Chem. Senses 28: 3-9,
2003
© Oxford University Press 2003
Effects of Gastrin-releasing Peptide1-27 on Taste Responses in the Rat
Millsaps College, 1701 N. State Street, Jackson, MS 39210, USA
Correspondence to be sent to: A. Kurt Thaw, Psychology Department, Millsaps College, 1701 N. State Street, Jackson, MS 39210, USA. e-mail: thawak{at}millsaps.edu
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Abstract |
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Gastrin-releasing-peptide1-27 (GRP) has been implicated in the regulation of satiety and appetite in numerous paradigms. However, the specific site and mode of action of this gut—brain peptide has not been elucidated. The following experiment examined the effects of GRP on taste responses to sucrose in the behaving rat. A brief-exposure, multi-bottle gustometer was used to provide rats with momentary access to six different concentrations of sucrose in a single test session. This procedure has been used previously, resulting in monotonically increased licking behavior as concentrations of sucrose increase. Differing injection procedures were employed such that rats were tested immediately after i.p. injection or 5 min after i.p. injection of 5 nmol/kg body wt of GRP. Results indicate that GRP does reduce the oral reinforcing properties of sucrose, but the effect is transient, diminishing significantly within 5 min after injection.
Key words: brief-exposure tests, curve-shift, gut peptides, satiety
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Introduction |
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The term `satiety' refers to the factors that contribute to the termination of a meal and the lengthening of time intervals between meals. If increased food intake leads to the development of certain eating disorders, such as obesity or bulimia nervosa, then an understanding of the normal mechanisms that control the size and frequency of meals is essential to the treatment of such disorders. Though knowledge of these mechanisms is still limited, uncovering the complex physiology involved in satiety has progressed steadily over the past 25 years (Blundell, 1984
), in large part due to the discovery of certain peptides
released by the gut in response to ingested food
(Gibbs and Smith, 1984). Work
in this area continues to accelerate, with particular interest focusing on a
small group of these integrative peptides that link the gastrointestinal tract
and brain (Hobel, 1985). These
peptides have been shown to act both by their release into the
gastrointestinal system (peripheral action) and via direct actions in certain
brain areas (central action) (Gibbs and
Smith, 1992).
One mammalian peptide in particular, gastrin-releasing
peptide1-27 (GRP), has been extensively studied because it has a
demonstrated effect on limiting meal sizes and increasing the intervals
between meals (Thaw, 1994). GRP has been shown to be involved in regulating
satiety in several paradigms such as sham feeding, ad libitum
feeding, feeding deprivation schedules, operant conditioning procedures and
with various species including rats, mice, hamsters, pigs, non-human primates
and humans (Gibbs et al.,
1979; Gibbs and Smith,
1980,
1992;
Kulkosky et al.,
1982; Smith et al.,
1982; Hsiao and Spencer,
1983; Woods et al.,
1983; Wiener et al.,
1984; Babcock et al.,
1985; Mindell et al.,
1985; Morley et al.,
1985; Ladenheim and Ritter,
1988; Flynn, 1989;
Thaw, 1994). Though there is little doubt that this peptide is involved in
satiety, the mechanisms by which it acts and even its site of action are not
completely understood (Kirkham et
al., 1991). However, several other manipulations that induce
satiety in rats, such as i.v. injections of glucose, insulin and glucagon, and
the induction of gastric distention (Glenn
and Erickson, 1976; Giza and Scott,
1983,
1987), have been shown to be
associated with changes in taste sensitivity. Also, stomach distention and
nutrient infusions have been shown to modify taste-elicited activity in nerves
from the tongue and stomach, as well as neurons in the hindbrain (NST)
(Brush and Halpern, 1970;
Glenn and Erickson, 1976; Giza
and Scott, 1983,
1987) and this has led to
modifications of human ratings of taste pleasantness
(Cabanac, 1971). It has been
postulated that changes in gustatory sensibility may accompany the inhibition
of food intake produced by the administration of certain gut peptides
(Giza et al., 1990).
Support for this comes from studies examining the effects of the gut peptide
cholecystokinin on palatability that have shown significant decreases in
ingestive responses to sucrose solutions
(Waldbillig and O'Callaghan,
1980; Waldbillig and Bartness,
1982; Bartness and Waldbillig,
1984; Eckel and Ossenkopp,
1994). Thus, GRP may exert its satiating effects, in part, through
a taste mechanism as well (Gosnell and
Hsiao, 1984; Giza et
al., 1990; Flynn,
1995).
Flynn (Flynn, 1995) has
examined the effect of GRP on taste using taste reactivity tests developed
earlier (Grill and Norgren,
1978). He found various concentrations of GRP to reduce the mean
ingestive responses, though not significantly, to a single test concentration
of sucrose. Flynn also examined effects with respect to NaCl
(Flynn, 1995). He reported no
reliable changes in taste reactivity to 0.5 M NaCl in rats on
sodium-restricted or normal diets. It may be that NaCl ingestion patterns
after GRP administration affect only low concentrations (0.01 or 0.05 M for
example) not tested in his procedure. If it is the case that only certain
concentrations of solutions are affected by GRP, this provides the necessity
to test a variety of concentrations, including sucrose solutions.
To test the hypothesis that GRP affects the oral reinforcing properties of
particular concentrations of sucrose, behavioral changes in taste perception
following injections of GRP into the peritoneal cavity of the intact rat were
examined in the behaving animal. Since the efficacy and speed of action of
this peptide was not known with respect to effects on taste, injections of the
peptide were administered either immediately before testing or 5 min prior to
testing. Given the brief half-life of GRP, it was postulated that the peptide
would exert its effect immediately (Bloom
et al., 1983; Knigge
et al., 1984). Using brief-exposure taste tests
(described below), rats were allowed to sample sucrose solutions from any one
of eight individual sipper tubes for 30 s. Baseline measures of sucrose
licking behavior were recorded (no injection) and followed by testing using
sucrose as the tastant with each subject receiving a single injection of
either 0.9% NaCl in distilled water (saline control), or 5 nmol/kg body wt GRP
dissolved in saline and administered either immediately before testing or 5
min prior to testing. The dose of GRP used for these studies was chosen for
two main reasons. First, 5 nmol/kg body wt represents a dose of GRP that
reliably increases the inter-meal interval in freely feeding rats
(Thaw et al., 1998).
This increased latency between meals is an indication of satiety and provides
evidence that such a dose of GRP is sufficient to produce the desired effect
of increased satiety. Since the present study was concerned with elucidating a
role for the taste system as one of the potential mechanisms of action for the
satiety effects of GRP, it was necessary to make use of a concentration of GRP
that has been determined to affect satiety. Smaller doses of GRP injected
peripherally have not led to reliable effects on satiety
(Thaw et al., 1998).
The second main reason for choosing 5 nmol/kg body wt GRP concerns the fact
that the present study set out to examine taste-related behaviors. The dose of
GRP used in this study has not been implicated in producing malaise or
conditioned taste aversions following peripheral injections into the
peritoneal cavity (Gibbs,
1985). However, larger doses of GRP and other bombesin-related
peptides have been implicated as potentially leading to malaise in rats
(Deutsch, 1980;
Deutsch and Parson, 1981).
Using the modest dose chosen for this study, results provide evidence that the
oral reinforcing properties of sucrose are reduced in the behaving rat
following peripheral administration of GRP.
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Subjects
Ten male Sprague—Dawley rats (200-250 g; Harlan-Teklad) were used as subjects. Rats were housed individually in standard polycarbonate cages. The animal room was maintained at 20 ± 2°C on a 12 h: 12 h light:dark cycle, with lights off at 07.00. Rats were maintained at all times on water and laboratory rodent diet (Teklad LM-485), with no deprivation of any kind. The testing apparatus was housed in a room directly adjacent to the animal room. All rats were tested during the dark phase. The room housing the testing apparatus was illuminated with a 25 W red light.
Procedure
Rats were tested individually using a multi-bottle gustometer similar to
that described previously (Smith,
2000). Any one of eight individual sipper tubes was presented to a
rat for brief periods of time. Postingestinal cues were minimized due to the
minute volume of fluid consumed (0.005 ml/lick). Thus, the rats' responses
were directed by the stimulating properties of the solutions tested. The
dependent measures produced (total licks, latency to lick and inter-lick
intervals) provided indications of the sensory experience of the rat. In this
way it was possible to determine each rat's baseline behavior to various
tastant concentrations and then compare them to behavioral data obtained
following injections of control and GRP solutions.
Training
Rats were trained to lick from the eight sipper tubes by filling each tube
with 0.25 M sucrose and presenting them in random order until all eight tubes
had been sampled during a single training session. A computer-controlled
shutter was used to block or allow access to the sipper tubes that protruded
through a small hole on the back wall of the apparatus. Each rat received 5-8
days of consecutive training until they all responded immediately to the
presentation of each tube. During this training period, access to each tube
was limited to 30 s. The 30 s access time began with the rat's first lick on a
tube. Once the access time expired there was an additional 30 s delay before
the next tube was presented. However, if a rat did not lick a tube within 100
s, the next tube in the series was presented. The apparatus training sessions
were followed by collection of baseline data on a variety of sucrose solutions
and water. Six of the eight available tubes were filled with sucrose
concentrations of 0.03, 0.06, 0.125, 0.25 and 0.5 M or water and were randomly
presented twice each during a single test session.
Testing
Baseline data were collected for four consecutive days, followed by eight
consecutive days of testing using the same procedure and including peptide or
control injections. GRP solutions were prepared such that 5 nmol of GRP was
contained in each milliliter of solution. Rats received a single i.p.
injection of either saline or 5 nmol/kg body wt GRP using a sterile 1
cm3 syringe with a 26 gauge needle. With this method, each rat
received the same relative amount of GRP, though the total volume injected
varied according to body wt. The rats were placed into the testing apparatus
either immediately following injection or 5 min post-injection and the various
tubes were presented in random order twice for a total of 12 presentations per
test session. The eight testing days consisted of counterbalanced injections
in which half of the subjects received saline and half received a GRP
injection. The injection solution was alternated each day to provide 48 h
between any two GRP injections. Each GRP injection procedure was employed
twice (Table 1). The testing
procedure required 
15 min to complete for each rat and there was no
significant difference in time to complete the test between the three
conditions (16.2, 14.5 and 15.7 min for saline, GRP and 5 min delay GRP,
respectively). After a completed test session the apparatus was cleaned with
distilled water and the next rat was placed in the apparatus.
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Results |
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Data analysis
The dependent variable of interest was the total number of licks on each
sucrose concentration. Results from this laboratory as well as others have
demonstrated a monotonically increasing curve for sucrose licking behavior in
the rat, i.e. the higher the concentration of sucrose, the more licks in brief
exposure taste tests, up to 1 M (Spector
et al., 1990; Thaw,
2001). Data from the baseline days were compared to saline
injection data using repeated-measures analysis of variance (ANOVA) to
determine if the injection procedure itself led to behavioral changes. No
significant differences were found [F(1,9) = 0.04; P =
0.77]. Data collected following saline injections were then compared to the
two GRP injection procedures using repeated-measures ANOVA for each
concentration tested and Fisher's LSD post hoc test to determine the
effectiveness of the two GRP injection procedures. Each rat received two
presentations of each solution during a single test session and both GRP
injection procedures were administered twice, while the saline procedure was
administered between each GRP test session. Therefore, the means for each
concentration were calculated for each rat and used to conduct the
repeated-measures ANOVA. Results indicated a significant decrease in the total
number of licks on the 0.5, 0.25, 0.125, 0.06 and 0.03 M sucrose
concentrations following GRP injections [F(2,18) = 9.67,
F(2,18) = 4.32, F(2,18) = 6.25, F(2,18) = 11.68 and
F(2,18) = 17.52, respectively; P < 0.05]. Even more
interesting was the finding that these significant differences were
attributable to the immediately tested group for all concentrations, with the
exception of 0.5 M sucrose that led to significantly reduced licking in both
GRP injection conditions (Fisher's LSD post hoc test, t =
2.25 for saline versus 5 min delay GRP; P < 0.05;
Figure 1). In fact, the
immediately injected GRP results were significantly different from the 5 min
delay GRP injections for all sucrose solutions, but not water (Fisher's LSD
post hoc test, t = 1.75, 1.98, 2.69, 3.09 and 4.05 for 0.5,
0.25, 0.125, 0.06 and 0.03 M sucrose, respectively; P < 0.05;
Figure 1). Given that each
concentration was presented twice during each 15 min test session, it was even
possible to identify changes in the effectiveness of the GRP as the test
progressed. For example, the mean number of licks on each sipper tube was
nearly identical when comparing the first and second presentations of sucrose
concentrations following saline injections. However, the mean number of licks
that occurred during the first series of sucrose solutions was notably less
than the number of licks for the second presentation with both GRP injection
procedures, indicating a decrease in the effectiveness of the GRP in reducing
licking behavior as time progressed during testing. Using a matched
t-test, the first series of sucrose solutions for both GRP injection
procedures resulted in significant differences in total licks for 0.125, 0.06
and 0.03 M sucrose (t = 2.29, 1.85, and 2.96, respectively;
P < 0.05; Figure
2). Using the same test, the second series of sucrose
presentations following the immediate GRP injection procedure was compared to
the first series of sucrose solutions following the 5 min delay GRP procedure
(Figure 3). It was not
surprising to find no significant differences between these two sets of data,
since in both cases 5 min had elapsed since the GRP had been
injected.
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The mean latency to begin licking and the inter-lick interval for each concentration of sucrose were also examined (Tables 2 and 3). There were no significant differences in the mean time elapsed before initiating the first lick on any of the solutions tested, nor were there any significant differences in the inter-lick intervals for any of the solutions presented (including water).
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Discussion
The above results demonstrate that peripheral injections of GRP lead to
significant reductions in licking behavior of sucrose solutions using
brief-exposure taste tests. These effects are more pronounced when rats are
tested immediately after injection as opposed to testing after a 5 min
post-injection delay. Also, the ability of GRP to reduce licking behavior
decreases within the test sessions described here, supporting the hypothesis
that the effects of GRP on taste rapidly diminish. Prior studies have shown
that the rate of licking solutions containing sucrose increases in a
predictable fashion as the concentration of the sucrose increases when using
brief-exposure tests (Davis,
1973,
1996;
Cagan and Maller, 1974). These
monotonically increasing curves allow investigators to infer the palatability
or oral reinforcing properties of the solutions. Also, by using tests of brief
duration the post-ingestive effects of calorically dense solutions is
minimized. This allows for the behaviors to be directed by the taste of the
solution more than by the metabolic effects that occur with accumulation of
nutrients in the stomach or intestines. The results of this study show that
specific decreases in licking produce a curve that is shifted downward
following GRP injections. Curve-shift studies by Weingarten and others (Sakic
et al., 1996; Weingarten et al., 1996) indicate that such
changes in behavior can be interpreted as reductions in the oral reinforcing
properties of sucrose. In fact, the similarity in results of this study and
Weingarten's study, which used sham feeding, further supports the
effectiveness of the brief-exposure taste test as a way to collect behavioral
data guided specifically by taste. Of course, more general effects of GRP on
behavior, such as locomotor or oromotor changes, may be contributing to the
decreases in licking behavior observed. This is unlikely for three main
reasons. First, Flynn (Flynn,
1995) found no differences in ingestive or aversive responses to
sucrose solutions following peripheral injections of GRP and saline in rats
using a taste reactivity test. Notable deficits in oromotor responses would
certainly have been detected with this procedure. Secondly, GRP does not
reduce sham feeding (Smith et
al., 1997). Rats that received GRP injections just prior to
being given access to 0.2 M sucrose solutions behaved similarly to
saline-injected rats. Specifically, GRP-injected rats licked a stainless steel
sipper tube consistently during a 30 min access period. In contrast, when
these same subjects had their cannulae closed, GRP led to a 44% decrease in
real feeding. This clearly demonstrates a lack of a generalized motor effect
of GRP in reducing licking behavior. Other studies comparing the effects of
cholecystokinin and bombesin-like peptides on licking behaviors revealed no
changes in licking characteristics with bombesin-like peptide injections,
though cholecystokinin injections did alter several licking behaviors
(Hsiao and Spencer, 1983).
Finally, the results from this study reveal no substantial changes in the
latency to initiate licking or the inter-lick interval for any concentrations
of sucrose or for any of the injection procedures. Decreases in the latency to
initiate licking may have implicated generalized decreases in motor activity
or even mild malaise as possible sources of reduced licking behavior. Since
rats had to make a volitional movement to get into place to lick the tubes
presented, deficits in motor ability would have been evident in the time it
took each rat to orient into the proper position. Inter-lick intervals have
been noted previously as a microstructural measure that tends to remain
constant in taste-elicited behaviors
(Davis and Smith, 1988). Thus,
a lack of change in the inter-lick interval can be used to support the
hypothesis that the procedure employed for this experiment reflects changes in
the oral reinforcing properties of sucrose following administration of
GRP.
The finding of more pronounced changes in licking behavior immediately
after injection of GRP compared to results following a 5 min delay between GRP
injection and testing are important. First, this demonstrates an immediate
effect of GRP on the taste-elicited behaviors of rats sampling sucrose
solutions. Reductions in the hedonics or palatability of sugar solutions have
already been established for another gut peptide (cholecystokinin) that has a
demonstrated satiety effect (Waldbillig
and Bartness, 1982; Eckel and
Ossenkopp, 1994). Similar reductions in taste responses may now be
noted for GRP. Given the inhibition of feeding behavior observed with GRP
injections (Gibbs et al.,
1994; Rushing et al.,
1996; Thaw et al.,
1998), it can be argued that GRP-induced satiety may rely in part
on reductions in the hedonics or palatability of ingested nutrients. Secondly,
the change in behavior reported here is significantly larger as compared to
the taste reactivity test conducted by Flynn
(Flynn, 1995). Two possible
reasons for this discrepancy emerge. The two tests (taste reactivity and brief
exposure) are either not comparable or the time elapsed between the
administration of GRP and testing may have differed. The comparability of the
two tests has not yet been fully established; however, studies using
cholecystokinin have produced similar results in both taste reactivity tests
(Eckel and Ossenkopp, 1994)
and brief-exposure tests (Waldbillig and
Bartness, 1982; Weingarten et al., 1996). Therefore, the
issue of time elapsed between injections of GRP and testing may be more
critical. Few data are presently available adequately to address the effect of
immediate versus delayed testing of GRP on feeding and taste. However,
physiological reports indicate that GRP has a relatively brief half-life of
disappearance of <3 min (Bloom et
al., 1983; Knigge et
al., 1984). The effects of GRP on feeding behavior are not
currently assumed to be influenced by the timing of administration, likely due
to GRP inducing release of other factors such as gastrin, which do not reach
maximum levels until nearly 15 min post-GRP injection
(Knigge et al.,
1984). Yet the taste responses reported here are clearly related
to temporal factors. The timing of GRP administration and subsequent testing
of its behavioral effects should be observed carefully in subsequent studies.
Lastly, the similarity in licking behaviors of sucrose solutions for the
second series of solutions following GRP injections and the first series of
solutions following a 5 min delay after GRP injection represent the relative
speed with which the effect of GRP on taste diminishes. Specifically, the
first sucrose solutions encountered by the subjects immediately after GRP
administration showed severely reduced lick totals. By the second presentation
of each sucrose concentration, the effects of GRP were already reduced
substantially, though not significantly. The same pattern of decreased
effectiveness is seen within the test sessions of the 5 min delay GRP
injection procedure. Though there is an overall effect of reduced licking
following the 5 min delay procedure, the majority of decreased lick totals
occurred during the first presentation of sucrose solutions. The second
presentation of solutions results in lick totals more similar to results
following saline injections than GRP injections. Taken together, the findings
presented here demonstrate a decrease in the orosensory-guided responses to
sucrose following peripheral GRP administration, though the effect diminishes
within a matter of minutes after initial injection. Thus GRP may act, in part,
by decreasing the oral reinforcing properties of food as a mechanism of action
to reduce caloric intake.
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Acknowledgments |
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The authors would like to thank James Gibbs and Gerry Smith of the E.W. Bourne Behavioral Research Laboratory for their generous donation of GRP. Additionally, we would like to acknowledge Jason Jones and Sarah Fontenelle for their support and assistance in carrying out the procedures described in this report. This research was funded in part by the Jeffress Memorial Trust and Millsaps College.
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Accepted June 21, 2002
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