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Area postrema lesions in rats appear to disrupt rapid feedback inhibition of fluid intake
BRAIN RESEARCH ELSEVIER
Brain Research 726 (1996) 31-38
Research report
Area postrema lesions in rats appear to disrupt rapid feedback inhibition of fluid intake Kathleen S. Curtis
a, Joseph
G. Verbalis b, Edward M. Stricker a, *
a Department of Neuroscience, 479 Crawford Hall, University of Pittsburgh, Pittsburgh, PA 15260, USA b Department of Medicine, Georgetown University, Medical School, Washington, DC 20007, USA
Accepted 20 February 1996
Abstract Area postrema lesions (APX) were produced by vacuum aspiration in adult male rats. After systemic administration of hypertonic saline solutions, significantly more water was consumed by rats with APX than by intact control rats. Similarly enhanced water intake by rats with APX also was observed when marked hypovolemia was induced by s.c. administration of a hyperoncotic colloidal solution. In both conditions, the increased water intake occurred within the first 15 min of the drinking tests. Intakes of liquid diet or 10% sucrose solution after food deprivation by rats with APX also were considerably larger than those of control rats. These and other results suggest that rats with APX experience less inhibition of ingestion while drinking. Thus, the AP may be important for the detection of early, inhibitory signals generated by fluid ingestion, and after its ablation increased drinking may occur because the feedback inhibition provided by such signals is diminished. Keywords: Area postrema; Hypertonic NaCl solution; Hypovolemia; Sucrose; Thirst; Water intake
1. Introduction
The area postrema (AP) is a caudal brainstem circumventficular organ that has been suggested to play a role in the central control of ingestive behavior. Rats with AP lesions (APX) are known to drink more water than do intact control rats after overnight water deprivation [12] and after systemic administration of angiotensin II [10,16], and to drink more sweetened liquid diet than do intact control rats [9]. In preliminary work [6], we observed similar effects when rats with APX were given systemic injections of hypertonic saline (HS) solutions. We now report that enhanced drinking by rats with APX also occurs when water intake is stimulated by severe hypovolernia, and that the increased intake after both HS treatment and hypovolemia occurs very early in the test period. Additionally, a pronounced drinking response is obtained when rats with APX are food-deprived and then consume unsweetened liquid diet or 10% sucrose solution. Thus, whereas previous studies have suggested that APX may remove an important inhibitory component in the intake of water stimulated by extracellular dehydration [10,16], and
* Corresponding author. Fax: (1) (412) 624-9198. 0006-8993/96/$15.00 © 1996 Elsevier Science B.V. All rights reserved PII S 0 0 0 6 - 8 9 9 3 ( 9 6 ) 0 0 2 7 7 - 6
also may enhance ingestive responses to palatable foods [9,18], it now appears that AP plays a more general role in the control of ingestion. Specifically, AP may be important for the detection of early signals generated by the rapid consumption of water or of liquid food, and after APX increased drinking may occur because the feedback inhibition provided by such signals is diminished.
2. Materials and methods
2.1. Animals Adult male Sprague-Dawley rats (Zivic-Miller, Allison Park, PA) weighing 250-375 g at the beginning of the experiments were individually housed in a colony room maintained at 20°C, with lights on from 08.00 h to 20.00 h. Rats had ad libitum access to Purina lab chow (#5001) and tap water except where noted.
2.2. Surgical procedures Rats were anesthetized with equithesin (3.0 m l / k g b.wt, injected i.p., of a solution containing pentobarbital
I ~c
c~
K.S. Curtis et al./Brain Research 726 (1996) 31-38
CONTROL
APX
33
APX
Fig. 1. (A) Photomicrographs of brainstem sections from an intact control rat (top) and a rat with AP lesions (bottom). (B) Camera lucida drawings of the rostral-caudal extent of the brainstem corresponding to AP from an intact control rat and two rats with AP lesions (APX). sodium 0.98 g / d l , chloral hydrate 4.25 g / d l , and M g S O 4 2.12 g / d l ) and placed in a stereotaxic frame with the head ventroflexed. A midline incision was made, the foramen m a g n u m was exposed and enlarged, and the meninges were incised. The A P was visualized using an operating microscope and aspirated through a 25-gauge needle with a blunted tip. The muscles and skin were sutured, and a broad spectrum antibiotic was administered. Rats with A P X (n = 34) were permitted 1 - 6 weeks to regain pre-operative body weights before functional tests for effectiveness of A P X were performed as described previously [7]. Briefly, rats were tested for the absence of either LiCl-induced conditioned taste aversion or LiCl-induced suppression of water intake stimulated by water deprivation. All rats with A P X met one of these criteria; unoperated, weight-matched rats (n = 48) served as controls. Chronic, indwelling jugular vein catheters were implanted in some rats for blood sampling, in which case a m i n i m u m 48-h recovery period was permitted before testing. Some rats were tested in more than one condition but none was tested in all. After completion of behavioral testing, rats with A P X were given an overdose of equithesin and perfused intracardially with 0.15 M NaC1 followed by 10% formalin solution. Brainstems were removed and cut into 33-p~m sections along the rostral-caudal plane corresponding to AP. Sections were mounted, stained with cresyl violet, and examined microscopically to determine completeness and extent of APX.
2.3. Behavioral testing 2.3.1. Experiment 1A HS was administered i.p. to rats with A P X and to control rats in doses of 1 ml of 2 M NaC1 (n = 9, n = 7, respectively) or 2 ml of 2 M NaC1 (n = 18, n = 9, respectively). After a 15-min delay to permit behavioral disruption due to HS injections to subside, drinking water was provided in calibrated tubes; intake was measured (_+ 1.0 ml) after 30 and 60 min, then hourly for a total of 4 h. F o o d was not available during the tests. Control experiments in which 0.15 M NaC1 rather than HS was given i.p. elicited a mean intake of 1.0 ml in 4 h. In separate groups of rats with A P X and control rats (n = 6, n = 5, respectively), blood samples were collected 30 min before and 15 min after the larger dose of HS was administered. Blood was replaced with equal volumes of 0.15 M NaC1; drinking water was not available after HS treatment. Plasma N a + concentration was determined by a sodium-sensitive electrode (Beckman Electrolyte Analyzer II; Beckman Instruments, Fullerton, CA).
2.3.2. Experiment 1B The same procedures were used as in Expt. 1A except that HS was administered s.c. to rats with A P X and to control rats in doses of 4 m l / k g body wt of 10% NaC1 (n = 9, n = 8, respectively) or 2 ml of 2 M NaC1 (for both n = 8). The smaller dose is similar to 1 ml of 2 M NaC1, and was chosen to duplicate procedures used previously
K.S. Curtis et al./Brain Research 726 (1996) 31-38
34
[10]. A d d i t i o n a l l y , m e a s u r e m e n t s o f w a t e r i n t a k e w e r e m a d e at e a r l i e r t i m e p o i n t s (5, 10, a n d 15 m i n ) in the test period, a n d b l o o d s a m p l e s w e r e n o t collected.
2.3.3. Experiment 2A R a t s w i t h A P X ( n = 8) a n d c o n t r o l rats ( n = 5) w e r e g i v e n 5 ml o f 3 0 % p o l y e t h y l e n e g l y c o l s o l u t i o n ( P E G ; C a r b o w a x , c o m p o u n d 2 0 - M , U n i o n C a r b i d e ) s.c. to i n d u c e i s o s m o t i c h y p o v o l e m i a . W a t e r i n t a k e w a s m e a s u r e d 15, 30, a n d 6 0 m i n after P E G t r e a t m e n t , t h e n h o u r l y for a total o f 4 h, d u r i n g w h i c h t i m e f o o d w a s n o t available.
2.3.4. Experiment 2B T h e s a m e p r o c e d u r e s w e r e u s e d as in Expt. 2 A e x c e p t t h a t rats w i t h A P X ( n = 8) a n d c o n t r o l rats ( n = 6) w e r e not p e r m i t t e d a c c e s s to d r i n k i n g w a t e r for 18 h after P E G t r e a t m e n t . F o o d w a s n o t a v a i l a b l e d u r i n g the d e l a y or the test.
Table 1 Plasma Na ÷ concentration (mEq/l) 30 min before (baseline) and 15 min after i.p. administration of 2 ml of 2 M NaCl (HS) to control rats and to rats with area postrema lesions (APX). Values = mean _+S.E. Group
n
Baseline
HS
Control APX
5 6
143.8 _+0.2 143.7 _+0.6
155.5 _+0.9 156.8 + 0.8
( a p p r o x i m a t e l y 10 g) w e r e g i v e n in the a f t e r n o o n . S t a b l e i n t a k e s d u r i n g the m o r n i n g f e e d i n g w e r e e s t a b l i s h e d after 2 - 5 days. B o d y w e i g h t s o f all rats d e c r e a s e d a b o u t 10% initially a n d t h e n w e r e m a i n t a i n e d at t h o s e r e d u c e d levels. O n the test day, i n t a k e s w e r e m e a s u r e d at 5 - m i n i n t e r v a l s for 60 m i n d u r i n g w h i c h w a t e r w a s n o t available.
2.3.6. Experiment 3B T h e s a m e p r o c e d u r e s w e r e u s e d as in Expt. 3 A e x c e p t that rats w e r e g i v e n 10% s u c r o s e s o l u t i o n (0.4 k c a l / m l ) d u r i n g the m o r n i n g f e e d i n g .
2.3.5. Experiment 3A Rats were placed on a restricted feeding schedule w h e r e b y a n u n s w e e t e n e d l i q u i d diet ( A I N diet, d i l u t e d 1:6 w i t h H 2 0 ; 0 . 1 4 k c a l / m l ) w a s a v a i l a b l e in c a l i b r a t e d t u b e s for 30 m i n in the m o r n i n g a n d t w o pellets o f lab c h o w
=
2.3.7. Experiment 3C T h e s a m e p r o c e d u r e s w e r e u s e d as in Expt. 3 A e x c e p t t h a t rats w e r e g i v e n p r e w e i g h e d , a m p l e a m o u n t s o f c h o w d u r i n g the m o r n i n g f e e d i n g ; s p i l l a g e a n d u n e a t e n c h o w
APX high dose HS
-.... 0 - - -
APX low dose HS Control high dose HS
I----D---
Control low dose HS
15
== 10 , m
5"
SC 0
1
2 Time
3 (h)
4
0.5
1
2 Time
3
4
(h)
Fig. 2. Cumulative water intakes (mean ___S.E.) by rats with AP lesions (APX) and intact control rats during 4-h tests following administration of HS. (left) Intakes after HS given i.p. in low (1 ml of 2 M NaCI; n = 9, n - 7, respectively) or high doses (2 ml of 2 M NaC1; n = 18, n = 9, respectively). (right) Intakes after HS given s.c. in low (4 ml/kg of 10% NaC1; n = 9, n = 8, respectively) or high doses (2 ml of 2 M NaC1; for both n = 8). Note that the x-axis has been expanded in the right panel to facilitate presentation of water intakes during the first 15 rain of the tests.
K.S. Curtis et al./ Brain Research 726 (1996) 31-38 were collected and weighed to determine intake. On the test day, uneaten chow and spillage were collected and another preweighed amount of chow was provided every 15 min for 60 min. The order of the three tests of stimulated food intake was varied. Rats with A P X ( n = 7) and control rats ( n = 6) were tested in all conditions except for one rat with A P X that was not tested for chow intake.
I
35
APX Iliqui0=/df ~ie¢~
:
T
~o°,.~, t0~,u=~,
---~---
l
40
E
e-
2.4. Statistical analysis
20"
All results are presented as mean values ± S.E. Statistical significance was determined by repeated measures A N O V A ; where applicable, post-hoc comparisons were made via Bonferroni protected t tests.
3.
,/
All lesions of the A P were complete and confined to the rostral-caudal plane corresponding to the AP. Sixteen of the 34 rats sustained minimal damage to adjacent structures. In the remaining animals varying amounts of additional damage were incurred, primarily to the subadjacent nucleus tractus solitarius (NTS). However, damage extended to the dorsal motor nucleus of the vagus in 9 rats
.L ----A---
30"
20
30
40
50
60
Time (min)
3.1. Histology
----
APX 18-h delay Control 18-h delay "[
APX immediate access
25"
m
p,
10
Results
E v
10
Fig. 4. Cumulative intakes (mean_+S.E.) of liquid diet or 10% sucrose solution by rats with AP lesions (APX; n = 7) and by intact control rats (n = 6) in 60-min tests during a schedule of restricted access to food.
and to the dorsal portion of the hypoglossal nucleus in 2 additional animals. Damage outside the AP, when it occurred, tended to be more extensive in the portion of the brainstem corresponding to the rostral A P region than in the caudal A P region (Fig. 1A,B). In any case, the extent of the lesion did not appear to be associated with its functional effects in these experiments, so rats with A P X were not segregated into subgroups according to variation in lesion size. 3.2. Experiment 1
20 ¸
15 ¸
10
0
1
2
3
4
Time (h) Fig. 3. Cumulative water intakes (mean_+ S.E.) by rats with AP lesions (APX) and by control rats in 4-h tests begun immediately (n = 8, n = 5,
respectively) or 18 h (n = 8, n = 6, respectively) after s.c. administration of 5 ml of 30% PEG solution.
After i.p. administration of both low and high doses of HS, rats with A P X drank almost two-fold more water than did control rats (Fig. 2, left panel; Fl,14 = 13.51, P < 0.01, and F~,25 = 15.53, P < 0.001, respectively). Rats with A P X also drank more water after the high dose of HS was given s.c. (F],~4 = 22.23, P < 0.001), and this effect was apparent as early as 5 rain into the test period (Fig. 2, right panel; P < 0.01). In contrast, there were no statistically significant differences in the stimulated water intakes of the two groups after the low dose was given s.c. (Fig. 1, right panel). Water intakes by both groups were dose-related regardless o f the route of administration, and intakes after the high dose of HS were comparable whether HS was administered i.p. or s.c. However, control rats also drank similar amounts when the low dose of HS was given i.p. or s.c., whereas rats with A P X unaccountably drank much less when the low dose of HS was given s.c. instead of i.p. (FI.16 = 5.67, P < 0.05). Baseline plasma Na + concentrations of rats with A P X were not different from those of control rats. After HS
K.S. Curtis et a l . / B r a i n Research 726 (1996) 31 38
36
12
4. D i s c u s s i o n
10 ¸
----:--- Control APX
///~j/./ /
)i
/
J4
¢=m
0 cO
0
15
30
45
60
Time (min) Fig. 5. Cumulative intakes (mean + S.E.) of chow by rats with AP lesions (APX; n = 6) and by intact control rats (n = 6) in 60-min tests during a schedule of restricted access to food.
administration, plasma Na + concentrations of both groups increased significantly and by comparable amounts (Table 1; both P < 0.001).
3.3. Experiment 2 W h e n water was provided immediately after PEG treatment, both control rats and rats with A P X drank gradually and in similar amounts. In contrast, when access to water was delayed for 18 h after PEG treatment, rats with A P X again drank approximately two-fold more than did control rats (Fig. 3; Fl,12 = 15.20, P < 0.01), and this difference was apparent by the first 15 rain of the test period ( P <
O.Ol). 3.4. Experiment 3 In 60-min tests conducted during the morning feeding, rats with A P X ingested approximately two-fold more liquid diet than did control rats (Fig. 4; Ft.ll = 65.14, P < 0.001), and this difference was statistically significant by 20 min ( P < 0.01). Similarly, rats with A P X drank equivalently more 10% sucrose solution than did control rats (Fig. 4; Fl,i1 = 18.18, P < 0.01), and this difference was significant by 30 min ( P < 0.01). In contrast, rats with A P X ate less chow than did control rats in the 60-rain tests (Fig. 5; Fl,10 = 15.82, P < 0.01), and this difference was statistically significant by 30 min ( P < 0.01).
The present experiments demonstrated that, under certain circumstances, rats with A P X consumed substantially more water and liquid food than did intact control rats. However, rats with A P X were not generally more responsive to stimuli for ingestion, inasmuch as their water intakes were not enhanced either after the low dose of HS was given s.c. (Expt. 1B) or immediately after PEG treatment (Expt. 2A), nor were their intakes of pelleted chow enhanced after food restriction (Expt. 3C). Further, even when increased consumption did occur, intakes were not indiscriminately large; like control rats, rats with A P X demonstrated dose-related drinking responses to HS treatment. Rats with A P X drank significantly more water after i.p. administration of HS than did control rats, a difference that was evident within 30 rain of drinking (in fact, it has been seen in the first 5 min of the test period; J.C. Smith, K.S. Curtis, K. Peacock, E.M. Stricker, unpublished observations, 1995). A previous report [10] that rats with APX drank water in amounts comparable to those of control rats when given 4 m l / k g of 10% NaCI s.c. was replicated in the present study. However, when HS was administered s.c. at the high dose, rats with A P X drank significantly more water than did control rats, and the difference was apparent as early as 5 min into the test period. These latter results indicate that the enhanced water intakes after HS treatment were not specific to the i.p. route of administration. Rats with A P X excrete Na + in urine less rapidly after an administered NaC1 load than do control rats [6]. However, the increased water intakes in Expts. 1A and 1B occurred very early in the test period, before differential Na + excretion influenced plasma Na + concentration (Table 1), and therefore the early enhancement of water intake after HS treatment does not appear to be a compensatory response to a greater degree of induced hypernatremia. Instead, it may reflect more general disruption of the central control of fluid ingestion. Consistent with this interpretation are previous findings that water intake by rats with A P X was potentiated after systemic administration of angiotensin II [10,16]. To investigate this possibility further, water intake also was examined after isosmotic hypovolemia was induced by s.c. administration of a hyperoncotic colloidal solution. PEG-induced hypovolemia occurs gradually, and the stimulated water intake is known to reflect the degree of plasma volume deficits [11,20]. When water was provided immediately after PEG treatment, rats with A P X drank relatively small amounts comparable to those consumed by control rats in 4-h tests (see also [10]). In contrast, when an 18-h delay was imposed to permit pronounced deficits to develop before access to drinking water, PEG-treated rats with APX consumed significantly more than did control rats, and the difference was apparent early in the test. Together, these observations
K.S. Curtis et al./'Brain Research 726 (1996) 31-38
clearly indicate that rats with APX consume more water than do control rats in response to severe hypovolemia as well as to an administered NaC1 load, and additionally suggest that this phenomenon is more likely to occur under conditions in which a relatively large response is induced in control rats. Previous studies have shown that enhanced ingestion by rats with APX does not occur only during conditions of stimulated water intake; rats with APX consumed more than did control rats when ingesting sweetened liquid diet [9]. In the present experiments, moreover, we found that after overnight food deprivation rats with APX consumed significantly more unsweetened dilute liquid diet or 10% sucrose solution than did control rats. Both groups drank both fluids at comparably high rates in the initial 15-min period (0.8-1.2 ml/min); however, rats with APX continued to drink at these high rates during the second 15-min period and at 0.3-0.5 m l / m i n during the final 30 rain, whereas control rats drank much more slowly then (0.2-0.3 m l / m i n , < 0.1 m l / m i n , respectively). In contrast, intake by rats with APX was not greater than that of control rats when animals were given pelleted chow to eat (see also
[9]). In explaining the enhanced consumption of palatable foods by rats with APX, Edwards and Ritter [9] proposed that AP lesions alter the hedonic value of taste stimuli. This hypothesis may be correct but it cannot account for all the data now available concerning the increased ingestion of fluids that occurred very early in the test periods. More specifically, the hypothesis clearly can explain the increased preference by rats with APX for sweetened liquid diet or glucose solution [18], and it certainly is consistent with the results of the present studies of rats with APX when they were food-deprived and given sucrose solution to drink. However, it accounts for neither their comparably large intakes of the less palatable, unsweetened liquid diet nor their relatively large water intakes after HS or PEG treatments. Consideration of these findings collectively suggests the possibility that rats with APX experience less inhibition of ingestion during rapid consumption, thereby enabling a high initial rate of intake to be sustained longer than that by control rats. Thus, rather than serving as an inhibitory mechanism that is specific to the intake of water stimulated by extracellular dehydration or to the ingestion of palatable foods, AP may instead serve a more general, integrative role in the central control of ingestive behavior. In this regard, the AP receives neural input [5,13] that may allow the detection of oropharyngeal or visceral signals which are common to the consumption of water and liquid food and are known to limit ingestion [1,2,8,21]. Additionally, the AP lacks a blood-brain barrier [4] and therefore is well-situated to detect early changes in circulating levels of electrolytes that occur as a consequence of ingestion [14,15]. Thus, rats with APX may lack the transient inhibition of water and liquid food intake pro-
37
vided by the act of swallowing, by gastric distention or nutrient content, a n d / o r by initial changes in plasma osmolality, and therefore consume larger amounts of fluids and at higher rates than do control rats. If so, then enhanced consumption would not be expected when smaller intakes occur at slower rates (e.g., water intake immediately after PEG treatment or chow intake after food deprivation) because those intakes should be less influenced by such rapid feedback mechanisms. Although common signals may mediate the early feedback inhibition of drinking that occurs during the rapid ingestion of water or liquid food, more specific signals of satiety for thirst and hunger are also well known to affect ingestion. In the present studies, stimulated water intake by rats with APX increased toward an asymptote within 30-60 rain, suggesting that the absorption of water and consequent decreased plasma osmolality was detected then and inhibited further intake, as in control rats. Rats with APX also ingested liquid diet or sucrose solution at initially high rates and in volumes similar to those consumed by rats after food deprivation when inhibitory feedback from the gastrointestinal tract was minimized by an open gastric fistula [23]. However, unlike 'sham-drinking' rats, rats with APX decreased their rate of drinking after 30 min, suggesting that some less rapidly-occurring inhibitory signal such as pronounced gastric distention or postabsorptive nutrient influx into the circulation was detected then and inhibited further intake. Thus, it appears that APX may impair early feedback inhibition of rapid fluid intake, whereas later inhibitory elements in the control of ingestion are less affected. Finally, although the experimental animals in this study are referred to as 'rats with APX', it should be emphasized that damage to the brainstem likely disrupted function in the adjacent NTS, which is reciprocally connected with AP [ 19,22] and is the primary recipient of gustatory and gastric afferent input [3,5,13]. In this regard, recent studies report increased c - f o s expression, a putative marker of neuronal activation, both in the AP and in the NTS following deprivation-induced consumption of a large meal, and comparable effects also were observed after plasma osmolality was increased by i.p. HS treatment [17]. Thus, the results now reported may be the consequence of damage to AP, to NTS, or to both areas. Further studies will be necessary to determine the signal or combination of signals that contributes to the rapid feedback inhibition of ingestion, and the relative contributions of AP and NTS to such inhibition.
Acknowledgements This research was supported in part by National Institute of Mental Health Research Grant MH-25140 (MERIT Award). Portions of this report were presented in preliminary form at the Society for Neuroscience meeting in Washington, DC, November 1993.
38
K.S. Curtis et al./Brain Research 726 (1996) 31-38
References [1] Adolph, E.F., Thirst and its inhibition in the stomach, Am. J. Physiol., 161 (1950) 374-386. [2] Blass, E.M. and Hall, W.G., Drinking termination: interactions among hydrational, orogastric and behavioral controls in rats, Psychol. Rev., 83 (1976) 356-374. [3] Blomquist, A.J. and Antem, A., Localization of the terminals of the tongue afferents in the nucleus of the solitary tract, J. Comp. Neurol., 124 (1965) 127-130. [4] Borrison, H.L., Area postrema: chemoreceptor circumventricular organ of the medulla oblongata, Prog. Neurobiol., 32 (1989) 351390. [5] Contreras, R.J., Beckstead, R.M. and Norgren, R., The central projections of the trigeminal, facial, glossopharyngeal and vagus nerves: an autoradiographic study in the rat, J. Auton. Nerv. Syst., 6 (1982) 303-322. [6] Curtis, K.S., Sved, A.F., Verbalis, J.G. and Stricker, E.M., Disrupted osmoregulation in rats after area postrema (AP) lesions, Soc. Neurol. Abstr., 19 (1993) 94. [7] Curtis, K.S., Sved, A.F., Verbalis, J.G. and Stricker, E.M., Lithium chloride-induced anorexia, but not conditioned taste aversions, in rats with area postrema lesions, Brain Res., 663 (1994) 30-37. [8] Deutsch, J.A., Gonzalez, M.F. and Young, W.G., Two factors that control meal size, Brain Res. Bull., 5 (Suppl. 4) (1980) 55-57. [9] Edwards, G.L. and Ritter, R.C., Ablation of the area postrema causes exaggerated consumption of preferred foods in the rat, Brain Res., 216 (1981) 265-276. [10] Edwards, G.L. and Ritter, R.C., Area postrema lesions increase drinking to angiotensin and extracellular dehydration, Physiol. Behay., 29 (1982) 943-947. [11] Fitzsimons, J.T., Drinking by rats depleted of body fluid without increase in osmotic pressure, Z Physiol. (Lond.), 159 (1961) 297309. [12] Hyde, T.M. and Miselis, R.R., Area postrema and adjacent nucleus
[13]
[14]
[15]
[16]
[17]
[18]
[19] [20]
[21]
[22]
[23]
of the solitary tract in water and sodium balance, Am. J. Physiol., 247 (1984) R173-R182. Norgren, R. and Smith, G.P., Central distribution of the subdiaphragmatic vagal branches in the rat, J. Comp. Neurol., 273 (1988) 207-223. Nose, H., Sugimoto, E., Okuno, T. and Morimoto, T., Changes in blood volume and plasma sodium concentration after water intake in rats, Am. J. Physiol., 253 (1987) R15-RI9. Novin, D., The relation between electrical conductivity of brain tissue and thirst in the rat, J. Comp. Physiol. Psychol., 55 (1962) 145-154. Ohman, L.E. and Johnson, A.K., Brainstem mechanisms and the inhibition of angiotensin-induced drinking, Am. J. Physiol., 256 (1989) R264-R269. Olson, B.R., Freilino, M., Hoffman, G.E., Stricker, E.M., Sved, A.F. and Verbalis, J.G., c-Fos expression in rat brain and brainstem nuclei in response to treatments that alter food intake and gastric motility, Mol. Cell. Neurosci., 4 (1993)93-106. Ritter, R.C. and Edwards, G.L., Area postrema lesions cause overconsumption of palatable foods but not calories, Physiol. Behav., 32 (1984) 923-927. Shapiro, R.E. and Miselis, R.R., The central neural connections of the area postrema of the rat, Z Comp. Neurol., 234 (1985) 344-364. Stricker, E.M., Some physiological and motivational properties of the hypovolemic stimulus for thirst, Physiol. Behat,., 3 (1968) 379-385. Thrasher, T.N., Nistal-Herrera, J.F., Keil, L.C. and Ramsay, D.J., Satiety and inhibition of vasopressin secretion after drinking in dogs, Am. J. Physiol., 240 (1981) E394-E401. van der Kooy, D. and Koda, L.Y., Organization of the projections of a circumventricular organ: the area postrema in the rat, J. Comp. Neurol., 219 (1983) 328-338. Young, R.C., Gibbs, J., Antin, J., Holt, J. and Smith, G.P., Absence of satiety during sham feeding in the rat, J. Comp. Physiol. Psychol., 87 (1974) 795-800.
Brain Research 726 (1996) 31-38
Research report
Area postrema lesions in rats appear to disrupt rapid feedback inhibition of fluid intake Kathleen S. Curtis
a, Joseph
G. Verbalis b, Edward M. Stricker a, *
a Department of Neuroscience, 479 Crawford Hall, University of Pittsburgh, Pittsburgh, PA 15260, USA b Department of Medicine, Georgetown University, Medical School, Washington, DC 20007, USA
Accepted 20 February 1996
Abstract Area postrema lesions (APX) were produced by vacuum aspiration in adult male rats. After systemic administration of hypertonic saline solutions, significantly more water was consumed by rats with APX than by intact control rats. Similarly enhanced water intake by rats with APX also was observed when marked hypovolemia was induced by s.c. administration of a hyperoncotic colloidal solution. In both conditions, the increased water intake occurred within the first 15 min of the drinking tests. Intakes of liquid diet or 10% sucrose solution after food deprivation by rats with APX also were considerably larger than those of control rats. These and other results suggest that rats with APX experience less inhibition of ingestion while drinking. Thus, the AP may be important for the detection of early, inhibitory signals generated by fluid ingestion, and after its ablation increased drinking may occur because the feedback inhibition provided by such signals is diminished. Keywords: Area postrema; Hypertonic NaCl solution; Hypovolemia; Sucrose; Thirst; Water intake
1. Introduction
The area postrema (AP) is a caudal brainstem circumventficular organ that has been suggested to play a role in the central control of ingestive behavior. Rats with AP lesions (APX) are known to drink more water than do intact control rats after overnight water deprivation [12] and after systemic administration of angiotensin II [10,16], and to drink more sweetened liquid diet than do intact control rats [9]. In preliminary work [6], we observed similar effects when rats with APX were given systemic injections of hypertonic saline (HS) solutions. We now report that enhanced drinking by rats with APX also occurs when water intake is stimulated by severe hypovolernia, and that the increased intake after both HS treatment and hypovolemia occurs very early in the test period. Additionally, a pronounced drinking response is obtained when rats with APX are food-deprived and then consume unsweetened liquid diet or 10% sucrose solution. Thus, whereas previous studies have suggested that APX may remove an important inhibitory component in the intake of water stimulated by extracellular dehydration [10,16], and
* Corresponding author. Fax: (1) (412) 624-9198. 0006-8993/96/$15.00 © 1996 Elsevier Science B.V. All rights reserved PII S 0 0 0 6 - 8 9 9 3 ( 9 6 ) 0 0 2 7 7 - 6
also may enhance ingestive responses to palatable foods [9,18], it now appears that AP plays a more general role in the control of ingestion. Specifically, AP may be important for the detection of early signals generated by the rapid consumption of water or of liquid food, and after APX increased drinking may occur because the feedback inhibition provided by such signals is diminished.
2. Materials and methods
2.1. Animals Adult male Sprague-Dawley rats (Zivic-Miller, Allison Park, PA) weighing 250-375 g at the beginning of the experiments were individually housed in a colony room maintained at 20°C, with lights on from 08.00 h to 20.00 h. Rats had ad libitum access to Purina lab chow (#5001) and tap water except where noted.
2.2. Surgical procedures Rats were anesthetized with equithesin (3.0 m l / k g b.wt, injected i.p., of a solution containing pentobarbital
I ~c
c~
K.S. Curtis et al./Brain Research 726 (1996) 31-38
CONTROL
APX
33
APX
Fig. 1. (A) Photomicrographs of brainstem sections from an intact control rat (top) and a rat with AP lesions (bottom). (B) Camera lucida drawings of the rostral-caudal extent of the brainstem corresponding to AP from an intact control rat and two rats with AP lesions (APX). sodium 0.98 g / d l , chloral hydrate 4.25 g / d l , and M g S O 4 2.12 g / d l ) and placed in a stereotaxic frame with the head ventroflexed. A midline incision was made, the foramen m a g n u m was exposed and enlarged, and the meninges were incised. The A P was visualized using an operating microscope and aspirated through a 25-gauge needle with a blunted tip. The muscles and skin were sutured, and a broad spectrum antibiotic was administered. Rats with A P X (n = 34) were permitted 1 - 6 weeks to regain pre-operative body weights before functional tests for effectiveness of A P X were performed as described previously [7]. Briefly, rats were tested for the absence of either LiCl-induced conditioned taste aversion or LiCl-induced suppression of water intake stimulated by water deprivation. All rats with A P X met one of these criteria; unoperated, weight-matched rats (n = 48) served as controls. Chronic, indwelling jugular vein catheters were implanted in some rats for blood sampling, in which case a m i n i m u m 48-h recovery period was permitted before testing. Some rats were tested in more than one condition but none was tested in all. After completion of behavioral testing, rats with A P X were given an overdose of equithesin and perfused intracardially with 0.15 M NaC1 followed by 10% formalin solution. Brainstems were removed and cut into 33-p~m sections along the rostral-caudal plane corresponding to AP. Sections were mounted, stained with cresyl violet, and examined microscopically to determine completeness and extent of APX.
2.3. Behavioral testing 2.3.1. Experiment 1A HS was administered i.p. to rats with A P X and to control rats in doses of 1 ml of 2 M NaC1 (n = 9, n = 7, respectively) or 2 ml of 2 M NaC1 (n = 18, n = 9, respectively). After a 15-min delay to permit behavioral disruption due to HS injections to subside, drinking water was provided in calibrated tubes; intake was measured (_+ 1.0 ml) after 30 and 60 min, then hourly for a total of 4 h. F o o d was not available during the tests. Control experiments in which 0.15 M NaC1 rather than HS was given i.p. elicited a mean intake of 1.0 ml in 4 h. In separate groups of rats with A P X and control rats (n = 6, n = 5, respectively), blood samples were collected 30 min before and 15 min after the larger dose of HS was administered. Blood was replaced with equal volumes of 0.15 M NaC1; drinking water was not available after HS treatment. Plasma N a + concentration was determined by a sodium-sensitive electrode (Beckman Electrolyte Analyzer II; Beckman Instruments, Fullerton, CA).
2.3.2. Experiment 1B The same procedures were used as in Expt. 1A except that HS was administered s.c. to rats with A P X and to control rats in doses of 4 m l / k g body wt of 10% NaC1 (n = 9, n = 8, respectively) or 2 ml of 2 M NaC1 (for both n = 8). The smaller dose is similar to 1 ml of 2 M NaC1, and was chosen to duplicate procedures used previously
K.S. Curtis et al./Brain Research 726 (1996) 31-38
34
[10]. A d d i t i o n a l l y , m e a s u r e m e n t s o f w a t e r i n t a k e w e r e m a d e at e a r l i e r t i m e p o i n t s (5, 10, a n d 15 m i n ) in the test period, a n d b l o o d s a m p l e s w e r e n o t collected.
2.3.3. Experiment 2A R a t s w i t h A P X ( n = 8) a n d c o n t r o l rats ( n = 5) w e r e g i v e n 5 ml o f 3 0 % p o l y e t h y l e n e g l y c o l s o l u t i o n ( P E G ; C a r b o w a x , c o m p o u n d 2 0 - M , U n i o n C a r b i d e ) s.c. to i n d u c e i s o s m o t i c h y p o v o l e m i a . W a t e r i n t a k e w a s m e a s u r e d 15, 30, a n d 6 0 m i n after P E G t r e a t m e n t , t h e n h o u r l y for a total o f 4 h, d u r i n g w h i c h t i m e f o o d w a s n o t available.
2.3.4. Experiment 2B T h e s a m e p r o c e d u r e s w e r e u s e d as in Expt. 2 A e x c e p t t h a t rats w i t h A P X ( n = 8) a n d c o n t r o l rats ( n = 6) w e r e not p e r m i t t e d a c c e s s to d r i n k i n g w a t e r for 18 h after P E G t r e a t m e n t . F o o d w a s n o t a v a i l a b l e d u r i n g the d e l a y or the test.
Table 1 Plasma Na ÷ concentration (mEq/l) 30 min before (baseline) and 15 min after i.p. administration of 2 ml of 2 M NaCl (HS) to control rats and to rats with area postrema lesions (APX). Values = mean _+S.E. Group
n
Baseline
HS
Control APX
5 6
143.8 _+0.2 143.7 _+0.6
155.5 _+0.9 156.8 + 0.8
( a p p r o x i m a t e l y 10 g) w e r e g i v e n in the a f t e r n o o n . S t a b l e i n t a k e s d u r i n g the m o r n i n g f e e d i n g w e r e e s t a b l i s h e d after 2 - 5 days. B o d y w e i g h t s o f all rats d e c r e a s e d a b o u t 10% initially a n d t h e n w e r e m a i n t a i n e d at t h o s e r e d u c e d levels. O n the test day, i n t a k e s w e r e m e a s u r e d at 5 - m i n i n t e r v a l s for 60 m i n d u r i n g w h i c h w a t e r w a s n o t available.
2.3.6. Experiment 3B T h e s a m e p r o c e d u r e s w e r e u s e d as in Expt. 3 A e x c e p t that rats w e r e g i v e n 10% s u c r o s e s o l u t i o n (0.4 k c a l / m l ) d u r i n g the m o r n i n g f e e d i n g .
2.3.5. Experiment 3A Rats were placed on a restricted feeding schedule w h e r e b y a n u n s w e e t e n e d l i q u i d diet ( A I N diet, d i l u t e d 1:6 w i t h H 2 0 ; 0 . 1 4 k c a l / m l ) w a s a v a i l a b l e in c a l i b r a t e d t u b e s for 30 m i n in the m o r n i n g a n d t w o pellets o f lab c h o w
=
2.3.7. Experiment 3C T h e s a m e p r o c e d u r e s w e r e u s e d as in Expt. 3 A e x c e p t t h a t rats w e r e g i v e n p r e w e i g h e d , a m p l e a m o u n t s o f c h o w d u r i n g the m o r n i n g f e e d i n g ; s p i l l a g e a n d u n e a t e n c h o w
APX high dose HS
-.... 0 - - -
APX low dose HS Control high dose HS
I----D---
Control low dose HS
15
== 10 , m
5"
SC 0
1
2 Time
3 (h)
4
0.5
1
2 Time
3
4
(h)
Fig. 2. Cumulative water intakes (mean ___S.E.) by rats with AP lesions (APX) and intact control rats during 4-h tests following administration of HS. (left) Intakes after HS given i.p. in low (1 ml of 2 M NaCI; n = 9, n - 7, respectively) or high doses (2 ml of 2 M NaC1; n = 18, n = 9, respectively). (right) Intakes after HS given s.c. in low (4 ml/kg of 10% NaC1; n = 9, n = 8, respectively) or high doses (2 ml of 2 M NaC1; for both n = 8). Note that the x-axis has been expanded in the right panel to facilitate presentation of water intakes during the first 15 rain of the tests.
K.S. Curtis et al./ Brain Research 726 (1996) 31-38 were collected and weighed to determine intake. On the test day, uneaten chow and spillage were collected and another preweighed amount of chow was provided every 15 min for 60 min. The order of the three tests of stimulated food intake was varied. Rats with A P X ( n = 7) and control rats ( n = 6) were tested in all conditions except for one rat with A P X that was not tested for chow intake.
I
35
APX Iliqui0=/df ~ie¢~
:
T
~o°,.~, t0~,u=~,
---~---
l
40
E
e-
2.4. Statistical analysis
20"
All results are presented as mean values ± S.E. Statistical significance was determined by repeated measures A N O V A ; where applicable, post-hoc comparisons were made via Bonferroni protected t tests.
3.
,/
All lesions of the A P were complete and confined to the rostral-caudal plane corresponding to the AP. Sixteen of the 34 rats sustained minimal damage to adjacent structures. In the remaining animals varying amounts of additional damage were incurred, primarily to the subadjacent nucleus tractus solitarius (NTS). However, damage extended to the dorsal motor nucleus of the vagus in 9 rats
.L ----A---
30"
20
30
40
50
60
Time (min)
3.1. Histology
----
APX 18-h delay Control 18-h delay "[
APX immediate access
25"
m
p,
10
Results
E v
10
Fig. 4. Cumulative intakes (mean_+S.E.) of liquid diet or 10% sucrose solution by rats with AP lesions (APX; n = 7) and by intact control rats (n = 6) in 60-min tests during a schedule of restricted access to food.
and to the dorsal portion of the hypoglossal nucleus in 2 additional animals. Damage outside the AP, when it occurred, tended to be more extensive in the portion of the brainstem corresponding to the rostral A P region than in the caudal A P region (Fig. 1A,B). In any case, the extent of the lesion did not appear to be associated with its functional effects in these experiments, so rats with A P X were not segregated into subgroups according to variation in lesion size. 3.2. Experiment 1
20 ¸
15 ¸
10
0
1
2
3
4
Time (h) Fig. 3. Cumulative water intakes (mean_+ S.E.) by rats with AP lesions (APX) and by control rats in 4-h tests begun immediately (n = 8, n = 5,
respectively) or 18 h (n = 8, n = 6, respectively) after s.c. administration of 5 ml of 30% PEG solution.
After i.p. administration of both low and high doses of HS, rats with A P X drank almost two-fold more water than did control rats (Fig. 2, left panel; Fl,14 = 13.51, P < 0.01, and F~,25 = 15.53, P < 0.001, respectively). Rats with A P X also drank more water after the high dose of HS was given s.c. (F],~4 = 22.23, P < 0.001), and this effect was apparent as early as 5 rain into the test period (Fig. 2, right panel; P < 0.01). In contrast, there were no statistically significant differences in the stimulated water intakes of the two groups after the low dose was given s.c. (Fig. 1, right panel). Water intakes by both groups were dose-related regardless o f the route of administration, and intakes after the high dose of HS were comparable whether HS was administered i.p. or s.c. However, control rats also drank similar amounts when the low dose of HS was given i.p. or s.c., whereas rats with A P X unaccountably drank much less when the low dose of HS was given s.c. instead of i.p. (FI.16 = 5.67, P < 0.05). Baseline plasma Na + concentrations of rats with A P X were not different from those of control rats. After HS
K.S. Curtis et a l . / B r a i n Research 726 (1996) 31 38
36
12
4. D i s c u s s i o n
10 ¸
----:--- Control APX
///~j/./ /
)i
/
J4
¢=m
0 cO
0
15
30
45
60
Time (min) Fig. 5. Cumulative intakes (mean + S.E.) of chow by rats with AP lesions (APX; n = 6) and by intact control rats (n = 6) in 60-min tests during a schedule of restricted access to food.
administration, plasma Na + concentrations of both groups increased significantly and by comparable amounts (Table 1; both P < 0.001).
3.3. Experiment 2 W h e n water was provided immediately after PEG treatment, both control rats and rats with A P X drank gradually and in similar amounts. In contrast, when access to water was delayed for 18 h after PEG treatment, rats with A P X again drank approximately two-fold more than did control rats (Fig. 3; Fl,12 = 15.20, P < 0.01), and this difference was apparent by the first 15 rain of the test period ( P <
O.Ol). 3.4. Experiment 3 In 60-min tests conducted during the morning feeding, rats with A P X ingested approximately two-fold more liquid diet than did control rats (Fig. 4; Ft.ll = 65.14, P < 0.001), and this difference was statistically significant by 20 min ( P < 0.01). Similarly, rats with A P X drank equivalently more 10% sucrose solution than did control rats (Fig. 4; Fl,i1 = 18.18, P < 0.01), and this difference was significant by 30 min ( P < 0.01). In contrast, rats with A P X ate less chow than did control rats in the 60-rain tests (Fig. 5; Fl,10 = 15.82, P < 0.01), and this difference was statistically significant by 30 min ( P < 0.01).
The present experiments demonstrated that, under certain circumstances, rats with A P X consumed substantially more water and liquid food than did intact control rats. However, rats with A P X were not generally more responsive to stimuli for ingestion, inasmuch as their water intakes were not enhanced either after the low dose of HS was given s.c. (Expt. 1B) or immediately after PEG treatment (Expt. 2A), nor were their intakes of pelleted chow enhanced after food restriction (Expt. 3C). Further, even when increased consumption did occur, intakes were not indiscriminately large; like control rats, rats with A P X demonstrated dose-related drinking responses to HS treatment. Rats with A P X drank significantly more water after i.p. administration of HS than did control rats, a difference that was evident within 30 rain of drinking (in fact, it has been seen in the first 5 min of the test period; J.C. Smith, K.S. Curtis, K. Peacock, E.M. Stricker, unpublished observations, 1995). A previous report [10] that rats with APX drank water in amounts comparable to those of control rats when given 4 m l / k g of 10% NaCI s.c. was replicated in the present study. However, when HS was administered s.c. at the high dose, rats with A P X drank significantly more water than did control rats, and the difference was apparent as early as 5 min into the test period. These latter results indicate that the enhanced water intakes after HS treatment were not specific to the i.p. route of administration. Rats with A P X excrete Na + in urine less rapidly after an administered NaC1 load than do control rats [6]. However, the increased water intakes in Expts. 1A and 1B occurred very early in the test period, before differential Na + excretion influenced plasma Na + concentration (Table 1), and therefore the early enhancement of water intake after HS treatment does not appear to be a compensatory response to a greater degree of induced hypernatremia. Instead, it may reflect more general disruption of the central control of fluid ingestion. Consistent with this interpretation are previous findings that water intake by rats with A P X was potentiated after systemic administration of angiotensin II [10,16]. To investigate this possibility further, water intake also was examined after isosmotic hypovolemia was induced by s.c. administration of a hyperoncotic colloidal solution. PEG-induced hypovolemia occurs gradually, and the stimulated water intake is known to reflect the degree of plasma volume deficits [11,20]. When water was provided immediately after PEG treatment, rats with A P X drank relatively small amounts comparable to those consumed by control rats in 4-h tests (see also [10]). In contrast, when an 18-h delay was imposed to permit pronounced deficits to develop before access to drinking water, PEG-treated rats with APX consumed significantly more than did control rats, and the difference was apparent early in the test. Together, these observations
K.S. Curtis et al./'Brain Research 726 (1996) 31-38
clearly indicate that rats with APX consume more water than do control rats in response to severe hypovolemia as well as to an administered NaC1 load, and additionally suggest that this phenomenon is more likely to occur under conditions in which a relatively large response is induced in control rats. Previous studies have shown that enhanced ingestion by rats with APX does not occur only during conditions of stimulated water intake; rats with APX consumed more than did control rats when ingesting sweetened liquid diet [9]. In the present experiments, moreover, we found that after overnight food deprivation rats with APX consumed significantly more unsweetened dilute liquid diet or 10% sucrose solution than did control rats. Both groups drank both fluids at comparably high rates in the initial 15-min period (0.8-1.2 ml/min); however, rats with APX continued to drink at these high rates during the second 15-min period and at 0.3-0.5 m l / m i n during the final 30 rain, whereas control rats drank much more slowly then (0.2-0.3 m l / m i n , < 0.1 m l / m i n , respectively). In contrast, intake by rats with APX was not greater than that of control rats when animals were given pelleted chow to eat (see also
[9]). In explaining the enhanced consumption of palatable foods by rats with APX, Edwards and Ritter [9] proposed that AP lesions alter the hedonic value of taste stimuli. This hypothesis may be correct but it cannot account for all the data now available concerning the increased ingestion of fluids that occurred very early in the test periods. More specifically, the hypothesis clearly can explain the increased preference by rats with APX for sweetened liquid diet or glucose solution [18], and it certainly is consistent with the results of the present studies of rats with APX when they were food-deprived and given sucrose solution to drink. However, it accounts for neither their comparably large intakes of the less palatable, unsweetened liquid diet nor their relatively large water intakes after HS or PEG treatments. Consideration of these findings collectively suggests the possibility that rats with APX experience less inhibition of ingestion during rapid consumption, thereby enabling a high initial rate of intake to be sustained longer than that by control rats. Thus, rather than serving as an inhibitory mechanism that is specific to the intake of water stimulated by extracellular dehydration or to the ingestion of palatable foods, AP may instead serve a more general, integrative role in the central control of ingestive behavior. In this regard, the AP receives neural input [5,13] that may allow the detection of oropharyngeal or visceral signals which are common to the consumption of water and liquid food and are known to limit ingestion [1,2,8,21]. Additionally, the AP lacks a blood-brain barrier [4] and therefore is well-situated to detect early changes in circulating levels of electrolytes that occur as a consequence of ingestion [14,15]. Thus, rats with APX may lack the transient inhibition of water and liquid food intake pro-
37
vided by the act of swallowing, by gastric distention or nutrient content, a n d / o r by initial changes in plasma osmolality, and therefore consume larger amounts of fluids and at higher rates than do control rats. If so, then enhanced consumption would not be expected when smaller intakes occur at slower rates (e.g., water intake immediately after PEG treatment or chow intake after food deprivation) because those intakes should be less influenced by such rapid feedback mechanisms. Although common signals may mediate the early feedback inhibition of drinking that occurs during the rapid ingestion of water or liquid food, more specific signals of satiety for thirst and hunger are also well known to affect ingestion. In the present studies, stimulated water intake by rats with APX increased toward an asymptote within 30-60 rain, suggesting that the absorption of water and consequent decreased plasma osmolality was detected then and inhibited further intake, as in control rats. Rats with APX also ingested liquid diet or sucrose solution at initially high rates and in volumes similar to those consumed by rats after food deprivation when inhibitory feedback from the gastrointestinal tract was minimized by an open gastric fistula [23]. However, unlike 'sham-drinking' rats, rats with APX decreased their rate of drinking after 30 min, suggesting that some less rapidly-occurring inhibitory signal such as pronounced gastric distention or postabsorptive nutrient influx into the circulation was detected then and inhibited further intake. Thus, it appears that APX may impair early feedback inhibition of rapid fluid intake, whereas later inhibitory elements in the control of ingestion are less affected. Finally, although the experimental animals in this study are referred to as 'rats with APX', it should be emphasized that damage to the brainstem likely disrupted function in the adjacent NTS, which is reciprocally connected with AP [ 19,22] and is the primary recipient of gustatory and gastric afferent input [3,5,13]. In this regard, recent studies report increased c - f o s expression, a putative marker of neuronal activation, both in the AP and in the NTS following deprivation-induced consumption of a large meal, and comparable effects also were observed after plasma osmolality was increased by i.p. HS treatment [17]. Thus, the results now reported may be the consequence of damage to AP, to NTS, or to both areas. Further studies will be necessary to determine the signal or combination of signals that contributes to the rapid feedback inhibition of ingestion, and the relative contributions of AP and NTS to such inhibition.
Acknowledgements This research was supported in part by National Institute of Mental Health Research Grant MH-25140 (MERIT Award). Portions of this report were presented in preliminary form at the Society for Neuroscience meeting in Washington, DC, November 1993.
38
K.S. Curtis et al./Brain Research 726 (1996) 31-38
References [1] Adolph, E.F., Thirst and its inhibition in the stomach, Am. J. Physiol., 161 (1950) 374-386. [2] Blass, E.M. and Hall, W.G., Drinking termination: interactions among hydrational, orogastric and behavioral controls in rats, Psychol. Rev., 83 (1976) 356-374. [3] Blomquist, A.J. and Antem, A., Localization of the terminals of the tongue afferents in the nucleus of the solitary tract, J. Comp. Neurol., 124 (1965) 127-130. [4] Borrison, H.L., Area postrema: chemoreceptor circumventricular organ of the medulla oblongata, Prog. Neurobiol., 32 (1989) 351390. [5] Contreras, R.J., Beckstead, R.M. and Norgren, R., The central projections of the trigeminal, facial, glossopharyngeal and vagus nerves: an autoradiographic study in the rat, J. Auton. Nerv. Syst., 6 (1982) 303-322. [6] Curtis, K.S., Sved, A.F., Verbalis, J.G. and Stricker, E.M., Disrupted osmoregulation in rats after area postrema (AP) lesions, Soc. Neurol. Abstr., 19 (1993) 94. [7] Curtis, K.S., Sved, A.F., Verbalis, J.G. and Stricker, E.M., Lithium chloride-induced anorexia, but not conditioned taste aversions, in rats with area postrema lesions, Brain Res., 663 (1994) 30-37. [8] Deutsch, J.A., Gonzalez, M.F. and Young, W.G., Two factors that control meal size, Brain Res. Bull., 5 (Suppl. 4) (1980) 55-57. [9] Edwards, G.L. and Ritter, R.C., Ablation of the area postrema causes exaggerated consumption of preferred foods in the rat, Brain Res., 216 (1981) 265-276. [10] Edwards, G.L. and Ritter, R.C., Area postrema lesions increase drinking to angiotensin and extracellular dehydration, Physiol. Behay., 29 (1982) 943-947. [11] Fitzsimons, J.T., Drinking by rats depleted of body fluid without increase in osmotic pressure, Z Physiol. (Lond.), 159 (1961) 297309. [12] Hyde, T.M. and Miselis, R.R., Area postrema and adjacent nucleus
[13]
[14]
[15]
[16]
[17]
[18]
[19] [20]
[21]
[22]
[23]
of the solitary tract in water and sodium balance, Am. J. Physiol., 247 (1984) R173-R182. Norgren, R. and Smith, G.P., Central distribution of the subdiaphragmatic vagal branches in the rat, J. Comp. Neurol., 273 (1988) 207-223. Nose, H., Sugimoto, E., Okuno, T. and Morimoto, T., Changes in blood volume and plasma sodium concentration after water intake in rats, Am. J. Physiol., 253 (1987) R15-RI9. Novin, D., The relation between electrical conductivity of brain tissue and thirst in the rat, J. Comp. Physiol. Psychol., 55 (1962) 145-154. Ohman, L.E. and Johnson, A.K., Brainstem mechanisms and the inhibition of angiotensin-induced drinking, Am. J. Physiol., 256 (1989) R264-R269. Olson, B.R., Freilino, M., Hoffman, G.E., Stricker, E.M., Sved, A.F. and Verbalis, J.G., c-Fos expression in rat brain and brainstem nuclei in response to treatments that alter food intake and gastric motility, Mol. Cell. Neurosci., 4 (1993)93-106. Ritter, R.C. and Edwards, G.L., Area postrema lesions cause overconsumption of palatable foods but not calories, Physiol. Behav., 32 (1984) 923-927. Shapiro, R.E. and Miselis, R.R., The central neural connections of the area postrema of the rat, Z Comp. Neurol., 234 (1985) 344-364. Stricker, E.M., Some physiological and motivational properties of the hypovolemic stimulus for thirst, Physiol. Behat,., 3 (1968) 379-385. Thrasher, T.N., Nistal-Herrera, J.F., Keil, L.C. and Ramsay, D.J., Satiety and inhibition of vasopressin secretion after drinking in dogs, Am. J. Physiol., 240 (1981) E394-E401. van der Kooy, D. and Koda, L.Y., Organization of the projections of a circumventricular organ: the area postrema in the rat, J. Comp. Neurol., 219 (1983) 328-338. Young, R.C., Gibbs, J., Antin, J., Holt, J. and Smith, G.P., Absence of satiety during sham feeding in the rat, J. Comp. Physiol. Psychol., 87 (1974) 795-800.