARMACOLOGY
1A-Adrenergic Receptors Are Functionally Expressed by a Subpopulation of Cornu Ammonis 1 Interneurons in Rat HippocampusDepartment of Pharmacology, Physiology, and Therapeutics, University of North Dakota School of Medicine and Health Sciences, Grand Forks, North Dakota
Received for publication
January 9, 2007
Accepted
March 1, 2007.
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Abstract |
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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 (Kb) 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 Kb 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 Kb 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 Kb 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.
1, 2, and AR types, these receptors traditionally signal through the heterotrimeric G proteins Gq/11, Gi, and Gs, respectively. The 1AR in particular has become of increasing interest in neuroscience because 1AR-mediated effects have been noted to regulate epileptiform activity (Weinshenker and Szot, 2002
; Giorgi et al., 2004), long-term synaptic depression (Kirkwood et al., 1999; Scheiderer et al., 2004), as well as attention and cognition processes (Arnsten et al., 1999; Lapiz and Morilak, 2006). Although these studies have identified 1AR-mediated effects through careful use of selective 1, 2, or AR pharmacological agents, further investigation into the specific 1AR subtypes involved has not been pursued.
Three subtypes for the 1AR are characterized: 1A, 1B, and 1D (for review, see Graham et al., 1996). In situ hybridization studies in rat illustrate all three receptor subtypes are present in the central nervous system (CNS), with the 1A and 1BAR subtypes most prevalent (Pieribone et al., 1994; Day et al., 1997). Recent studies utilizing enhanced green fluorescent protein-tagged 1A or 1BARs have provided further insights into distribution of these receptors in the rodent CNS on both gross anatomical as well as cellular levels (Papay et al., 2004, 2006). It is noteworthy that these latter studies offer increased resolution of 1AR subtype expression in the hippocampus, a cortical structure implicated in many of the neuronal processes mentioned above. 1AR activation in the hippocampus is associated with decreased excitability of the principal pyramidal neurons (Pang and Rose, 1987; Curet and de Montigny, 1988; Mynlieff and Dunwiddie, 1988). This effect of 1AR activation has been attributed to increased presynaptic GABA release from inhibitory interneurons (Bergles et al., 1996), as well as postsynaptic NMDA receptor modulation (Scheiderer et al., 2004).
We have previously reported 1AAR and 1BAR mRNA present in a subpopulation of interneurons in CA1, the most apical region of the hippocampus (Hillman et al., 2005b). Cells containing these 1AR transcripts predominate in stratum oriens and constitute a subpopulation of somatostatin-containing, GABAergic interneurons. Application of the selective AR agonist 6-fluoronorepinephrine produces a concentration-dependent increased action potential frequency in these cells, which is blocked by the selective 1AR antagonist prazosin but not the 2AR selective antagonist rauwolscine (unpublished data). Although this response supports our molecular evidence of 1AR transcription, it is unclear whether the 1A, the 1B,or both 1AR subtypes are responsible for this increased action potential frequency. Therefore, the goal of this study was to characterize the 1AR subtype(s) functionally expressed by this subpopulation of CA1 interneurons. Clearly deducing which 1AR subtype excites these interneurons will provide a greater level of specificity for future studies examining the influence of AR activation in the hippocampus.
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Materials and Methods |
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Research Animals. Sprague-Dawley rat pups were obtained from Harlan (Indianapolis, IN) and housed with their mothers before weaning. After arrival, rats were allowed to acclimate for at least 2 days before their use. All protocols described have been approved by the Institutional Animal Care and Use Committee at the University of North Dakota, which is in accordance with the National Institutes of Health Guide for the Care and Use of Laboratory Animals.
Slice Preparation. Sprague-Dawley rats weighing 25 to 55 g were deeply anesthetized with isoflurane and decapitated. Brains were rapidly removed and placed in chilled solution containing 110 mM choline chloride, 25 mM NaHCO3, 25 mM D-glucose, 11.6 mM sodium ascorbate, 7 mM MgSO4, 3.1 mM sodium pyruvate, 2.5 mM KCl, 1.25 mM NaPO4, and 0.5 mM CaCl2. Using an HM650V vibratome (Microm, Walldorf, Germany), 400-µm coronal sections were cut and transferred to a holding solution of 130 mM NaCl, 3.5 mM KCl, 5 mM MgCl2, 0.5 mM CaCl2, 1.25 mM NaH2PO4, 24 mM NaHCO3, and 10 mM D-glucose. Slices were incubated for 30 min at 37°C and then moved to room temperature. During experimentation, individual slices were continually bathed in artificial cerebral spinal fluid (aCSF) consisting of 119 mM NaCl, 5 mM KCl, 1.3 mM MgSO4, 2.5 mM CaCl2, 1 mM NaH2PO4, 26.2 mM NaHCO3, and 11 mM D-glucose. To pharmacologically isolate the cell of interest from primary excitatory inputs, 1 µM atropine, 10 µM 6,7-dinitroquinoxaline-2,3-dione, and 50 µM D-(-)-2-amino-5-phosphonopentanoic acid were also included in the aCSF. All solutions were continually aerated with 95% O2 and 5% CO2.
Cell-Attached Recording. Micropipettes were prepared from borosilicate glass using a vertical PP-830 puller (Narishige, Tokyo, Japan). Pipettes were filled with an internal solution of 135 mM KCH3SO4, 8 mM NaCl, 10 mM HEPES, 2 mM MgATP, 0.3 mM NaGTP, and 0.1 mM 1,2-bis(2-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid, tetrapotassium salt. Using a BX51WI upright microscope (Olympus, Melville, NY), the hippocampus was visualized under infrared-differential interference contrast optics. A candidate CA1 interneuron from stratum oriens or stratum radiatum was identified and centered in the visual field. With the micropipette, a gigaohm seal was formed on the soma of the candidate interneuron, enabling an isolated recording while maintaining integrity of the cell membrane. A baseline action potential frequency was recorded for 25 min, allowing time for equilibration of an AR antagonist if warranted by the experiment. Increasing concentrations of a specified AR agonist were then added to the perfusion line in 8-min increments. Changes in action potential frequency were visualized in real time and recorded for subsequent analysis. To avoid issues of receptor desensitization and depolarization block, only one hippocampal slice was used per experimental paradigm. After a single concentration-response curve was generated from an interneuron, generating an n = 1, the hippocampal slice was discarded, and a new slice was equilibrated in aCSF. Action potentials were detected using an Axoclamp 700B (Molecular Devices Corporation, Sunnyvale, CA), digitized with a Digidata 1322A analog-to-digital converter (Molecular Devices), and recorded using Axoscope 9.2 software (Molecular Devices). Postexperimental analysis was completed using Mini Analysis 5.0 (Synaptosoft, Decatur, GA) and Prism 4.03 (GraphPad Software Inc., San Diego, CA).
Statistical Analysis. All values are reported as the mean ± S.E., n 
3 as indicated. Action potential frequencies recorded during the course of each functional experiment were used to plot a concentration-response curve expressed as a percentage of the maximal AR agonist response. A fitted iterative nonlinear regression curve was used to determine the effective AR agonist concentrations that caused EC50. The fitted iterative nonlinear regression curve that best represented the data were determined using a partial F-test, F = [(SS1 - SS2)/SS2]/[(df1 - df2)/df2], where SS is sum of the squares, and df is degrees of freedom (p < 0.05). Significance between experimental groups was tested using a one-way analysis of variance with a post hoc Bonferroni test (Fig. 1) or an unpaired two-tailed Student's t test (p < 0.05). Equilibrium dissociation constants (Kb) for subtype-selective 1AR antagonists were estimated as described previously (Hillman et al., 2005a), using the method of Arunlakshana and Schild (1959). Schild regression slopes are expressed as the mean ± S.E. and were considered different from unity if the 95% confidence interval did not include a value of 1 (Kenakin, 1997).
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Results |
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1AR Activation Produces a Concentration-Dependent Increase in Action Potential Frequency. To understand the relationship between previously characterized mRNA expression patterns and functional receptor expression, a cell-attached configuration was used to record action potential frequencies from visually identified CA1 interneurons. Interneurons that provided a stable baseline recording for at least 25 min were challenged with increasing concentrations of the selective 1AR agonist phenylephrine (PE), the selective 2AR agonist clonidine, or the selective AR agonist isoproterenol. As shown in Fig. 1, PE produced a concentration-dependent increase in action potential frequencies, reaching a maximal effect at 100 µM. Contrary to the effect of PE, no change in action potential frequency was observed with increasing concentrations of clonidine or isoproterenol. Results from these initial experiments suggest a specific CA1 interneuron population is excited in response to 1AR activation.
1AAR Antagonism Alters the CA1 Interneuron Response to PE. To determine which 1AR subtype(s) are functionally expressed by CA1 interneurons, we examined the effect of subtype-selective 1AAR antagonists on the PE-mediated increased action potential frequency. Hippocampal slices were allowed to equilibrate with fixed concentrations of competitive receptor antagonist for at least 25 min before the onset of experimentation. Pretreatment of slices with 20, 50, or 100 nM of the selective 1AAR antagonist 5-methylurapidil produced consecutive parallel rightward shifts in the PE concentration-response curve (Fig. 2A). PE dose ratios in the presence and absence of each 5-methylurapidil concentration were calculated from individual experiments and used to generate a Schild regression line (Fig. 2B). This analysis estimated an equilibrium dissociation constant (Kb) for 5-methylurapidil of 10.0 ± 5.0 nM, a value that best correlates to previously published affinities of this competitive AR antagonist at the 1AAR (Table 1).
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A second subtype-selective 1AAR antagonist, WB-4101, was used to further support the idea that the CA1 interneuron response to PE is mediated by 1AAR activation. Fixed WB-4101 concentrations of 10, 30, and 50 nM produced consecutive parallel rightward shifts in the PE concentration-response curve (Fig. 2C). EC50 values obtained from these experiments were used to calculate dose ratios required for Schild regression analysis (Fig. 2D), which provided an estimated Kb of 5.0 ± 1.2 nM for WB-4101 in our system. Although WB-4101 is not as selective for the 1AAR subtype as 5-methylurapidil (Table 1), the high-affinity experimental value calculated for WB-4101 to inhibit PE-mediated increased action potential frequencies in CA1 interneurons suggests involvement of the 1AAR and/or 1DAR subtype. Although 1AAR expression is supported by our experimentation using 5-methyurapidil, as well as our previously published mRNA profiling, one cannot discount the possibility that 1DARs are also expressed by these cells. As evident in Table 1, the estimated Kb of WB-4101 in our system could correlate to previously published affinity values for this competitive AR antagonist at the 1DAR. Therefore, we next used a selective 1DAR competitive antagonist to test any contribution that this AR subtype may have to the PE-mediated increase in action potential frequencies observed for CA1 interneurons.
Subtype-Selective 1D or 1BAR Competitive Antagonists Alter CA1 Interneuron Responses to PE Only at Nonspecific Concentrations. The selectivity for the competitive receptor antagonist BMY7378 is over 100-fold for the 1D versus the 1A or 1BAR subtypes, as determined using both functional and radioligand binding techniques (Goetz et al., 1995; Piascik et al., 1995). Therefore, to establish whether the 1DAR subtype is contributing to agonist-mediated changes in action potential frequency observed for CA1 interneurons, this selective 1DAR antagonist was used in conjunction with increasing concentrations of PE. BMY7378 did not significantly affect the interneuron response to PE when this competitive antagonist was used at selective concentrations that block the 1DAR subtype (data not shown). The lowest concentration of BMY7378 needed to provide a statistically significant shift of the PE concentration-response curve was 0.5 µM (Fig. 3A). PE EC50 dose ratios calculated from each individual experiment containing a fixed concentration of BMY7378 were subsequently used for Schild regression analysis, which estimated a Kb value of 316 ± 120 nM for this selective 1DAR antagonist in our system (Fig. 3B). Compared with previous reports, this Kb value does not correlate to calculated affinities of BMY7378 for the 1DAR, thus eliminating the possibility that activation of this 1AR subtype contributes to the PE-mediated increase in CA1 interneuron action potential frequency (Table 1).
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1A or 1BAR, we used another AR competitive antagonist, L-765,314, that has demonstrated high affinity for the 1BAR subtype in both functional and radioligand binding analysis (Patane et al., 1998; Jähnichen et al., 2004). L-765,314 did not produce significant shifts in the PE concentration-response curve when used at nanomolar concentrations that are selective for competitively interacting with the 1BAR (data not shown). Significant shifts in the PE concentration-response curve were observed only when L-765,314 was used at nonselective, micromolar concentrations (Fig. 4A). Schild regression plots of the PE EC50 dose ratio data points versus receptor antagonist concentration estimated a 794 ± 60 nM Kb value for L-765,314 (Fig. 4B). This experimental equilibrium dissociation constant calculated for L-765,314 is approximately 150 times greater than its published binding affinity at the 1BAR, which strongly suggests that this 1AR subtype is not responsible for the PE-initiated effect observed in our system (Table 1). Furthermore, this calculated Kb is over 15-fold greater than the affinity of L-765,314 documented for the 1DAR, again substantiating our results using BMY7378, which showed no involvement of the 1DAR subtype in mediating this same response. Taken together, experimental Kb values obtained in our studies for both receptor antagonists L-765,314 and BMY7378 most closely associate to affinity values published for the 1AAR. Therefore, the experimental Kb profile of subtype-selective 1AR antagonists used in this study implicates functional expression of the 1AAR subtype in PE-responsive CA1 interneurons.
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Discussion |
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1AR subtypes expressed by CA1 interneurons in rat hippocampus. Using single-cell reverse transcription-polymerase chain reaction, we have shown previously 1AR transcripts are present in a subpopulation of GABAergic interneurons in this region of the hippocampus (Hillman et al., 2005b). Preliminary experiments in our laboratory revealed a concentration-dependent increase of interneuron action potential frequencies following application of the selective AR agonist 6-fluoronorepinephrine or the selective 1AR agonist PE. Although this functional response substantiated our molecular studies, it was not clear which specific 1AR subtype(s) mediated this effect. Using four different subtype-selective 1AR antagonists to competitively inhibit the PE-mediated increased action potential frequency, we have demonstrated here that a subpopulation of CA1 interneurons functionally express the 1AAR. This report represents the first description for the functional distribution of a specific 1AR subtype in a defined region of the hippocampus.
As summarized in Table 1, the calculated Kb profile of all four subtype-selective 1AR antagonists used in our analysis best correlate with previously published Ki values of these same compounds for the 1AAR. The competitive receptor antagonists 5-methylurapidil and WB-4101, which are most selective for the 1AAR subtype, demonstrated a high affinity to inhibit PE-initiated action potentials in CA1 interneurons, suggesting 1AAR subtypes are probably expressed in these cells. Although our estimated Kb values for 5-methylurapidil and WB-4101 were slightly higher than earlier reported Ki values at the 1AAR, this discrepancy is probably attributable to our use of hippocampal slice preparations. For example, previous studies using 5-methylurapidil were performed on transfected COS-1 (Perez et al., 1994), COS-7 (Laz et al., 1994), or fibroblast cultures (Saussy et al., 1996), allowing an isolated environment in which to study 1AR expression. Although these earlier studies provide important information regarding 1AR subtype characterization, the goal of our investigation was to examine 1AR subtype expression in a more physiological context within a specific region of the CNS. The use of hippocampal slices, although enabling us to identify 1AR expression patterns of individual interneurons within the brain, also introduces intact neuronal networks not present in transfected cell systems. Although much care is taken to pharmacologically isolate the interneuron of interest from primary inputs, residual network activity probably accounts for minor discrepancies between our experimental Kb and previously published Ki values for 5-methylurapidil and WB-4101. Regardless, the high-affinity values calculated for 5-methylurapidil and WB-4101 to inhibit PE-initiated action potentials in our system suggest 1AARs are probably expressed by this subpopulation of CA1 interneurons. However, we could not completely rule out the possibility that our results obtained using WB-4101 suggest expression of the 1AAR and/or the 1DAR subtypes.
To delineate functional expression between these two 1AR subtypes, BMY7378, a compound that has over a 100-fold selectivity for the 1D versus the 1A or 1BAR, was employed (Goetz et al., 1995). The calculated low affinity of BMY7378 in our system (>300 nM) suggests that 1DARs are not functionally responsible for the PE-mediated increase in action potential frequency seen in CA1 interneurons, substantiating our conclusions for 1AAR expression based on affinity values of 5-methylurapidil and WB-4101. This calculated low-affinity value for BMY7378 is supported by previous in situ studies that report almost no hybridization for the 1DAR subtype in rat hippocampus (Day et al., 1997) and substantiates our earlier findings that 1DAR transcripts are absent in CA1 interneurons (Hillman et al., 2005b).
Although the low Kb value estimated for BMY7378 in our system suggests 1DARs are not involved in the PE-mediated increase in action potential frequency, it does not further distinguish between functional expression of the 1A or 1BAR subtype (Table 1); therefore, the selective 1BAR competitive antagonist L-765,314 was used for further analysis. The calculated low affinity (>700 nM) of L-765,314 in our system strongly implies that the 1BAR subtype does not contribute to the observed PE-mediated increased action potential frequency. L-765,314 produced significant shifts of the PE concentration-response curve only when used at very high concentrations, which relates to receptor antagonism of the 1A or 1DAR subtype. However, the published Ki value for L-765,314 at the 1DAR is 50 nM, which is 15-fold lower than the functional Kb calculated in our study for this same receptor antagonist. Consequently, this calculated equilibrium dissociation constant of L-765,314 is most indicative for the expression of an 1AAR subtype, further substantiating our results using 5-methylurapidil and WB-4101. Moreover, the low-affinity value calculated for BMY7378 rules out any possible contribution of an 1DAR subtype mediating this PE-initiated response, significantly supporting our conclusions that only 1AAR subtypes are functionally coupled to increasing action potential frequencies on these interneurons.
A lack of 1BAR involvement was surprising, given the fact that transcripts for both the 1A and 1BAR were found in cytoplasmic samples taken from CA1 interneurons (Hillman et al., 2005b). Previous in situ studies also demonstrate 1BAR mRNA in CA1 (Pieribone et al., 1994; Day et al., 1997), although these studies often report 1AAR expression in the hippocampus at a greater density. The predominance of 1AAR subtype expression in the hippocampus is supported by binding studies (Wilson and Minneman, 1989) and more specifically in CA1 hippocampus by enhanced green fluorescent protein-tagged 1AR localization experiments (Papay et al., 2006). One could speculate that both 1A and 1BAR subtypes are transcribed in CA1, with only the 1AAR translating into a functional protein. Considering that neurotransmitter receptor dysregulation and neuronal cell death has been observed in transgenic animals overexpressing the 1BAR subtype, this lack of functional 1BAR expression may be a beneficial adaptation (Yun et al., 2003).
Alternatively, the 1BAR may be a functionally expressed membrane protein that simply is not linked to the receptor agonist-mediated increases in action potential frequency monitored for this study. In our experiments, we elected to use single-cell, cell-attached recordings to enable generation of complete concentration-response curves from individual interneurons within the CA1 hippocampus. Although the approach allowed us to perform pharmacological analysis on single cells in an in vitro physiological context, this technique is limited in that it detects only the all-or-none action potential. With regard to functional 1BAR or 1DAR expression in CA1, monitoring subthreshold changes in membrane potential by performing whole-cell interneuron recordings may provide better insight into possible functional contributions of these other 1AR subtypes. However, due to dialysis of cell contents over time, this more sensitive technique of wholecell recording would not allow for generation of entire concentration-response curves, thus limiting complete characterization using pharmacological analysis.
It should be noted that not all CA1 interneurons examined responded to selective 1AR agonism. Approximately 75% of interneurons in stratum oriens and 25% in stratum radiatum generated concentration-dependent increases in action potential frequencies following PE application. The remaining interneurons tested showed no change in baseline action potential frequency following applications of up to 100 µM PE. This is consistent with our previous molecular findings that 1AR transcripts are present only in a subset of somatostatin-positive interneurons (Hillman et al., 2005b), a subpopulation of interneurons that predominate in stratum oriens of CA1 (Freund and Buzsáki, 1996). Interestingly, voltage-activated K+ conductance was recently shown to modulate cell excitability in this same subset of CA1 interneurons (Lawrence et al., 2006), perhaps suggesting, at least in part, a possible mechanism behind the PE-mediated interneuron depolarization we observed in this study. Presently, it is important to consider our observed 1AAR-mediated effects only within the confines of a specific CA1 cell population, at least until further characterizations can be made throughout the entire hippocampal network.
On a wider scope, current laboratory investigations suggest that 1AAR activation on CA1 interneurons decreases activity of neighboring principal pyramidal cells via both neurotransmitter and neuropeptide release. This observation of a selective 1AAR-mediated effect represents a potentially novel therapeutic target for antiepileptic drug exploration. The hippocampus is a focal point for the majority of temporal lobe epilepsies, and CA1 neurons are particularly susceptible to cell death following instances of epileptiform activity. 1AR activation has been shown to decrease spontaneous excitatory activity in cultured hippocampal neurons (Croce et al., 2003), as well as increase CA1 inhibitory tone in hippocampal slices (Bergles et al., 1996). In a recent case study, administration of an 1AR antagonist in a patient with temporal lobe epilepsy was recently shown to be highly proconvulsant (Ivañez and Ojeda, 2006). Therefore, it can be speculated that selective activation of 1AAR subtypes in the CA1 hippocampus may represent a novel way to increase inhibitory tone, which would serve to decrease epileptiform activity and promote neuronal survival in this region of the CNS.
In summary, by functionally determining affinity values for a panel of competitive subtype-selective 1AR antagonists, we demonstrate for the first time at a single-cell level that 1AAR activation can mediate an increased action potential frequency in CA1 interneurons. Although 1AAR-mediated responses cannot be assumed to be present throughout the entire hippocampus, the identification of a specific functional 1AR subtype in CA1 will help focus future adrenergic studies in this region.
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Acknowledgements |
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Footnotes |
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A preliminary report of these findings was presented at the Annual Meeting of the American Society for Pharmacology and Experimental Therapeutics; 2006 Apr; Washington, DC. American Society for Pharmacology and Experimental Therapeutics, Bethesda, MD; and in the Annual Meeting of the American Epilepsy Society; 2006 Dec 1–5; San Diego, CA. American Epilepsy Society, West Hartford, CT.
V.A.D. and J.E.P. contributed equally to this work.
Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.
ABBREVIATIONS: AR, adrenergic receptor; CNS, central nervous system; CA1, cornu ammonis 1; BMY7378, 8-[2-[4-(2-methoxyphenyl)-1-piperazinyl]ethyl]-8-azaspiro[4.5]decane-7,9-dione dihydrochloride; L-765,314, (2S)-4-(4-amino-6,7-dimethoxy-2-quinazolinyl)-2-[[(1,1-dimethylethyl)amino]carbonyl]-1-piperazinecarboxylic acid; WB-4101, 2-[(2,6-dimethoxyphenoxyethyl)aminomethyl]-1,4-benzodioxane hydrochloride; aCSF, artificial cerebral spinal fluid; PE, phenylephrine.
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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