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NEUROPHARMACOLOGY
Department of Anesthesia and Critical Care, University Hospital Giessen-Marburg GmbH, Marburg, Germany (D.R., H.W., A.S.); Institute of Physiology and Pathophysiology, Division of Neuroendocrinology and Neurodynamics, Marburg University, Marburg, Germany (B.M.); and Department of Anesthesia and Critical Care, Massachusetts General Hospital, Boston, Massachusetts (D.E.R.)
Received December 18, 2006; accepted March 2, 2007.
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Abstract |
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; Davies et al., 1999; Dubin et al., 1999; Karnovsky et al., 2003; Niesler et al., 2003). However, only the 5-HT3A and the 5-HT3B subunit have been shown to form functional receptors. Furthermore, whereas 5-HT3A subunits can form functional homomeric receptors, 5-HT3B subunits must combine with 5-HT3A subunits to form functional heteromeric receptors. In general, 5-HT3A receptors are more widely distributed in the central nervous system than 5-HT3AB receptors. Expression of the latter has been detected by some (Davies et al., 1999; Dubin et al., 1999; Monk et al., 2001; Reeves and Lummis, 2006) but not all (Morales and Wang, 2002) studies in specific areas of the mammalian brain with strongest expression found in the amygdala and the hippocampus.
5-HT3 receptors are thought to play an important role in alcoholism (McBride et al., 2004), and clinical studies have shown that 5-HT3 receptor antagonists are effective at reducing the craving for alcohol, the number of drinking episodes, and the symptoms of anxiety, depression, and hostility that are frequently associated with alcoholism (Johnson et al., 2000; Johnson et al., 2002, 2003; Dawes et al., 2005). Therefore, understanding how alcohols act on 5-HT3 receptors has important implications for developing new pharmacological strategies for treating alcoholism.
In addition, 5-HT3 receptors have been shown to modulate the release of GABA in neurons located in the amygdala (Koyama et al., 2000), cerebral cortex (Zhou and Hablitz, 1999; Puig et al., 2004), hippocampus (McMahon and Kauer, 1997), and spinal cord (Alhaider et al., 1991), suggesting an indirect role for 5-HT3 receptors in generating the state of anesthesia.
Alcohols modulate currents mediated by 5-HT3 receptors found in neuroblastoma cells (Lovinger, 1991; Lovinger and White, 1991; Jenkins et al., 1996) and mammalian neurons (Lovinger and White, 1991; Lovinger and Zhou, 1993) as well as 5-HT3A receptors recombinantly expressed in a mammalian cell line (Lovinger and Zhou, 1994) and Xenopus oocytes (Machu and Harris, 1994). Such modulation is dependent on the size of the alcohol (Jenkins et al., 1996; Stevens et al., 2005b) and the subunit combination of the receptor (Stevens et al., 2005a). Alcohols with small (but not large) molecular volumes increase the amplitude of currents evoked by low 5-HT concentrations and shift the 5-HT concentration-response curve for 5-HT3 receptor activation leftward, indicative of increased receptor sensitivity to agonist (Stevens et al., 2005b). However, this action is significantly smaller when currents are mediated by 5-HT3AB receptors compared with 5-HT3A receptors (Stevens et al., 2005a).
Alcohols may increase the sensitivity of receptors for agonist by increasing either the affinity of the agonist to the receptor and/or the efficacy of channel gating once agonist has bound. Disentangling the effects of alcohols on these two kinetic steps is not possible when using a highly efficacious agonist (e.g., 5-HT for 5-HT3 receptors) because in either case, the agonist concentration-response curve shifts leftward with no detectable increase in the maximal evoked current evoked by high concentrations of agonist. However, changes in binding affinity and gating efficacy are readily distinguished when using an inefficacious agonist because an increase in channel gating efficacy produces a measurable increase in the peak current amplitude evoked by high, receptor-saturating concentrations of agonist. In this study, we used the inefficacious 5-HT3 agonist dopamine (DA) to resolve the effects of alcohols on 5-HT3 receptor agonist binding affinity and channel gating efficacy to better understand why incorporation of the 5-HT3B subunit into 5-HT3 receptors attenuates alcohol sensitivity.
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Materials and Methods |
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Molecular Biology
cDNA encoding the human 5-HT3A and 5-HT3B subunits was generously provided by E. Kirkness (The Institute for Genomic Research, Rockville, MD) and transcribed into mRNA using the mMessage mMachine High Yield Capped RNA Transcription kit (Ambion, Austin, TX).
Oocyte Procedures and Receptor Expression
Oocytes were harvested from human chorionic gonadotropin-injected adult female X. laevis (H. Kähler, "Bedarf für Forschung und Lehre", Hamburg, Germany) under anesthesia with 0.2% ethyl 3-aminobenzoate methanesulfonate salt (tricaine) and hypothermia. Defolliculated stage V and VI oocytes were injected with 30 to 50 nl of mRNA encoding for the 5-HT3A subunit or with a mRNA mixture encoding for both the 5-HT3A and 5-HT3B subunits (in the ratio of 1:2 by concentration for the 5-HT3A subunit/5-HT3B subunit). Oocytes were incubated at 18°C in ND96 solution (96 mM NaCl, 2 mM KCl, 10 mM HEPES, 1.8 mM CaCl2, and 1.0 mM MgCl2, pH 7.5) supplemented with 20 µg/ml gentamicin and 2.5 mM pyruvate.
Drugs, Chemicals, and Preparation of Solutions
Tricaine, collagenase IA, 5-HT, DA, ethanol, propanol, butanol, pentanol, hexanol, and octanol were purchased from Sigma-Aldrich (St. Louis, MO).
The anesthetizing concentrations of n-alcohols were defined as aqueous concentrations that cause loss of righting reflex in tadpoles (Alifimoff et al., 1989). Alcohol stock solutions containing eight times the anesthetizing concentration were prepared by adding the appropriate quantity of alcohol to ND96 solution and stirring for at least 12 h before dilution with ND96 solution to obtain the final desired alcohol concentration. To minimize DA oxidation and precipitation, ND96 solution was deoxygenated by stirring under vacuum for at least 30 min and then cooled to 4°C before adding DA. Immediately before experimental use, solutions containing DA were warmed to room temperature using a water bath.
Electrophysiology
Electrophysiological experiments using the two-microelectrode voltage-clamp technique were carried out at room temperature (21°C) 1 to 7 days following the injection of the mRNA encoding the 5-HT3A or the mRNA mix encoding the 5-HT3A subunit and the 5-HT3B subunit, respectively. Oocytes were placed in a 40-µl custom-made flow chamber. They were impaled with two capillary glass pipettes filled with 3 mM KCl (resistance <5M
, voltage-clamped at -50 mV, Turbo TEC 10CX amplifier; Science Products GmbH, Hofheim, Germany) and constantly superfused with ND96 solution at a rate of 5 ml/min. The perfusion apparatus was constructed of glass syringes and Teflon tubing to minimize absorptive loss of alcohols. Superfusion was controlled with a six-channel valve controller (Hugo Sachs Elektronik-Harvard Apparatus GmbH, March-Hugstetten, Germany). Currents were recorded on a personal computer running custom-made software (PC.DAQ1.1, developed at the Institute of Physiology, University of Marburg, Marburg, Germany), filtered at 1 kHz, and sampled at 100 Hz.
Experimental Protocols
Agonist Concentration-Response Studies. The 5-HT and DA concentration ranges were chosen based on previous studies (Solt et al., 2005; Stevens et al., 2005a,b). The duration of 5-HT and DA application was varied from 15 to 60 s, depending upon the concentration of agonist studied, to achieve a peak current response. Each test experiment using the desired agonist concentration was preceded and followed by a control experiment using a maximally activating concentration of 5-HT (100 µM for 5-HT3A receptors and 300 µM for 5-HT3AB receptors). The average of these two controls was used to normalize the submaximal agonist peak current response. To assess the effect of alcohol on DA concentration-response relationship, oocytes were perfused for 30 s with alcohol in ND96 solution and then with alcohol plus DA in ND96 solution. In all experiments, a 3- to 5-min recovery period was used to minimize the impact of desensitization on peak current response.
Alcohol Concentration-Response Relationship Experiments. To study the concentration-dependent effects of n-alcohols on peak currents elicited by a maximally activating concentration of DA (1 mM in 5-HT3A receptors and 3 mM in 5-HT3AB receptors), oocytes were preincubated for 30 s with ND96 solution containing the desired concentration of alcohol (0.5, 1, 2, and 4 times their anesthetizing concentration), followed by a coapplication of alcohol plus DA for 30 s in 5-HT3A and 20 s in 5-HT3AB receptors (test experiment). Each test experiment was preceded and followed by DA (1 mM in 5-HT3A receptors and 3 mM in 5-HT3AB receptors, control experiment), to normalize peak current responses. Each sweep (test and control) was followed by a recovery period of 3 to 5 min.
Data Analysis
Agonist Concentration-Response Relationship Analysis. Agonist concentration-response curves were fitted by nonlinear least-squares to the following Hill equation:
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Alcohol Concentration-Response Relationship and Alcohol Comparison Analysis. Peak currents elicited by DA in the presence of alcohol were normalized to the average of peak current responses elicited by a maximally activating concentration of DA (1 mM in 5-HT3A receptors and 3 mM in 5-HT3AB receptors) immediately preceding and following the test sweep.
Statistical Analysis
Comparison of modulation of normalized peak currents elicited by maximally activating concentrations of DA in 5-HT3A receptors to those in 5-HT3AB receptors in the presence of select alcohols at various concentrations was performed using the two-way analysis of variance followed by the Student's t test (Prism 4.0 software; GraphPad Software Inc., San Diego, CA) with a statistical significance set at p < 0.05 for the former and at p < 0.0125 for the latter (Bonferroni correction due to the four concentrations studied).
Comparison of potentiation by butanol of peak currents evoked by maximally activating concentrations of DA in the absence of octanol to potentiation by butanol in the presence of octanol in 5-HT3A and 5-HT3AB receptors was done using the Student's t test (Prism 4.0 software; GraphPad Software Inc.) with a statistical significance set at p < 0.05.
Miscellaneous
The molecular volumes of all agents were determined using MacSpartan Pro version 1.01 (Wavefunction, Inc., Irvine, CA) on an Apple MacIntosh G4 computer (Apple Computer, Cupertino, CA). Geometry optimization was achieved using ab initio molecular orbital calculations (Hartree-Fock, 3-21G basis set).
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Results |
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Alcohol Concentration-Response Relationships. Figure 2 shows sample traces demonstrating the effects of a representative small (butanol) and large (octanol) alcohol at 21.6 and 0.11 mM, respectively (twice their anesthetizing concentrations) on currents elicited by a maximally activating concentration of DA (1 mM in 5-HT3A receptors and 3 mM in 5-HT3AB receptors). Enhancement of peak currents by butanol was markedly greater in 5-HT3A receptors compared with 5-HT3AB receptors, whereas inhibition of peak currents by octanol was similar in both receptor subtypes.
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Alcohol Competition Experiments. To test the hypothesis that the potentiating actions of small alcohols and the inhibitory actions of large alcohols are mediated by different alcohol binding sites, the magnitude of the potentiation by butanol was determined in the presence versus the absence of octanol. In 5-HT3A receptors (n = 8), potentiation by 21.6 mM butanol in the absence (449 ± 53.6%) and presence (445 ± 62.5%) of 0.11 mM octanol was not statistically different (p = 0.9). Likewise, in 5-HT3AB receptors (n = 7), potentiation by 21.6 mM butanol in the absence (200 ± 20.3%) and presence (211 ± 25.4%) of 0.11 mM octanol was not different (p = 0.39).
DA Concentration-Response Relationships in the Absence and Presence of n-Alcohols. To further resolve the actions of alcohols on the agonist affinity and channel gating efficacy of the two receptor subtypes, DA concentration-response curves were generated in the absence and presence of a representative small (butanol) and large (octanol) alcohol. As shown in Table 3 and illustrated in Fig. 4, butanol had profound effects on currents elicited by high DA concentrations (Imax) in both receptor subtypes. However, the increase in DA Imax induced by butanol was greater when currents were mediated by 5-HT3A receptors compared with 5-HT3AB receptors (4.9-fold increase versus 1.8-fold increase). In contrast, the reduction of Imax induced by octanol was similar in both receptor subtypes. Moreover, both butanol and octanol only minimally changed the agonist EC50 and the Hill coefficient in both 5-HT3A and 5-HT3AB receptors.
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Discussion |
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Our finding that small alcohols enhance 5-HT3A and 5-HT3AB receptor function by facilitating receptor gating is consistent with the results of a previous study that applied a similar approach to investigate potentiation of 5-HT3 receptors by ethanol and trichloroethanol (Lovinger et al., 2000). In that study, ethanol and trichloroethanol were found to potentiate responses to a receptor-saturating concentration of DA in 5-HT3 receptors expressed in NCB-20 neuroblastoma cells. These results indicated that one action of ethanol and trichloroethanol on 5-HT3 receptors is to increase the efficacy of channel opening independently of any effect on agonist binding affinity to the 5-HT3 receptor. However, since NCB-20 neuroblastoma cells produce mRNA for both 5-HT3A and 5-HT3B receptor subunits (Hanna et al., 2000), it was not possible to determine whether the agonist-evoked currents recorded in that study were mediated by 5-HT3A receptors, 5-HT3AB receptors, or both. We therefore chose a heterologous expression system (X. laevis oocytes) that enabled us to study the underlying mechanism accounting for the difference in alcohol-induced sensitivity in recombinant human 5-HT3A and 5-HT3AB receptors separately.
Partial agonists have been used in various other ligand-gated ion channel systems to resolve the underlying mechanism(s) of action of modulators such as alcohols. Wu et al. (1994) used suberyldicholine, a partial agonist for nicotinic acetylcholine receptors, to study the underlying mechanisms of potentiation of nicotinic acetylcholine receptor activity by ethanol. Using rapid flux techniques, they demonstrated that the primary action of ethanol is to stabilize the nicotinic acetylcholine receptor's open channel state. Suberyldicholine was also used to examine the potentiating effects of isoflurane on nicotinic acetylcholine receptors (Raines and Zachariah, 2000). In contrast to ethanol's action on nicotinic acetylcholine receptors, isoflurane potentiates nicotinic acetylcholine receptor activity by enhancing agonist binding affinity with little effect on channel gating efficacy. The mechanisms underlying the potentiating effects of isoflurane and etomidate in GABAA receptors were studied electrophysiologically using the partial agonist piperidine-4-sulfonic acid (Topf et al., 2003; Rusch et al., 2004). These studies found that both anesthetics exert at least some of their modulating effects on GABAA receptors by enhancing channel gating. More recently, the potentiating effects of small volatile anesthetics on 5-HT3A and 5-HT3AB were studied electrophysiologically using DA (Solt et al., 2005). The results of that study parallel our findings with alcohols in the present study: 1) volatile anesthetics potentiate receptor function by enhancing gating efficacy, and 2) gating enhancement is dependent on receptor subunit composition with the magnitude of gating enhancement being greater in 5-HT3A relative to 5-HT3AB receptors.
Previous studies by Stevens et al. (2005a,b) demonstrated that there is a strong inverse correlation between alcohol molecular volume and the magnitude of current potentiation produced by equianesthetic concentrations of alcohols in both 5-HT3 receptor subtypes. They also found that alcohols larger than pentanol produce no potentiation at all. Based upon these results, it was suggested that alcohols enhance currents elicited by low concentrations of agonist by binding to a protein cavity that physically limits the binding of alcohols larger than 
110 Å3, the molecular volume of pentanol.
Consistent with Stevens et al. (2005a,b), we found that only alcohols smaller than hexanol enhanced channel gating efficacy and that the magnitude of this enhancement (as reflected in the increase in maximal DA-evoked currents produced by alcohols) correlated inversely with alcohol molecular volume. However, ethanol, which would be expected to have the greatest effect on channel gating efficacy because of its small size, had less effect than either propanol or butanol on both 5-HT3 receptor subtypes (Fig. 5). One possible reason for this apparent anomaly is that the small volume (relative to that of the protein cavity) of ethanol impairs its ability to simultaneously engage in all possible attractive van der Waals interactions with the cavity's lining (Eckenhoff and Johansson, 1997). This could explain why, when normalized to their anesthetizing concentrations, trichloroethanol (99 Å3) produces significantly more potentiation than ethanol (57 Å3) (Lovinger et al., 2000; Hayrapetyan et al., 2005).
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) that 5-HT3 receptors have different sites for potentiation and inhibition of agonist-evoked currents: a smaller binding site having a volume of less than 110 Å3 that mediates the potentiating effects of small alcohols and a larger binding site that mediates the inhibitory actions of larger alcohols. The results of our alcohol competition experiments are consistent with the existence of two distinct binding sites on 5-HT3 receptors as potentiation of peak currents evoked by maximally activating concentrations of DA by butanol was not reduced by the presence of octanol.
In summary, our study demonstrates that small alcohols potentiate 5-HT3 receptor function by enhancing receptor gating efficacy without affecting agonist binding affinity in both 5-HT3 receptor subtypes. However, gating enhancement by small alcohols is greater in 5-HT3A receptors compared with 5-HT3AB receptors. In addition, our study reveals that the magnitude of gating enhancement by small n-alcohols depends on size of the n-alcohol, consistent with the existence of a receptor binding site into which alcohols must fit optimally to most efficaciously enhance channel gating.
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Acknowledgements |
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Footnotes |
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Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.
ABBREVIATIONS: 5-HT, 5-hydroxytryptamine (serotonin); 5-HT3, 5-hydroxytryptamine type 3; DA, dopamine.
Address correspondence to: Dr. Dirk Rüsch, Department of Anesthesia and Critical Care, University Hospital Giessen-Marburg GmbH, Marburg Campus, Baldingerstrasse, 35033 Marburg, Germany. E-mail: ruesch{at}staff.uni-marburg.de
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References |
|---|
|
TopAbstractMaterials and MethodsResultsDiscussionReferences |
|---|
Alhaider AA, Lei SZ, and Wilcox GL (1991) Spinal 5-HT3 receptor-mediated antinociception: possible release of GABA. J Neurosci 11: 1881-1888.[Abstract]
Alifimoff JK, Firestone LL, and Miller KW (1989) Anaesthetic potencies of primary alkanols: implications for the molecular dimensions of the anaesthetic site. Br J Pharmacol 96: 9-16.[Medline]
Davies PA, Pistis M, Hanna MC, Peters JA, Lambert JJ, Hales TG, and Kirkness EF (1999) The 5-HT3B subunit is a major determinant of serotonin-receptor function. Nature (Lond) 397: 359-363.[CrossRef][Medline]
Dawes MA, Johnson BA, Ma JZ, Ait-Daoud N, Thomas SE, and Cornelius JR (2005) Reductions in and relations between "craving" and drinking in a prospective, open-label trial of ondansetron in adolescents with alcohol dependence. Addict Behav 30: 1630-1637.[CrossRef][Medline]
Dubin AE, Huvar R, D'Andrea MR, Pyati J, Zhu JY, Joy KC, Wilson SJ, Galindo JE, Glass CA, Luo L, et al. (1999) The pharmacological and functional characteristics of the serotonin 5-HT(3A) receptor are specifically modified by a 5-HT(3B) receptor subunit. J Biol Chem 274: 30799-30810.
Eckenhoff RG and Johansson JS (1997) Molecular interactions between inhaled anesthetics and proteins. Pharmacol Rev 49: 343-367.
Hanna MC, Davies PA, Hales TG, and Kirkness EF (2000) Evidence for expression of heteromeric serotonin 5-HT(3) receptors in rodents. J Neurochem 75: 240-247.[CrossRef][Medline]
Hayrapetyan V, Jenschke M, Dillon GH, and Machu TK (2005) Co-expression of the 5-HT(3B) subunit with the 5-HT(3A) receptor reduces alcohol sensitivity. Brain Res Mol Brain Res 142: 146-150.[Medline]
Jenkins A, Franks NP, and Lieb WR (1996) Actions of general anaesthetics on 5-HT3 receptors in N1E-115 neuroblastoma cells. Br J Pharmacol 117: 1507-1515.[Medline]
Johnson BA, Ait-Daoud N, Ma JZ, and Wang Y (2003) Ondansetron reduces mood disturbance among biologically predisposed, alcohol-dependent individuals. Alcohol Clin Exp Res 27: 1773-1779.[CrossRef][Medline]
Johnson BA, Roache JD, Ait-Daoud N, Zanca NA, and Velazquez M (2002) Ondansetron reduces the craving of biologically predisposed alcoholics. Psychopharmacology (Berl) 160: 408-413.[CrossRef][Medline]
Johnson BA, Roache JD, Javors MA, DiClemente CC, Cloninger CR, Prihoda TJ, Bordnick PS, Ait-Daoud N, and Hensler J (2000) Ondansetron for reduction of drinking among biologically predisposed alcoholic patients: a randomized controlled trial. J Am Med Assoc 284: 963-971.
Karnovsky AM, Gotow LF, McKinley DD, Piechan JL, Ruble CL, Mills CJ, Schellin KA, Slightom JL, Fitzgerald LR, Benjamin CW, et al. (2003) A cluster of novel serotonin receptor 3-like genes on human chromosome 3. Gene (Amst) 319: 137-148.[CrossRef][Medline]
Koyama S, Matsumoto N, Kubo C, and Akaike N (2000) Presynaptic 5-HT3 receptor-mediated modulation of synaptic GABA release in the mechanically dissociated rat amygdala neurons. J Physiol (Lond) 529: 373-383.
Lovinger DM (1991) Ethanol potentiation of 5-HT3 receptor-mediated ion current in NCB-20 neuroblastoma cells. Neurosci Lett 122: 57-60.[CrossRef][Medline]
Lovinger DM, Sung KW, and Zhou Q (2000) Ethanol and trichloroethanol alter gating of 5-HT3 receptor-channels in NCB-20 neuroblastoma cells. Neuropharmacology 39: 561-570.[CrossRef][Medline]
Lovinger DM and White G (1991) Ethanol potentiation of 5-hydroxytryptamine3 receptor-mediated ion current in neuroblastoma cells and isolated adult mammalian neurons. Mol Pharmacol 40: 263-270.[Abstract]
Lovinger DM and Zhou Q (1993) Trichloroethanol potentiation of 5-hydroxytryptamine3 receptor-mediated ion current in nodose ganglion neurons from the adult rat. J Pharmacol Exp Ther 265: 771-776.
Lovinger DM and Zhou Q (1994) Alcohols potentiate ion current mediated by recombinant 5-HT3RA receptors expressed in a mammalian cell line. Neuropharmacology 33: 1567-1572.[CrossRef][Medline]
Machu TK and Harris RA (1994) Alcohols and anesthetics enhance the function of 5-hydroxytryptamine3 receptors expressed in Xenopus laevis oocytes. J Pharmacol Exp Ther 271: 898-905.
Maricq AV, Peterson AS, Brake AJ, Myers RM, and Julius D (1991) Primary structure and functional expression of the 5HT3 receptor, a serotonin-gated ion channel. Science (Wash DC) 254: 432-437.
McBride WJ, Lovinger DM, Machu T, Thielen RJ, Rodd ZA, Murphy JM, Roache JD, and Johnson BA (2004) Serotonin-3 receptors in the actions of alcohol, alcohol reinforcement, and alcoholism. Alcohol Clin Exp Res 28: 257-267.[CrossRef][Medline]
McMahon LL and Kauer JA (1997) Hippocampal interneurons are excited via serotonin-gated ion channels. J Neurophysiol 78: 2493-2502.
Monk SA, Desai K, Brady CA, Williams JM, Lin L, Princivalle A, Hope AG, and Barnes NM (2001) Generation of a selective 5-HT3B subunit-recognising polyclonal antibody; identification of immunoreactive cells in rat hippocampus. Neuropharmacology 41: 1013-1016.[CrossRef][Medline]
Morales M and Wang SD (2002) Differential composition of 5-hydroxytryptamine3 receptors synthesized in the rat CNS and peripheral nervous system. J Neurosci 22: 6732-6741.
Niesler B, Frank B, Kapeller J, and Rappold GA (2003) Cloning, physical mapping and expression analysis of the human 5-HT3 serotonin receptor-like genes HTR3C, HTR3D and HTR3E. Gene (Amst) 310: 101-111.[CrossRef][Medline]
Puig MV, Santana N, Celada P, Mengod G, and Artigas F (2004) In vivo excitation of GABA interneurons in the medial prefrontal cortex through 5-HT3 receptors. Cereb Cortex 14: 1365-1375.
Raines DE and Zachariah VT (2000) Isoflurane increases the apparent agonist affinity of the nicotinic acetylcholine receptor by reducing the microscopic agonist dissociation constant. Anesthesiology 92: 775-785.[CrossRef][Medline]
Reeves DC and Lummis SC (2006) Detection of human and rodent 5-HT3B receptor subunits by anti-peptide polyclonal antibodies. BMC Neurosci 7: 27.[CrossRef][Medline]
Rüsch D, Zhong H, and Forman SA (2004) Gating allosterism at a single class of etomidate sites on 
1
2
2L GABA A receptors accounts for both direct activation and agonist modulation. J Biol Chem 279: 20982-20992.
Solt K, Stevens RJ, Davies PA, and Raines DE (2005) General anesthetic-induced channel gating enhancement of 5-hydroxytryptamine type 3 receptors depends on receptor subunit composition. J Pharmacol Exp Ther 315: 771-776.
Stevens R, Rusch D, Solt K, Raines DE, and Davies PA (2005a) Modulation of human 5-hydroxytryptamine type 3AB receptors by volatile anesthetics and n-alcohols. J Pharmacol Exp Ther 314: 338-345.
Stevens RJ, Rusch D, Davies PA, and Raines DE (2005b) Molecular properties important for inhaled anesthetic action on human 5-HT3A receptors. Anesth Analg 100: 1696-1703.
Topf N, Jenkins A, Baron N, and Harrison NL (2003) Effects of isoflurane on gamma-aminobutyric acid type A receptors activated by full and partial agonists. Anesthesiology 98: 306-311.[CrossRef][Medline]
Wu G, Tonner PH, and Miller KW (1994) Ethanol stabilizes the open channel state of the Torpedo nicotinic acetylcholine receptor. Mol Pharmacol 45: 102-108.[Abstract]
Zhou FM and Hablitz JJ (1999) Activation of serotonin receptors modulates synaptic transmission in rat cerebral cortex. J Neurophysiol 82: 2989-2999.
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