Repeated treatment in ontogeny with the
dopamine (DA) D(2)/D(3) receptor agonist
quinpirole is associated with enhanced
quinpirole-induced yawning and other behaviors
such as vacuous chewing, vertical jumping, and
antinociception. To determine if the reputedly
DA D(3) agonist
(+/-)-2-(dipropylamino)-7-hydroxy-1,2,3,
4-tetrahydronaphthalene (7-OH-DPAT) would prime
for yawning in a manner analogous to that for
quinpirole, rats were treated for the first 11
days after birth with an equimolar dose of
either quinpirole or 7-OH-DPAT (195.4
nmol/kg/day) and tested for agonist-induced
yawning in adulthood. While enhanced
quinpirole-induced and 7-OH-DPAT-induced yawning
was observed in quinpirole-primed rats, acute
treatments with quinpirole and 7-OH-DPAT did not
produce an enhanced yawing response in
7-OH-DPAT-"primed" rats. Our findings indicate
that 7-OH-DPAT, unlike quinpirole, does not
prime for quinpirole- or 7-OH-DPAT-induced
yawning in rats.
Introduction
Quinpirole induces characteristic behaviors
in rats, most notably oral activity and yawning.
Oral activity is the type behavior described by
Waddington [24] as spontaneous chewing
movements that are not directed onto physical
material (i.e., vacuous chewing). Quinpirole is
thought to induce vacuous chewing via
stimulation of the dopamine (DA) D2 receptor
class (i.e., D2, D3, and D4 receptors), because
its effect is blocked by spiperone. However,
some interaction with receptors is evident, as
the D1 receptor antagonist R(+) -7- chloro -8
-hydroxy 3-methyl - 1 -phenyl- 2,3,4,5 -
tetrahydro - 1H-3 -benzazepine (SCH 23390)
similarly attenuates the quinpirole effect
[3]. A number of other behaviors are
induced by DA D2 agonists, including eating,
vertical jumping, rearing, paw treading, and
antinociception. Each of these behaviors has
been shown to be enhanced by ontogenetic
quinpirole priming [13-17]. Until now,
there have been no published data concerning the
ability of (± ) -2- (dipropylamino) -7
-hydroxy -1,2,3,4 - tetrahydronaphthalene (7OH -
DPAT) to prime receptors for subsequent enhanced
effects by agonists.
Both quinpirole and 7-OH - DPAT reportedly
induce yawning behavior in rats via stimulation
of the DA D2 receptor class
[7,12,13,19]. In a series of studies
involving the induction of DA receptor
supersensitization, we found that ontogenetic
treatments with quinpirole would produce
long-lived sensitization of receptors mediating
quinpirole-induced yawing response in adult rats
[13]. In addition, it is evident that
these DA receptors can be permanently sensitized
by extraordinarily low doses of quinpirole,
administered once a day for the first 11 days
after birth [15].
The current study was conducted to determine
if quinpirole and 7-OH - DPAT, applied in
equimolar doses, would be equi-effective in
inducing yawning in rats. Moreover, we sought to
determine if repeated low equimolar doses of
quinpirole and 7-OH - DPAT, administered during
postnatal ontogeny, would sensitize receptors
for both quipirole and 7OH-DPAT induced yawning
later un life.
Discussion
In accordance with previous findings,
repeated quinpiroie treatments of rats in early
postnatal ontogeny produced long-term
enhancement of quinpirole-induced yawning in
adulthood [4,13,15]. Other long-lived D2
agonist-enhanced behaviors occurring in these
rats include locomotor activity with rearing
[5,6,17], age-related jumping with paw
treading [16], eating [16], and
antinociception [14]. The induction of
long-lived sensitization of DA receptors,
produced by repeated agonist treatments during
ontogenetic development, is readily achieved in
rats that are largely DA denervated [2],
and this phenomenon has been designated as a
"priming" process.
Szechtman et al. [211 have demonstrated
that the number of injections of DA agonist,
rather than the dosing interval between
injections, is the predominant factor regulating
development of long-lived quinpirole
sensitization in rats. The dose of quinpirole
within a defined range has additional impact on
sensitization to later quinpirole enhancement of
behaviors in these rodents with primed DA
receptors. For example, Szechtman's group
reported that repeated treatments of rats with a
quinpirole dose of 0.025 mg/kg did not induce
enhanced quinpirole effects, even after 10
consecutive daily treatments. However, higher
doses (0.25 and 2.5 mg/kg) did sensitize this
receptor complex. This same group further found
that long-term intermittent treatments with
quinpirole (0.5 mg/kg) induced pronounced
sensitization to quinpirole - induced locomotor
response (i.e., sixfold increase)
[10].
As previously stated, 7-OH -DPAT was
approximately equi - effective with quinpirole
in inducing yawing episodes in male rats. It
should be noted that quinpirole-induced yawning
has been associated with reduced microdialysate
levels of DA, presumably by action at DA D3
receptors [7]. In addition, quinpirole
and 7-OH -DPAT have similar affinities for DA D3
receptors [18]. Therefore, it is not
surprising that quinpirole and 7-OH -DPAT had
similar effects on yawning number in
"saline-primed" rats in the current study.
Presumed long-lived sensitization of DA "D2
complex" receptors was observed as enhanced
yawning responses to both quinpirole and
7-OH-DPAT in male rats; and as enhanced
quinpirole responses in female rats. However,
unlike quinpirole, ontogenetic treatments with
7-OH-DPAT did not appear to prime receptors. In
rats in which there was attempted ontogenetic
priming with 7OH -DPAT, there was no later
enhancement of yawning by acute quinpirole
treatment or 7-OHDPAT treatment. Others have
shown that repeated 7-OH - DPAT treatments (0.01
to 1.0 mg/kg) do not result in cross
-sensitization to apomorphine- or
cocaine-induced locomotor activity in rats
[20]. Conversely, the 10-day treatment
with a high dose of 7-OH-DPAT (1000 p.g/kg)
produced progressive increases in locomotor
activity, demonstrating that 7-OH DPAT is
inherently capable of inducing behavioral
sensitization [20]. In the current
study, failure of 7-OH -DPAT to induce
sensitivity to a later challenge dose of 7-OH
DPAT is therefore likely to be related to the
purposeful low dose of 7-OH-DPAT that was used
for priming. It is noteworthy, that quinpirole
at an equimolar dose, did prime receptors to
later challenges with quinpirole.
There is a question of whether quinpirole
acts preferentially at a population of DA D2 or
D3 receptors, different from those activated by
7-OH-DPAT; or whether each of these D2/D3
agonists acts with different efficacy on the
same receptor population. Currently, this
problem is not easily addressed. One might
approach this, using the preferential DA D3
agonist (+) - trans - 3,4,4a, lOb -tetrahydro 4-
propyl - 2H,SH- (1 )benzopyrano(4,3b) - 1,4-
oxasin -9- ol [PD 128907], which has
been used in a behavioral model of D3 receptor
activation, namely hypothermia and prepulse
inhibition [23], and failure to lower
serum prolactin levels [9]. However,
more recent findings clearly demonstrate,
nonetheless, that PD128907 is also a partial
agonist at DA D3 receptors [22]. In
addition, even the locomotor and hypothermic
actions of reputed D3 agonists now has been
ascribed to DA D2 receptor effects
[1,8]. Therefore, even when
more-selective D3 agonists are developed, it
will remain difficult to definitively ascribe DA
receptor populations to the observed priming
(behavioral) responses of quinpirole and
7-OH-DPAT.
From these behavioral experiments, we can
conclude that 7-OH-DPAT is unable to prime
receptors in the same way as a low equimolar
dose of quinpirole, but that quinpiroleprimed
rats display greater responses to both
quinpirole and 7-OH - DPAT. Differences between
quinpirole and 7-OH DPAT in effectively priming
DA receptors, conceivably could be related to
their respective effects on other neurochemical
systems (see Ref. [11]), but this has
not been systematically studied.
In summary, there is a major
difference in the abilities of quinpirole and
7-OH-DPAT to prime rats for yawning responses to
low doses of these respective DA agonists. It is
premature to preferentially assign either
specific D2 or D3 receptors to this effect, but
the findings bring into question the generally
assumed categorization of D3 receptors with DA
agonist-induced yawning.
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