Influence
of body weight and type of chow on the
sensitivity of rats to the behavioral effects of
the direct-acting dopamine-receptor agonist
quinpirole
Baladi MG, Newman AH, France CP.
Department of Pharmacology,
University of Texas
Health Science Center San
Antonio USA
Abstract
Amount and type of food can alter dopamine
systems and sensitivity to drugs acting on those
systems.
This study examined whether changes in body
weight, food type, or both body weight and food
type contribute to these effects. Rats had free
or restricted access (increasing, decreasing, or
maintaining body weight) to standard (5.7% fat)
or high-fat (34.3%) chow.
In rats gaining weight with restricted or
free access to high-fat chow, both limbs of the
quinpirole yawning dose-response curve
(0.0032-0.32 mg/kg) shifted leftward compared
with rats eating standard chow. Restricting
access to standard or high-fat chow (maintaining
or decreasing body weight) decreased or
eliminated quinpirole-induced yawning; within 1
week of resuming free feeding, sensitivity to
quinpirole was restored, although the descending
limb of the dose-response curve was shifted
leftward in rats eating high-fat chow. These are
not likely pharmacokinetic differences because
quinpirole-induced hypothermia was not different
among groups. PG01037 and L-741,626 antagonized
the ascending and descending limbs of the
quinpirole dose-response curve in rats eating
high-fat chow, indicating D3 and D2 receptor
mediation, respectively. Rats eating high-fat
chow also developed insulin resistance.
These results show that amount and type of
chow alter sensitivity to a direct-acting
dopamine-receptor agonist with the impact of
each factor depending on whether body weight
increases, decreases, or is maintained. These
data demonstrate that feeding conditions,
perhaps related to insulin and insulin
sensitivity, profoundly impact the actions of
drugs acting on dopamine systems.
-Baladi MG, Newman
AH, France CP. Dopamine D3 receptors mediate
the discriminative stimulus effects of
quinpirole in free-feeding rats. J Pharmacol Exp
Ther. 2010;332(1):308-315
-Baladi MG,
Newman AH, France CP. Influence of body
weight and type of chow on the sensitivity of
rats to the behavioral effects of the
direct-acting dopamine-receptor agonist
quinpirole.Psychopharmacology (Berl).
2011;217:573&endash;585
-Baladi
MG, Thomas YM, France CP. Sensitivity to
apomorphine-induced yawning and hypothermia in
rats eating standard or high-fat chow.
Psychopharmacology (Berl). 2012
-Collins GT, JM
Witkin et al Dopamine agonist-induced
yawning in rats: a dopamine d3 receptor mediated
behavior. J Pharmacol Exp Ther
2005;314(1):310-9.
-Collins GT, Newman
AH,Woods JH et al.Yawning and hypothermia in
rats: effects of dopamine D3 and D2 agonists and
antagonists. Psychopharmacology
(Berl).
2007;193(2):159-170
-Collins GT. et
al. Food restriction alters
pramipexole-induced yawning, hypothermia, and
locomotor activity in rats: Evidence for
sensitization of dopamine D2 receptor-mediated
effects. JEPT 2008;325:691-697
-Collins
GT et al. Narrowing in on compulsions:
dopamine receptor functions Exp Clin
Psychopharmacol 2008,16(4):498-502
-Collins
GT et al. Pro-erectile Effects of Dopamine
D2-like Agonists are Mediated by the D3 Receptor
in Rats and Mice JPEP 2009;329(1):210-217
-Collins GT,
Truong YN, et al. Behavioral sensitization
to cocaine in rats: evidence for temporal
differences in dopamine D(3) and D (2) receptor
sensitivity. Psychopharmacology (Berl).
2011;215(4):609-20
Discussion
Dopamine systems are altered in various
diseases, and they are the target of many drugs
that are used clinically as well as drugs of
abuse. Dopamine systems also mediate, at least
in part, the reinforcing effects of many drugs
and of food. Moreover, it is clear that
feeding conditions impact the activity of
dopamine systems in brain as well as the
effects of drugs acting on those systems.
Because feeding conditions (i.e., amount and
type of food) can vary markedly within and among
individuals, it is possible that variations in
food intake and nutritional status contribute to
the development of psychopathologies (e.g.,
vulnerability to drug abuse) and impact the
response of individuals to drugs. This study
examined the impact of how much rats eat
(increasing, decreasing, or maintaining body
weight) and the type of chow they eat (standard
or high fat) on the behavioral effects of the
direct-acting dopamine-receptor agonist
quinpirole. While the type of chow appeared to
be the predominant factor in determining
quinpirole effects under some conditions, under
other conditions, body weight appeared to be the
predominant factor.
It is well established that restricting
access to food significantly alters brain
neurochemistry and the behavioral effects of
drugs. It is also clear that allowing animals to
eat certain foods (e.g., high fat) can affect
brain neurochemistry and the behavioral effects
of drugs. In this study, quinpirole-induced
yawning varied significantly across eating
conditions and across different periods of
time. For example, after 21 (free-feeding)
or 28 (restricted) days of eating high-fat chow
while gaining body weight (Experiment 1), the
descending limb of the quinpirole
dose&endash;response curve was shifted leftward,
reflecting increased sensitivity at dopamine D2
receptors. In contrast, the descending limb of
the quinpirole dose&endash;response curve was
shifted leftward after just 7 or 14 days in rats
eating high-fat chow and losing (Experiment 2)
or maintaining (Experiment 3) body weight,
respectively. Thus, although qualitatively
similar effects were observed across conditions
(shift left in the descending limb of the
dose&endash;response curve), those effects
occurred at different times among groups.
Moreover, increased sensitivity to
quinpirole-induced yawning was correlated with
the emergence of insensitivity to
insulin-induced hypoglycemia (Experiment 5).
Upon resumption or continuation of free-feeding,
the descending limb of the quinpirole
dose&endash;response curve remained shifted
leftward in all rats eating high-fat chow. In
contrast, when rats that previously had
restricted access to standard chow were allowed
free access to standard chow, their sensitivity
to quinpirole returned and was not different
from rats that had only free access to standard
chow throughout the study (compare Group 1 to
Groups 4 and 6, Panel E), indicating the
reversibility of food restriction (standard
chow)-induced changes in sensitivity to
quinpirole.
In rats eating high-fat chow and gaining
weight, the shift leftward in the ascending limb
of the dose&endash;response curve was evident
after 14 days and persisted until the end of the
study. A similar shift leftward in the ascending
limb (D3) of the dose&endash;response curve was
evident after 14 days in rats eating high-fat
chow and maintaining body weight, although that
shift was no longer evident 7 days later,
presumably because of an even greater increase
in sensitivity at D2 receptors that masked any
expression of yawning. In the same rats (i.e.,
eating high-fat chow with body weight
maintained, Group 7), normal sensitivity to
quinpirole was apparent after just 7 days of
free access to high-fat chow (Day 42, panel D,
Fig. 3). With continued free access to high-fat
chow and with further body weight gain, the
ascending limb of the quinpirole
dose&endash;response curve shifted leftward and
was not different from what was observed in rats
that had free access to high-fat chow throughout
the study (compare Groups 2 and 7). In rats
losing weight, eating high-fat chow also
appeared to delay, but not prevent, the
elimination of quinpirole-induced yawning,
perhaps reflecting increased sensitivity at D3
receptors that eventually was overcome by a
greater increase at D2 receptors. Collectively,
two major trends are apparent from these data:
(1) eating high-fat food increases sensitivity
to D3 (leftward shift in the ascending limb) and
D2 (leftward shift in the descending limb)
receptor-mediated effects of quinpirole; and (2)
regardless of chow type, food restriction (so
that body weight does not increase) increases
sensitivity to D2 receptor-mediated effects of
quinpirole and, eventually, suppresses
quinpirole-induced yawning.
Sensitivity to the behavioral effects of
drugs acting on dopamine systems sometimes
increases after repeated intermittent drug
administration (i.e., sensitization) and feeding
conditions can impact those increases in
sensitivity. For example, eating high-fat chow
accelerates the rate at which sensitivity
increases to the locomotor-stimulating effects
of the indirect-acting dopamine-receptor agonist
methamphetamine in rats.
Although sensitization can also develop to
the locomotorstimulating effects of quinpirole,
there was no evidence in the current study for
sensitization to quinpirole-induced yawning. The
quinpirole-yawning dose&endash;response curve in
rats with free access to standard chow was very
consistent across many weeks of once per week
quinpirole testing. It also appears unlikely
that feeding conditions (e.g., eating high-fat
chow) selectively enhance the development of
sensitization to quinpirole since rats that eat
high-fat chow and are tested just once with
quinpirole show the same changes in sensitivity
that were observed in the current study in rats
that were tested weekly with quinpirole. Feeding
conditions (e.g., food restriction) that
significantly altered the descending limb of the
quinpirole yawning dose&endash;response curve
(mediated by D2 receptors) had no effect on
quinpirole-induced hypothermia, which also is
thought to be mediated by D2 receptors. That
quinpirole-induced hypothermia did not vary
across feeding conditions suggests that changes
in quinpirole-induced yawning were not due to
pharmacokinetic factors and, possibly, that the
receptors mediating the hypothermic effects of
quinpirole are not the same receptors mediating
yawning (i.e., D2 and D1). Both yawning and
hypothermia are thought to be centrally
mediated, although different populations of
dopamine receptors might mediate these effects
(the anterior hypothalamus/preoptic area for
quinpirole-induced hypothermia and the
paraventricular nucleus of the hypothalamus for
quinpirole-induced yawning.
Moreover, other (non-dopamine) mechanisms
might also contribute to the regulation of body
temperature in a manner that attenuates
nutrition-related changes in dopamine-receptor
sensitivity that might otherwise be expected to
impact body temperature.
While the current study examined changes in
a behavioral effect (i.e., yawning) that is
thought to be mediated by dopamine receptors in
the paraventricular nucleus of the hypothalamus,
it is likely that dopamine receptors in some
other brain regions are also impacted by feeding
conditions. For example, food restriction
increases sensitivity to the
locomotor-stimulating effects of direct-acting
dopamine-receptor agonists, including
quinpirole, possibly indicating changes in
receptor sensitivity in the mesolimbic dopamine
pathway .
The mechanism(s) mediating changes in the
behavioral effects of quinpirole across eating
conditions are not known and might include
changes in dopamine content or turnover,
receptor number, or function. It is well
established that different feeding conditions
(amount and type of food) can significantly
modify circulating concentrations of hormones
such as insulin, leptin, and ghrelin that are
known to have effects on dopamine systems. These
hormones can activate specific receptors on
dopamine neurons and either inhibit (insulin and
leptin) or stimulate (ghrelin) dopamine
signaling. Food restriction decreases while
eating high-fat chow increases circulating
insulin. Moreover, plasma concentrations of
insulin and leptin are increased similarly in
rats with free or restricted (body weight
matched to rats with free access to high-fat
chow) access to high-fat chow, consistent with
the similar behavioral effects observed in the
current study between rats with free or
restricted access to high-fat chow (Experiment
1). Whether hormonal changes contribute to
altered behavioral effects of drugs acting on
dopamine systems is yet to be determined,
although a growing body of literature obtained
in diabetic animals and in animals eating
different amounts and types of chow strongly
implicates insulin and leptin as playing major
roles in drug effects that are mediated by
dopamine systems (e.g., reinforcing effects).
For example, in the current study, eating
high-fat chow changed the behavioral effects of
quinpirole and, in parallel, induced insulin
resistance, supporting the view that
insulinsignaling pathways play a role in
diet-induced changes in drug response.
Finally, these data indicate that response
to drugs (therapeutic and recreational) might be
profoundly impacted by eating conditions,
including body weight and type of food and that
changes in drug sensitivity might be long
lasting. Thus, modest weight loss or weight gain
might contribute to individual differences in
response to drugs. Moreover, the type of food
eaten might impact brain neurochemistry
resulting in an altered response to drugs. While
the current obesity epidemic (more than one
third of adults in the USA were obese in
2007&endash;2008) is a pressing public health
problem that is relevant to the current study,
data in rats indicate that being overweight per
se might not be the most important factor
affecting response to drugs.
Rather, it appears to be the consumption of
fat and, perhaps, resulting hormonal changes
that markedly alter dopamine systems.
Understanding the relationship between feeding
conditions and drug response could facilitate
our understanding of individual differences in
response to therapeutic drugs and in
vulnerability to drug abuse.
Dopamine
D3 receptors mediate the discriminative stimulus
effects of quinpirole in free-feeding
rats
Baladi MG, Newman AH, France
CP.
Department of
Pharmacology, The University of Texas Health
Science Center at San Antonio, Texas.
USA.
Abstract
The discriminative stimulus effects of
dopamine (DA) D3/D2 receptor agonists are
thought to be mediated by D2 receptors. To
maintain responding, access to food is often
restricted, which can alter neurochemical and
behavioral effects of drugs acting on DA
systems. This study established stimulus control
with quinpirole in free-feeding rats and tested
the ability of agonists to mimic and antagonists
to attenuate the effects of quinpirole. The same
antagonists were studied for their ability to
attenuate quinpirole-induced yawning and
hypothermia. DA receptor agonists apomorphine
and lisuride, but not amphetamine and morphine,
occasioned responding on the quinpirole lever.
The discriminative stimulus effects of
quinpirole were attenuated by the D3
receptor-selective antagonist
N-{4-[4-(2,3-dichlorophenyl)-piperazin-1-yl]-trans-but-2-enyl}-4-pyridine-2-yl-benzamide
HCl (PG01037) and the nonselective D3/D2
receptor antagonist raclopride, but not by the
D2 receptor-selective antagonist
3-[4-(4-chlorophenyl)-4-hydroxypiperidin-1-yl]methyl-1H-indole
(L-741,626); the potencies of PG01037 and
raclopride to antagonize this effect of
quinpirole paralleled their potencies to
antagonize the ascending limb of the quinpirole
yawning dose-response curve (thought to be
mediated by D3 receptors). L-741,626 selectively
antagonized the descending limb of the
quinpirole yawning dose-response curve, and both
L-741,626 and raclopride, but not PG01037,
antagonized the hypothermic effects of
quinpirole (thought to be mediated by D2
receptors). Food restriction (10 g/day/7 days)
significantly decreased quinpirole-induced
yawning without affecting the quinpirole
discrimination. Many discrimination studies on
DA receptor agonists use food-restricted rats;
together with those studies, the current
experiment using free-feeding rats suggests that
feeding conditions affecting the behavioral
effects of direct-acting DA receptor agonists
might also have an impact on the effects of
indirect-acting agonists such as cocaine and
amphetamine.
....................
Yawning induced by DA receptor agonists
yields an inverted U-shaped dose-response curve,
and it is thought that the ascending limb of
this curve (induction of yawning) is mediated by
actions at D3 receptors and the descending limb
(inhibition of yawning) is mediated by actions
at D2 receptors (Collins et al., 2005). The same
antagonists that were compared for their ability
to antagonize the discriminative stimulus
effects of quinpirole also were compared for
their ability to antagonize quinpiroleinduced
yawning. The D3 receptor-selective antagonist
PG01037 attenuated the ascending limb of the
quinpirole dose-response curve in a dose-related
manner without affecting the descending limb. In
contrast, a dose of the D2 receptor-selective
antagonist L-741,626 (1.0 mg/kg) that attenuated
the descending limb of the quinpirole
doseresponse curve had no effect on the
ascending limb. The nonselective D3/D2 receptor
antagonist raclopride dose dependently
attenuated both limbs of the dose-response curve
for quinpirole-induced yawning. The ability of
these antagonists to attenuate the discriminate
stimulus effects of quinpirole in free-feeding
rats parallels their ability to attenuate the
ascending and, presumably, D3 receptormediated
limb of the dose-response curve for
quinpiroleinduced yawning. In particular, the
potencies of PG01037 and raclopride, but not of
L-741,626, to antagonize the discriminative
stimulus effects of quinpirole parallel their
relative potencies in attenuating the ascending
limb of the yawning dose-response curve (Table
1), further supporting the view that the
discriminative stimulus effects of quinpirole in
free-feeding rats are mediated predominantly, if
not exclusively, by D3 receptors.
Based on the effects of various DA receptor
agonists administered alone and in combination
with different DA receptor antagonists, it is
thought that the hypothermic effects of D3/D2
receptor agonists (e.g., including quinpirole)
are mediated by D2 receptors (Nunes et al.,
1991; Chaperon et al., 2003; Collins et al.,
2007). Consistent with that view,
quinpirole-induced hypothermia was attenuated by
the D2 receptor-selective antagonist L-741,626
and the nonselective D3/D2 receptor antagonist
raclopride but not by the D3 receptor- selective
antagonist PG01037.
Food restriction markedly decreases
sensitivity of rats to quinpirole-induced
yawning (Sevak et al., 2008; Baladi and France,
2009); interpretations of that observation might
include decreased sensitivity of D3 receptors to
agonists, increased sensitivity of D2 receptors
to agonists, or both decreased sensitivity of D3
and increased sensitivity of D2 receptors.
However, results of behavioral as well as
molecular studies indicate that the effect of
food restriction is to increase sensitivity of
D2 receptors (Carr et al., 2003; Collins et al.,
2008; Thanos et al., 2008). If the
discriminative stimulus effects of DA receptor
agonists in freefeeding rats are mediated by D2
receptors, then it might be expected that food
restriction would increase sensitivity to those
effects, as reflected by a leftward shift in the
doseresponse curve. However, food restriction
(10 g/day for 7 days) that markedly decreased
sensitivity to quinpiroleinduced yawning had no
effect on the discriminative stimulus effects of
quinpirole in the same group of rats, supporting
the hypothesis that D2 receptors are not
involved in the discriminative stimulus effects
of quinpirole in freefeeding rats. Food
restriction in the current study reduced body
weight to approximately 90% of free-feeding
weight, somewhat less than body weight loss
reported in other studies using food restriction
and studying dopamine drugs (e.g.,
80&endash;85%; Weathersby and Appel, 1986; Carr
et al., 2003; Collins et al., 2008; Koffarnus et
al., 2009). Together with the current antagonism
studies, these data support the view that D3
receptors mediate the discriminative stimulus
effects of quinpirole in free-feeding rats and
that sensitivity of D3 receptors to agonists is
not markedly affected by food restriction.
Future studies might include establishing a
discrimination with a highly selective D2
receptor agonist in free-feeding rats (i.e.,
acute food restriction might shift the
dose-response curve leftward) or with a highly
selective D3 receptor agonist in food-restricted
rats (i.e., D3 and not D2 receptor antagonists
should block the training stimulus). Moreover,
it is not clear whether the reinforcer used to
maintain responding (i.e., shock) influences the
contribution of different DA receptors in the
discriminative stimulus effects of agonists. In
summary, although D2 receptors are thought to
mediate the discriminative stimulus effects of
quinpirole in food-restricted rats, D3 receptors
seem to mediate the discriminative stimulus
effects of quinpirole in free-feeding rats.
Thus, feeding conditions can affect the
contribution of D3 and D2 receptors to the
discriminative stimulus effects of quinpirole.
Several mechanisms are thought to underlie the
effects of food restriction on DA receptors,
including increased DA receptor number and
signaling and reduced plasma levels of hormones
such as insulin and leptin that can directly
affect DA systems. Understanding the link
between feeding condition and DA
neurotransmission might be critical for
understanding the comorbidity of eating
disorders and drug abuse and also has
implications for understanding how feeding
condition might affect the behavioral effects of
other drugs acting on DA systems, including
drugs of abuse such as cocaine and
amphetamine.
