CNS Diseases Research,
Upjohn Company, Kalamazoo, USA
Apomorphine induced yawning in both
Sprague-Dawley and F344 rats in the same dose
range, but F344 rats emitted only about 1/4 as
many yawns as did Sprague-Dawley rats. At higher
doses, rats of both strains exhibited
stereotypic behavior with a comparable
intensity. Pretreatment with either SCH 23390
[R(+)-8-chloro-2,3,4,5-tetrahydro-3-methyl-5-phenyl-1H-3-benzazepine-7-o
l] or pindolol increased apomorphine-induced
yawning further in Sprague-Dawley rats, but had
little effect on the low yawning score produced
by apomorphine in F344 rats. The low yawning
response to apomorphine in F344 rats is,
therefore, not due to a high baseline
dopaminergic or adrenergic activity.
Apomorphine-induced yawning in F344 rats was
increased after an acute injection of
physostigmine, or 24 h after an injection of
reserpine. It is postulated that a low baseline
cholinergic activity in F344 rats may be
responsible, in part, for their lower yawning
response to dopaminergic receptor
stimulation.
1. Introduction
The in-bred Fischer 344 (F344) rats have a
number of biochemical, neuroendocrine and
behavioral differences from other rat strains.
Compared to 5 other in-bred strains and the
out-bred Sprague-Dawley rats, F344 rats were
least active in spontaneous locomotor activity,
but had the highest level of tyrosine
hydroxylase activity in the midbrain and
striatum (Segal et al., 1972). Blaker et al.
(1983) reported that F344 rats performed better
than four other strains of rats in a shuttiebox
conditioned avoidance task. They also found
inter-strain differences in acetylcholine
concentration and turnover rate in several
regions of the brain; but the neurochemical
differences did not correlate with the
behavioral performance. Several studies compared
dopaminergic differences between F344 rats and
the Buffalo strain of rats. Apomorphine produced
more intense stereotypy in F344 than in Buffalo
rats. The former strain also have more dopamine
D2 receptors in the striatum and the olfactory
tubercle, and more a2-adrenoceptors in the
frontal cortex than the latter strain (Helmeste
et al., 1981). Kerr et al. (1988) also found a
higher dopamine D2 receptor density in the
forebrain of F344 than Buffalo rats, but a
similar number of dopamine D1 receptors. Based
on brain dopamine receptors and responses to
amphetamine, Helmeste and Seeman (1983)
suggested that the F344 rat may serve as a model
for childhood attention deficit disorder with
hyperactivity.
The response of F344 rats to acute and
chronic stress has been compared to other rat
strains. F344 rats are much more sensitive than
Sprague-Dawley rats to foot-shock stress by
several neurochemical and behavioral endpoints
(Rosecrans et al., 1986). The greater
responsiveness of the
hypothalamic-pituitary-adrenal axis in the F344
rats was thought to be responsible for their
greater resistance to experimentally induced
inflammation (Sternberg et al., 1992). To our
knowledge, the dopaminergic responses to acute
stress in F344 rats have not been specifically
compared to other strains.
In the course of a study on the
dopaminergic-induced yawning in rats, we noticed
that F344 rats emitted less yawning after a
variety of dopamine agonists. Since the yawning
response in rats is subject to dopaminergic and
cholinergic influences (Yamada and Furukawa,
1980; Urba-Holmgren et al., 1993), this study
investigated the pharmacological difference in
the yawning response to apomorphine for F344 and
Sprague-Dawley rats. Stereotypic chewing and
licking were scored for each animal
simultaneously.
4. Discussion
Apomorphine induced yawning in rats with a
inverted bell-shape dose-response relationship.
In the male Sprague-Dawley rats, apomorphine at
the optimal dose induced about 12 yawns during
the 30 min post-injection period. This is
similar to that reported by other investigators
using this strain of rats (Serra et al., 1987;
Urba-Holmgren et al., 1993). In male Wistar
rats, the best dose of apomorphine produced from
6 to 15 yawns (Yamada et al., 1989; Protais et
al., 1983). Male F344 rats, in contrast, respond
to apomorphine with about three yawns at the
optimal dose. We are therefore interested in the
biological differences involved with this
dopaminergic response.
In rats, dopamine receptor agonist-induced
yawning appears to be incompatible with
stereotypic movements, with the former being
suppressed when doses are sufficiently high to
induce sniffing (Protais et al., 1983). Helmeste
et al. (1981) reported that apomorphine produced
slightly more stereotypy in F344 rats than the
Buffalo strain of rat. In this study, we found
little difference in the potency of apomorphine
to induce stereotypy between F344 and
Sprague-Dawley rats. Selective D2-receptor
agonists, such as quinpirole (unpublished
observation), talipexole and SND 919 (Yamada et
al., 1990), induced yawning in rats with a
bell-shaped dose-response relationship similar
to apomorphine, although no stereotypy was
observed in high doses. It appears that factors
other than stereotypy account for the low
yawning response to apomorphine in F344
rats.
In the Sprague-Dawley rats,
apomorphine-induced yawning was enhanced by
blockade of dopamine D1 receptors by SCH 23390.
Our result is similar to that reported by
Zarrindast and Poursoltan (1989), but opposite
to that of Serra et al. (1987), who also used
Sprague-Dawley rats in their study. It is
noteworthy that blockade of stereotypy by SCH
23390 increased yawning scores without shifting
the optimal dose to the left. The potentiation
is, therefore, different from receptor
supersensitivity which produces a leftward shift
of the dose-response relationship. If D1
receptor activation has a dampening effect on
yawning, at least in our experiments with
Sprague-Dawley rats, the lower yawning response
to apomorphine in F344 rats could be due to a
higher baseline activation. This did not seem to
be the case as pretreatment with SCH 23390 did
not release additional yawning in F344 rats as
it did in Sprague-Dawley rats. However, the
effective doses to elicit yawning in F344 rats
extended to a higher level as stereotypy was
antagonized by SCH 23390.
Yamada et al. (1989) reported that
apomorphine-induced yawning in Wistar rats was
potentiated by centrally active /3-adrenoceptor
blockers and inhibited by /3-adrenoceptor
agonists. We have confirmed the above finding in
Sprague-Dawley rats that pindolol potentiated
apomorphine-induced yawning with no effect on
stereotypy. The same treatment with pindolol,
however, did not potentiate apomorphine-induced
yawning in F344 rats. The low yawning response
in F344 rats is probably not due to a high tonic
activity of central adrenergic mechanism.
A central muscarinic mechanism of yawning in
rats
has been proposed by Urba-Holmgren et al.
(1977) in that physostigmine and pilocarpine
induced yawning which was antagonized by
scopolamine. Scopolamine also completely
antagonized apomorphine-induced yawning (Yamada
and Furukawa, 1980). We found that physostigmine
potentiated yawning induced by apomorphine in
F344 rats to a degree not seen with pretreatment
with SCH 23390 or pindolol. Physostigmine
induced some spontaneous yawning in
SpragueDawley rats, with only a slight additive
effect on apomorphine. The results are
consistent with the existence of a cholinergic
link in the dopamine agonist-induced yawning
response for both strains of rats. A lower
cholinergic tone in F344 rats may account for
its normally lower yawning score produced by
apomorphine. The potentiation of yawning after
reserpine in F344 rats can also be interpreted
in terms of increased cholinergic activities
when central catecholamines are depleted. The
potentiation of yawning after reserpine also did
not change the optimal dose of apomorphine. A
difference in cholinergic tone alone, however,
cannot account for the low yawning response in
F344 rats since a combined treatment of
physostigmine, SCH 23390 and apomorphine in the
F344 rats still did not elicit the maximal
yawning as elicited in Sprague-Dawley rats after
D1-receptor blockade. Apomorphine-induced
yawning can be powerfully influenced by sex and
pituitary hormones (Berendsen and Nickolson,
1981; Serra et al., 1983). A difference in
endocrine functions should be investigated.
/
In summary, the weaker yawning response to
apomorphine in F344 rats appeared unrelated to a
greater propensity for stereotypy. Increasing
cholinergic tone can potentiate the apomorphine
effect in F344 rats, but does not account for
all the differences.
