Drinking
sucrose or saccharin enhances
sensitivity
of rats
to quinpirole-induced yawning
Katherine M. Serafine, Todd A. Bentley,
Dylan J. Kilborn,
Wouter Koek, Charles P. France
Department of Pharmacology,
University of Texas Health Science Center at San
Antonio. USA
ABSTRACT
Diet can impact sensitivity of rats to some
of the behavioral effects of drugs acting on
dopamine systems. The current study tested
whether continuous access to sucrose is
necessary to increase yawning induced by the
dopamine receptor agonist quinpirole, or if
intermittent access is sufficient. These studies
also tested whether sensitivity to
quinpirole-induced yawning increases in rats
drinking the non-caloric sweetener saccharin.
Dose-response curves (0.0032-0.32 mg/kg) for
quinpirole-induced yawning were determined once
weekly in rats with free access to standard chow
and either continuous access to water, 10%
sucrose solution, or 0.1% saccharin solution, or
intermittent access to sucrose or saccharin
(i.e., 2 days per week with access to water on
other days). Cumulative doses of quinpirole
increased then decreased yawning, resulting in
an inverted U-shaped dose-response curve.
Continuous or intermittent access to sucrose
enhanced sensitivity to quinpirole-induced
yawning. Continuous, but not intermittent,
access to saccharin also enhanced sensitivity to
quinpirole-induced yawning. In all groups,
pretreatment with the selective D3 receptor
antagonist PG01037 shifted the ascending limb of
the quinpirole dose-response curve to the right,
while pretreatment with the selective D2
receptor antagonist L-741,626 shifted the
descending limb to the right. These results
suggest that even intermittent consumption of
diets con-taining highly palatable substances
(e.g. sucrose) alters sensitivity to drugs
acting on dopamine systems in a manner that
could be important in vulnerability to abuse
drugs.
Résumé
Le régime alimentaire peut avoir un
impact sur la sensibilité
manifestée par des rats à certains
des effets comportementaux induits par des
médicaments agissant sur le
système dopaminergique.
La présente étude a
testé si un accès continu au
saccharose est capable d'augmenter les
bâillements induits par l'agoniste des
récepteurs de la dopamine, le quinpirole,
ou si l'accès intermittent est suffisant.
Ces études ont également
vérifié si la sensibilité
aux bâillements augmente chez les rats
buvant l'édulcorant non-calorique, la
saccharine au bâillements induits par le
quinpirole.
Les résultats suggèrent que la
consommation, même intermittente
d'alimentaire contenant des substances
sucrés hautement agréables au
goût (par exemple, le saccharose) modifie
la sensibilité aux médicaments qui
agissent sur les systèmes dopaminergiques
d'une manière qui pourrait être
important face à la
vulnérabilité à l'abus de
drogues.
1. Introduction
Diet (e.g., type and amount of food
consumed) can impact sensitivity to drugs acting
on dopamine systems (Avena and Hoebel, 2003;
Collins et al., 2008; Gosnell, 2005; Baladi et
al., 2012a, 2011a; Puhl et al., 2011). For
example, rats eating a high fat chow or drinking
a 10% sucrose solution are more sensitive than
rats eating standard chow and drinking water to
the behavioral effects of direct- (i.e.,
quinpirole; Baladi et al., 2011a, b) and
in-direct-acting (i.e., cocaine; Baladi et al.,
2012b) dopamine receptor agonists. Although
consumption of foods high in fat or sugar
contributes to the development of obesity,
sensitivity changes to the behavioral effects of
drugs acting on dopamine systems even in the
absence of weight gain (Baladi et al., 2011a,
b); specifically, consuming a high fat or high
sugar diet can markedly affect drug sensitivity
in the absence of accelerated body weight
gain.
Rats drinking sucrose are more sensitive
than rats drinking water to the behavioral
effects of quinpirole (Baladi et al., 2011b).
Like many other direct-acting dopamine receptor
agonists, quin-pirole dose-dependently increases
then decreases yawning in rats (Collins et al.,
2008; Baladi and France, 2010) resulting in an
in-verted U-shaped dose-response curve.
Experiments using selec-tive dopamine receptor
antagonists have revealed that the as-cending
limb (initiation of yawning) is mediated by
dopamine D3 receptors, while the descending limb
(inhibition of yawning) is mediated by dopamine
D2 receptors (Collins et al., 2008; Baladi et
al., 2011a; though see Depoortere et al. (2009),
Sanna et al. (2011, 2012)). The D3
receptor-mediated ascending limb of the
quinpirole dose-response curve is shifted to the
left in rats drinking sucrose (Baladi et al.,
2011b). When consumption of highly preferred
substances (fat or sugar) is restricted or
access is intermittent, animals often increase
consumption which is ac-companied by an enhanced
sensitivity to drugs acting indirectly on
dopamine systems (Avena and Hoebel, 2003;
Gosnell, 2005; Puhl et al., 2011). However,
intermittency of access varied mark-edly across
these studies and it is not known whether
intermittent access to sucrose enhances
sensitivity of rats to the behavioral effects of
the direct-acting dopamine receptor agonist
quinpirole. While the mechanism(s) underlying
these changes in sensi-tivity is not known,
consumption of a diet high in sucrose or fat
also causes metabolic changes (e.g., insulin
resistance) that could impact drug sensitivity.
Changes in insulin signaling can impact dopamine
neurotransmission (Daws et al., 2011); however,
non-caloric sweeteners such as saccharin are
also highly preferred (compared with water) by
rats (Carroll et al., 2007, 2008) but do not
cause insulin resistance. Animals that show the
greatest pre-ference for sweeteners often are
also more sensitive to drugs acting on dopamine
systems (Carroll et al., 2008). The current
study examined the effects of continuous or
intermittent access to sucrose or saccharin
solutions on sensitivity of rats to
quinpirole-induced yawning.
4. Discussion
It is well established that sensitivity to
the behavioral effects of quinpirole is enhanced
in rats drinking sucrose (Baladi et al„
2011b); however, it was not known whether
continuous access is necessary, or if
intermittent access to sucrose is sufficient to
cause such changes. Moreover, sucrose is high in
calories and it is not known whether consumption
of non-caloric sweet solutions might also change
the sensitivity of rats to the behavioral
effects of quinpirole. This study examined the
effects of continuous and in-termittent access
to sucrose or saccharin on sensitivity of rats
to quinpirole-induced yawning. Rats with
continuous access to a 10% sucrose solution were
more sensitive than rats drinking water to
quinpirole-induced yawning. Moreover, rats
drinking a 10% su-crose solution only two days
per week (i.e., intermittent access) also were
more sensitive than rats drinking water to
quinpirole-induced yawning, although to a lesser
extent than those with continuous access to
sucrose (i.e., significant leftward shift of the
ascending limb only on week 8). Rats with
continuous access to saccharin, but not rats
with intermittent access to saccharin, were more
sensitive than rats drinking water to
quinpirole-induced yawning (similar shifts in
ascending and descend limbs to those seen with
intermittent sucrose group). These results are
consistent with a previous report showing that
consuming sucrose enhances sensitivity of rats
to quinpirole-induced yawning (Baladi et
al„ 2011b) and they extend those results by
revealing that inter-mittent access to sucrose
is sufficient to significantly enhance
sensitivity to quinpirole-induced yawning. These
results further demonstrate that the non-caloric
sweetener saccharin enhances sensitivity of rats
to quinpirole, suggesting that highly palatable
taste in the absence of calories is sufficient
to change sensitivity to direct-acting dopamine
receptor agonists such as quinpirole.
There were significant differences among
some groups with regard to the enhanced
sensitivity to quinpirole-induced yawning. For
example, only in rats with continuous access to
sucrose were both the ascending (D3 receptor
mediated) and the descending (D2 receptor
mediated; see Depoortere et al. (2009); Sanna et
al. (2011, 2012)) limbs of the quinpirole
dose-response curve shifted left-ward (Figs. 3
and 4) in week 8. In contrast, only the
ascending limb of the quinpirole yawning
dose-response curve was shifted left-ward in
rats with intermittent access to sucrose (week
8). This difference regarding shifting one limb
but not the other might be related to previous
studies showing that the duration of access to a
highly palatable diet determines the magnitude
of effect on do-pamine neurotransmission and on
sensitivity to drugs acting on dopamine systems
(Avena and Hoebel, 2003; Avena et ah, 2008; Puhl
et ah, 2011; Spangler et ah, 2004). By week 9,
both the as-cending and descending limbs of the
quinpirole dose-response curve were
significantly shifted to the left both in rats
with in-termittent access to sucrose and in rats
with continuous access to saccharin. Previous
studies have shown that feeding conditions can
differentially impact the two limbs of the
quinpirole yawning dose-response curve
(similarly to what has been demonstrated with
food restriction; Collins et ah, 2008). However,
by week 9, a leftward shift in both limbs of the
dose-response curve was re-vealed in rats with
intermittent access to sucrose, suggesting that
a longer duration of access causes a greater
shift in the dose-response curve. Although
differences in sensitivity have been re-ported
using a shorter duration of access to sucrose
(Baladi et ah, 2011b), in that study only the
ascending limb of the quinpirole dose-response
curve was shifted to the left. A final
quinpirole dose-response curve generated in week
16 did not reveal any further change in
sensitivity to quinpirole in any group,
suggesting a potential ceiling effect with
regard to the impact of sucrose or saccharin on
sensitivity to the behavioral effects of
quinpirole. It is not known if other
concentrations of sucrose or saccharin might
have resulted in different consumption or
further impacted sen-sitivity to
quinpirole.
Insulin resistance can develop in rats
drinking sucrose or eating a high fat chow
(Baladi et ah, 2011a) and insulin signaling has
been shown to regulate dopamine
neurotransmission (Daws et ah, 2011). However,
it is not clear whether insulin resistance is
ne-cessary to change sensitivity to the
behavioral effects of drugs acting on dopamine
systems, since rats with restricted access to
high fat chow (such that their body weights are
not increased relative to control rats eating
standard chow) are more sensitive to quinpirole
(Baladi et al. unpublished observation), but do
not de-velop insulin resistance (see Serafine et
al. (2014) for an example in female rats).
Similarly, in the present experiment rats
drinking saccharin were more sensitive than rats
drinking water to quin-pirole-induced yawning,
further suggesting that diet-induced
en-hancement in sensitivity to drugs acting on
dopamine systems can occur in the absence of
insulin resistance. That the hypothermic effects
of quinpirole were not significantly altered by
the feeding conditions used in this study is
consistent with previous reports using highly
palatable diets (e.g., high fat chow or sucrose;
Baladi et al., 2011a, b). These results are also
consistent with other reports demonstrating that
D2 receptor antagonists attenuate dopamine
agonist-induced hypothermia in rats (Chaperon et
al., 2003; Col-lins et al., 2007; see Millan et
al. (2000, 2008) for examples of D3 receptor
antagonists modulating agonist-induced
hypothermia in a different outbred rat strain)
as well as in mice (Boulay et al., 1999a,
b).
Intake of highly palatable foods often
escalates when access is limited (Avena and
Hoebel, 2003; Puhl et al., 2011). In the present
study, food and fluid intake changed
systematically between days when rats in the
intermittent access groups drank water and days
when they drank either sucrose or saccharin
(Table 1); however, body weight gain was similar
between rats with intermittent ac-cess and those
with continuous access. Moreover, there was no
evidence of escalated intake; in fact, rats with
intermittent access to sucrose drank similar
amounts across days throughout the duration of
the experiment (data not shown). It is possible
that a different schedule of intermittent
access, similar to what was used by others
(e.g., Avena and Hoebel, 2003; Puhl et al.,
2011), might have escalated intake, changed
patterns of consumption, or changed in
sensitivity to quinpirole differently or to a
greater extent. The results of the present study
add to the growing body of literature showing
that changing feeding conditions, content or
access conditions, can dramatically impact
dopamine systems and sensitivity to drugs acting
on those systems. Non-caloric sweet-eners are
often used in place of caloric sweeteners to
reduce the risk of negative health consequences
(i.e., diabetes, obesity) asso-ciated with
sweeteners like sucrose. The results of the
present study demonstrate that consuming
non-caloric sweeteners might significantly
impact dopamine systems. Many drugs, including
those used clinically and those used
recreationally, target dopa-mine systems;
although consuming non-caloric sweeteners might
reduce the risk of some adverse health
consequences (e.g., obesity and diabetes),
consuming saccharin or other non-caloric
sweet-eners could also change sensitivity to
drugs in a manner that alters therapeutic
effectiveness of drugs or vulnerability to abuse
drugs. Given a continuing escalation in the
consumption of foods high in fat and sugar
across much of the world (e.g., U.S. Department
of Agriculture, U.S. Department of Health and
Human Services, 2010), it is becoming
increasingly important to understand the impact
of these dietary conditions on sensitivity to
drugs.
