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1Section of Neurobiology, Physiology, and Behavior, University of California, Davis, California; 2Givaudan Flavors Corporation, Cincinnati, Ohio; and 3Unité de Formation et de Recherche d’Odontologie, University Paris 7, Paris, France
Submitted 3 April 2006; accepted in final form 6 June 2006
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONMETHODSRESULTSDISCUSSIONGRANTSREFERENCES |
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONMETHODSRESULTSDISCUSSIONGRANTSREFERENCES |
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; Dessirier et al. 2000b; Jinks and Carstens 1999; Sudo et al. 2002). Nicotine also has a bitter taste and excites chorda tympani and glossopharyngeal nerve fibers (Dahl et al. 1997) as well as gustatory neurons in NTS (e.g., Lemon and Smith 2005) and cerebral cortex (Katz et al. 2001; Scott et al. 1999). Moreover, nicotine has been reported to alter certain taste qualities (Grunberg 1982). We were therefore interested in investigating possible effects of nicotine on gustatory transmission. We previously reported that capsaicin, the pungent irritant in red chili peppers, reduces the perceived intensity of sucrose-induced sweetness and quinine-induced bitterness in humans (Simons et al. 2002) and depresses tastant-evoked responses of gustatory neurons in the nucleus of the solitary tract (NTS) of rats (Simons et al. 2003a). The NTS is the first central relay in the gustatory pathway from taste buds of the tongue and represents a nodal point for modulation of taste signals (Boucher et al. 2003; Smith et al. 2005). In the present study, we investigated whether nicotine delivered to the oral cavity affects the gustatory responses of rat NTS neurons. |
METHODS |
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TOPABSTRACTINTRODUCTIONMETHODSRESULTSDISCUSSIONGRANTSREFERENCES |
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A total of 45 adult male Sprague–Dawley rats (Simonsen, Gilroy, CA), weighing approximately 450 g, were used. They were housed two per cage in a vivarium maintained on a 12-h light/dark cycle at about 21°C with unrestricted access to food and water. All procedures were in accordance with the National Institutes of Health animal welfare guide and were approved by the University of California Davis Animal Use and Care Advisory committee.
Surgery
Anesthesia was induced with sodium pentobarbital [65 mg/kg, administered intraperitoneally (ip)]. Core body temperature was maintained at about 37°C with a heating pad and external heat. A midline incision was made and the hypoglossal nerve was cut bilaterally to prevent spontaneous tongue movement, followed by tracheostomy and jugular cannulation for constant infusion of pentobarbital (10 mg · kg–1 · h–1). The head was fixed in a stereotaxic frame with atraumatic ear bars, a midline incision was made, and bone was removed to expose the brain stem. The transverse sinus was ligated bilaterally and the cerebellum was aspirated to expose the medulla. The mouth was opened and maintained moist with distilled water to prevent desiccation.
For rats receiving bilateral trigeminal ganglionectomy (n = 7), the identical procedures were followed except that the trigeminal ganglia were additionally exposed bilaterally after decerebration and sectioned with a microknife as in our previous studies (Boucher et al. 2003a; Simons et al. 2003a). The ganglionectomy was verified visually. Ganglionectomy disrupts input from all three branches of the trigeminal nerve bilaterally.
Recording and stimulation
A Teflon-insulated tungsten recording electrode (18–20 M
; FHC, Brunswick, ME) was advanced into the brain stem (2.7 mm anterior to obex; 1.8 mm lateral to midline) by hydraulic microdrive (David Kopf Instruments, Tujunga, CA). Gustatory NTS units with receptive fields anterior to the premolar eminence were encountered at depths ranging from about 700 to 1,000 µm below the brain stem surface. Extracellular single-unit activity was amplified, displayed, and routed to a computer for analysis and storage. During recording sessions that rarely lasted more than 2 h, the identity of the action potential based on amplitude (usually 3:1 or greater signal-to-noise ratio) and waveform was continually checked on-line. Action potential data wereanalyzed off-line using software that allowed sorting of action potentials using a template-matching procedure (Forster and Handwerker 1990). An example of our procedure to ensure single-unit identity is provided in Fig. 1, which shows 10 consecutively recorded and superimposed action potentials at the beginning of the recording session (left spike inset) and 10 more near the end of the recording session (right spike inset).
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), using a taste mixture containing the following reagent-grade chemicals: sucrose (0.3 M; Mallinkrodt, Paris, KY), NaCl (0.1 M; Fisher Scientific, Fair Lawn, NJ), citric acid (0.03 M; Mallinkrodt), quinine HCl (0.01 M; Sigma, St. Louis, MO), and monosodium glutamate (MSG, 0.2 M; Sigma). When a responsive unit was isolated, each of the five tastants was applied individually at a constant rate (about 0.2 ml/s) to the anterior lingual surface for 15 s and left on for an additional 15 s, followed immediately by a distilled water rinse (3 ml). Recordings were made for a 90-s period beginning 30 s before the stimulus until 30 s after stimulus cessation. Responses were quantified as the total number of impulses during the 30-s stimulus period. Each tastant was applied at least twice to establish which elicited the relatively largest response. The "best" tastant was then reapplied three times successively to establish response reproducibility. All solutions were delivered at room temperature. After establishing a stable response (±10% of mean response to three stimuli), the unit was tested with one concentration of nicotine (0.87, 8.7, or 600 mM in distilled water; Sigma), which was applied by a hand-held syringe at a constant flow rate (about 0.1 ml/s) to the anterior tongue for 4 min. Nicotine-evoked responses were quantified as the number of impulses during the 4-min application period. Immediately after the end of the nicotine application, the "best" tastant was reapplied as before at 3-min intervals for 12 min. This range of nicotine concentrations was chosen for comparison with our previous studies of nicotinic excitation of trigeminal caudalis neurons (Carstens et al. 1998; Desserier et al. 2000b).
We tested the effect of the nicotinic antagonist mecamylamine (4.9 mM [0.1%] in distilled water; Sigma) by applying it topically to the dorsal tongue surface 2 min before and during the 4-min nicotine application. This concentration of mecamylamine was selected based on our previous studies showing that 4.9 mM mecamylamine significantly reduced c-fos expression and Vc neuronal responses elicited by nicotine delivered to the tongue surface (Carstens et al. 1998, 2000). Moreover, this mecamylamine concentration selectively reduced lingual irritation in humans (Dessirier et al. 1998) and rat Vc neuronal responses (Carstens et al. 1998) elicited by nicotine but not capsaicin.
Histology
At the end of each experiment, an electrolytic lesion was made at the recording site by passing DC (6 V) through the microelectrode for 30 s. Animals were killed by an intravenous overdose of pentobarbital. Brain stems were postfixed in 10% formalin and later cut in 50-µm frozen sections and counterstained with Neutral Red. Lesions were identified under the light microscope and were all localized within the rostral pole of NTS as in our previous study (Simons et al. 2003a).
Data analysis
To determine whether gustatory units responded to nicotine, the total number of spikes elicited during each 1 s before and after the start of nicotine delivery was compared using one-way ANOVA followed by post hoc Dunnett’s test. The gustatory responses evoked by 8.7 and 600 mM nicotine were subsequently compared using ANOVA (group and time as main effects). The effect of mecamylamine and ganglionectomy on nicotine-evoked gustatory responses was measured using repeated-measures ANOVA (group as between-subjects effect and time as within-subjects effect). Finally, the ability of nicotine to modulate tastant-evoked responses was evaluated by comparing the averaged tastant-evoked responses before nicotine with that elicited immediately, 3, 6, 9, and 12 min postnicotine using two-way ANOVA (neuron and time as main effects) followed by post hoc Tukey HSD multiple-comparison tests. Unit tastant-evoked responses were averaged in 1-s bins to construct averaged peristimulus time histograms (PSTHs). All data are presented as means ± SE and P < 0.05 was taken as significant.
Plasma extravasation
Rats were anesthetized with sodium pentobarbital (65 mg/kg, ip). Evans blue dye (50 mg/kg) was injected intravenously and either nicotine (600 mM, n = 4) or vehicle (Ringers solution, n = 8) was applied for 4 min by constant flow (about 0.2 ml/s) to the dorsal surface of the tongue. Animals were then perfused intracardially with saline.
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RESULTS |
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TOPABSTRACTINTRODUCTIONMETHODSRESULTSDISCUSSIONGRANTSREFERENCES |
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Recordings were made from 26 gustatory neurons in 26 intact rats. All units were histologically localized to the rostral pole of NTS. In the intact rats, the unit sample consisted of four sucrose-best, 11 NaCl-best, nine citric acid–best, and two MSG-best. A typical example of a unit that responded best to sucrose and MSG, but also to NaCl and citric acid but not quinine, is shown in Fig. 1. In seven additional rats receiving bilateral trigeminal ganglionectomy, we recorded six citric acid–best and one NaCl-best unit; recording sites were also at the rostral pole of NTS.
Nicotine excitation of gustatory NTS units
After tastant-evoked responses were recorded, nicotine was delivered to the tongue. Figure 2 plots each individual unit’s response to nicotine versus its response to the preferred tastant. Several points are apparent. First, nicotine excited NTS units in a concentration-dependent manner, weakly exciting two of five cells at the lowest concentration (0.87 mM; Fig. 2A) and exciting eight of nine and five of six units at the 8.7 and 600 mM concentrations, respectively (Fig. 2, B and C). An example of a unit’s response to 8.7 mM nicotine is shown in Fig. 1. Figure 3, A–C shows averaged PSTHs of responses of separate groups of units to 0.87, 8.7, and 600 mM nicotine, respectively. The lowest nicotine concentration (0.87 mM) did not significantly increase the mean firing rate [F(359,1436) = 0.942; P = 0.756, Fig. 3A], whereas there was a significant increase in firing above baseline levels [F(359,2872) = 7.165; P < 0.001] after the onset of the 8.7 mM nicotine application (P < 0.001, post hoc Dunnett test; Fig. 3B). The averaged response of a different group of six units to 600 mM nicotine similarly elicited a significant increase in firing [F(359,1795) = 3.091; P < 0.001] (Fig. 3C). However, the overall size of the response evoked by 600 mM nicotine was significantly [F(1,4213) = 393.4; P < 0.001] smaller than the response evoked by 8.7 mM nicotine.
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Nicotine has a bitter taste, and we were interested whether its excitation of NTS units is mediated by neuronal nicotinic acetylcholine receptors (nAChRs). We therefore tested whether the nicotinic antagonist mecamylamine reduced nicotine-evoked responses. Figure 2D shows that, in the presence of 0.1% mecamylamine, four of six units responded weakly or not at all to 8.7 mM nicotine, although two units responded appreciably. The averaged PSTH shown in Fig. 3D shows that the response during the first minute of nicotine application was reduced in magnitude when compared with the group of animals not receiving mecamylamine pretreatment [F(1,55) = 3.7, P = 0.06]. Mecamylamine by itself did not change unit firing rates, which suggests that nicotinic excitation of gustatory NTS units may partly involve nAChRs.
Nicotine might activate NTS units by exciting gustatory afferent fibers in the chorda tympani or by exciting trigeminal afferent fibers with collaterals projecting to gustatory NTS. To investigate the latter possibility, we recorded responses of gustatory NTS units in rats that had received bilateral trigeminal ganglionectomy. Figure 2E shows that NTS units still responded to nicotine after ganglionectomy, with four units exhibiting large responses to nicotine and three weak responses. In this group, magnitudes of nicotine- and tastant-evoked responses were significantly correlated (Fig. 2E). Furthermore, the mean firing rate during nicotine administration was significantly [F(359,2154) = 3.06; P < 0.001] greater than prenicotine baseline (Fig. 3D) and similar to that observed in intact animals (Fig. 3B). The averaged nicotine-evoked response of NTS units from ganglionectomized rats was not significantly different compared with that from intact rats [F(1,5399) = 0.131; P = 0.718]. These results indicate that nicotine excites NTS units by the taste nerves.
Nicotine suppression of tastant-evoked responses
Nicotine reduced tastant-evoked responses of NTS units in a concentration-dependent manner. Figure 1 shows an individual example in which sucrose-evoked responses were reduced postnicotine. The depressant effect of nicotine was generally similar, regardless of the unit’s preferred tastant. Figure 4 plots individual NTS units’ responses to the preferred tastant before nicotine versus its response after nicotine. At the lowest concentration, nicotine had little effect (Fig. 4A). At the intermediate dose, responses of sucrose- and NaCl-best units were depressed immediately postnicotine, as were responses of two of the four citric acid–best units (Fig. 4B). At the highest (600 mM) nicotine concentration, all tastant-evoked responses were considerably depressed postnicotine (Fig. 4C).
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). The lowest nicotine concentration (0.87 mM) did not significantly affect tastant-evoked responses. The intermediate (8.7 mM) concentration significantly depressed the mean tastant-evoked response of all units 
6 min postnicotine, compared with the mean prenicotine response (Fig. 5B). Responses of the sucrose-best and all NaCl-best units, as well as three of the four citric acid–best units, were reduced >20% at some time point postnicotine, with recovery within 9–12 min postnicotine. At the highest (600 mM) concentration, tastant-evoked responses were significantly depressed to a greater degree, with recovery within 9–12 min (Fig. 5C). Figure 6 shows averaged responses of NTS units to all tastants before (left column), immediately after application of nicotine (middle column), and 12 min later (right column). Although the lowest nicotine concentration (0.87 mM) had no effect [F(5,20) = 1.87, P = 0.145, Fig. 6A)], the 8.7 and 600 mM nicotine concentrations (Fig. 6, B and C, respectively) significantly reduced tastant-evoked responses to 54 ± 16% [F(5,400) = 4.20, P = 0.004] and 27 ± 7% [F(5,33) = 6.058, P = 0.001], respectively, followed by recovery.
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Mecamylamine given before and during nicotine application attenuated the depressant effect of nicotine on tastant-evoked responses of most NTS units. Figure 4D shows that in the presence of mecamylamine, there was little depression of tastant-evoked responses in four of six units, whereas two units still exhibited some suppression postnicotine. On average, whereas 8.7 mM nicotine significantly depressed tastant-evoked responses (Figs. 5B and 6B), after pretreatment with mecamylamine the same concentration of nicotine did not significantly [F(5,25) = 1.48, P = 0.232] suppress tastant-evoked response at any time point evaluated (Fig. 5D). Figure 6D shows that mecamylamine reduced the depressant effect of nicotine on the mean tastant-evoked response (compare Fig. 6, B and D). These results support a role for nAChRs in nicotinic depression of gustatory NTS responses.
Trigeminal ganglionectomy
To investigate whether the depressant effect of nicotine is mediated by excitation of trigeminal afferents innervating the oral cavity, we tested whether nicotine depressed tastant-evoked responses of NTS units in rats with bilateral trigeminal ganglionectomy. Figures 4E, 5E, and 6E show that 8.7 mM nicotine, which depressed responses in intact rats by roughly 50%, failed to reduce tastant-evoked responses in ganglionectomized rats [F(5,30) = 0.990, P = 0.441]. These results suggest that the depressant effect of nicotine is mediated by a central mechanism involving trigeminal modulation of gustatory processing in NTS. However, the ability of nicotine to directly excite NTS units in trigeminal ganglionectomized rats (Figs. 2E and 3E) indicates that nicotine also excites gustatory afferents.
Plasma extravasation
In a previous study (Simons et al. 2003a) we observed that topical application of capsaicin to the dorsal tongue resulted in a punctuate distribution of Evans Blue plasma extravasation. We presently tested whether nicotine had a similar effect. In four rats receiving systemic injection of Evans Blue and lingual nicotine (600 mM) and in eight control rats receiving lingual Ringers solution there was no localized or generalized coloration of the tongue, indicating that nicotine does not induce plasma extravasation.
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DISCUSSION |
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TOPABSTRACTINTRODUCTIONMETHODSRESULTSDISCUSSIONGRANTSREFERENCES |
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Nicotine was presently shown to excite gustatory NTS units in a manner that was partially antagonized by mecamylamine, implicating nAChRs. One possible pathway is by nicotinic excitation of nAChR-expressing trigeminal nociceptors (Liu and Simon 1996; Liu et al. 1993) in the oral cavity that project to trigeminal subnucleus caudalis (Vc) (Carstens et al. 1998; Dessirier et al. 2000b; Simons et al. 2003b; Sudo et al. 2002), some of which may give off collateral projections to the gustatory region of rostral NTS (Hamilton and Norgren 1984; Jacquin et al. 1983; Marfurt et al. 1991; Whitehead and Frank 1983). However, the observation that nicotine still excited gustatory NTS units in animals with bilateral trigeminal ganglionectomy (Figs. 2E and 3D) indicates that the excitatory effect was mediated by gustatory nerves. Nicotine was previously shown to excite chorda tympani and glossopharyngeal nerve fibers (Dahl et al. 1997) as well as gustatory NTS units (e.g., Lemon and Smith 2005). In the latter study, nicotine preferentially excited an "H/Q" subset of NTS units that responded nonselectively to acids, sodium salts, quinine, and other bitters (Lemon and Smith 2005), consistent with our present data. The attenuation in the initial nicotine-evoked response of NTS units by mecamylamine (Fig. 5C) suggests that nicotine acts, at least partially, by nAChRs expressed in taste receptor cells. Whereas nAChRs are expressed in peripheral nerves and skin cells (Gotti and Clementi 2004; Holladay et al. 1997) we are unaware of data showing nAChR expression in taste receptor cells as might be predicted by the present results. Nicotine has a bitter taste that might be mediated by a speculative nAChR-mediated activation of taste receptor cells or by muscarinic M1 (Ogura 2002) and/or one of the family of "bitter" T2R receptors (Chandrashekar et al. 2000; Mueller et al. 2005) that have been shown to be expressed in taste receptor cells.
An alternate possibility is that nicotine excites nociceptors with afferent fibers projecting by the chorda tympani to excite gustatory NTS units, although there is currently no evidence for this. It is noteworthy that capsaicin also excited a fraction of gustatory NTS units (Simons et al. 2003a), a finding that might also be attributed to activation of speculative nociceptive afferents or to its recently described bitter taste (Green and Schullery 2003).
Nicotine modulation of gustatory responses
Lingual nicotine dose-dependently reduced tastant-evoked responses of gustatory NTS units. The depression appeared in general to be equivalent regardless of which tastant best excited the unit (Figs. 4 and 5), similar to our previous study showing capsaicin depression of gustatory NTS units (Simons et al. 2003a). Mecamylamine significantly attenuated the depressant effect of nicotine on tastant-evoked responses (Fig. 5D), although there was some variation in its effects in individual units (Fig. 4D). Moreover, the depressant effect of nicotine was abolished after bilateral trigeminal ganglionectomy, suggesting an nAChR-mediated excitation of trigeminal afferents that exert a central inhibitory effect on gustatory NTS units (Fig. 7). Trigeminal afferents have collateral projections to the gustatory region of rostral NTS (Hamilton and Norgren 1984; Jacquin et al. 1983; Marfurt et al. 1991; Whitehead and Frank 1983) and electrical stimulation of the central cut end of the mandibular nerve can inhibit or enhance tastant-evoked responses of NTS units (Boucher et al. 2003). The gustatory NTS contains opioid peptide–and 
-aminobutyric acid (GABA)–containing neurons (Davis 1993; Davis and Kream 1993; Lynch et al. 1985) and GABA inhibits gustatory NTS neurons (Bradley and Grabauskas 1998). We propose that nicotine activates trigeminal afferents with collaterals to rostral NTS that excite inhibitory interneurons that, in turn, depress gustatory NTS units (Fig. 7). If such a circuit were tonically active, eliminating trigeminal input would be expected to enhance NTS responses to nicotine or tastants by disinhibition. However, even if the circuit were not tonically active, nicotine-evoked responses of NTS units in animals with trigeminal ganglionectomy would be expected to be larger compared with those in intact animals. This is because in the intact animals, nicotine directly excites NTS neurons by gustatory nerves, while simultaneously activating the trigeminally mediated inhibitory circuit that would serve to reduce the NTS response. Our observation that the mean NTS response to nicotine was actually smaller for the high (600 mM) versus intermediate (8.7 mM) concentration in intact animals is consistent with this because the larger nicotine stimulus may have generated stronger trigeminally mediated inhibition that outweighed nicotinic excitation of NTS units. Furthermore, our model would predict that nicotine-evoked responses should be larger in trigeminal ganglionectomized compared with intact animals. Our present data are suggestive in this regard, in that two units with the largest responses to nicotine were recorded after trigeminal ganglionectomy (Fig. 2E). However, there was variability in nicotine-evoked response magnitude such that the mean NTS unit response to 8.7 mM nicotine was not significantly different between intact and trigeminal ganglionectomized animals (Fig. 2, B and E). A direct test of the model would require comparing the same NTS unit’s responses to nicotine before and after trigeminal ganglionectomy; however, this would be confounded by the prolonged desensitizing effect induced by the initial nicotine stimulus.
Because nicotine has a bitter taste, another potential explanation for its effect on NTS units would be peripheral suppression of gustatory nerve responses to tastants, particularly sweets (e.g., Frank et al. 2005). Such a peripheral effect should still be observed at the level of NTS neurons after elimination of trigeminal input. Our observation that nicotine failed to suppress NTS tastant-evoked responses in animals with bilateral trigeminal ganglionectomy mitigates against a peripheral effect.
Comparison with capsaicin modulation of taste
Using similar methods we previously showed that 330 µM capsaicin reduced gustatory responses of NTS units by an average of roughly 40%, with a comparable degree of suppression (range: 44–73% of control) of responses to citric acid, sucrose, NaCl, and MSG (Simons et al. 2003a). The present results are similar in that nicotine dose-dependently reduced responses to all tastants tested. However, the proposed mechanism for nicotinic modulation of gustatory NTS activity appears to contrast with that of capsaicin. After bilateral trigeminal ganglionectomy, capsaicin still depressed gustatory NTS responses to almost the same degree (to 65.5% of control) as that in intact animals (to 61.5%) (Simons et al. 2003a), whereas nicotine suppression was eliminated (Figs. 4E and 5E). Moreover, capsaicin elicited a punctuate distribution of plasma extravasation matching the distribution of taste buds (Simons et al. 2003a), suggesting a peripheral site of action. One possibility is that local edema might alter accessibility of tastants to taste receptor cells within the taste buds, resulting in reduced tastant-evoked activity. This differs from our present observation of an absence of plasma extravasation after lingual nicotine. This latter finding is somewhat surprising given that nicotine excites roughly 20% of capsaicin-sensitive trigeminal ganglion cells (Liu and Simon 1996). It may be that nicotinic excitation of such a low percentage of capsaicin-sensitive trigeminal fibers is not sufficient to produce plasma extravasation by the axon reflex.
Nicotine depressed NTS tastant-evoked responses, regardless of the unit’s preferred tastant (Fig. 5). A potential explanation for this nonselective effect is a depression of taste receptor neuron excitability by nicotinic inhibition of voltage-sensitive Na+ channels (Liu et al. 2004). However, this possibility is mitigated by our finding that trigeminal ganglionectomy prevented nicotine modulation of NTS responses.
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GRANTS |
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FOOTNOTES |
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Address for reprint requests and other correspondence: E. Carstens, Section of Neurobiology, Physiology, and Behavior, University of California, Davis, 1 Shields Ave., Davis, CA 95616 (E-mail: eecarstens{at}ucdavis.edu)
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