Departamento Preclinicas,
Facultad de Medicina, Universidad de Chile,
Santiago
Abstract
The effects of the pretreatment with LHRH on
the behavioral effects induced by low doses of
apomorphine were studied in male rats. Three
doses of apomorphine (31.25, 62.50 and 125
µg/kg) were subcutaneously administered two
hours after LHRH 100 µg/kg or solvent SC
treatment. Apomorphine induced repeated episodes
of yawning and genital grooming. Pretreatment
with LHRH abolished or reduced yawning
and genital grooming induced by the three doses
of apomorphine, suggesting that the peptide
could induce subsensitivity of DA receptors
responsible for yawning and genital
grooming.
Recent reports have postulated that LHRH is
capable of modulating dopamine (DA) transmission
in experimental animals. In fact, behavioral and
biochemical findings support the hypothesis of
an inhibitory effect of LHRH upon presynaptic
synthesis and release of DA. Incubation of rat
corpus striatum synaptosomes in the presence of
LHRH decreased DA synthesis. Subcutaneous and
intracerebral injection of LHRH in rats
inhibited a conditioned avoidance response,
which is considered as a characteristic of drugs
which block DA transmission. In addition, LHRH
is able to antagonize the stimulatory effect
induced by amphetamine on motor activity and
acquisition of conditioned avoidance responses.
L-DOPA, precursor of DA, reverted the inhibitory
effects of LHRH and counteracted the
antagonistic effect of LHRH on the action of
amphetamine.
The administration of small doses of
apomorphine produces a behavioral syndrome
characterized by hypomotility, yawning,
penile erection and genital grooming. These
effects are considered to be the consequence of
the stimulation of presynaptic DA receptors in
the CNS. The purpose of the present study was to
provide further evidence for a possible
interaction between LHRH and DA mechanisms. We
studied the influence of LHRH on the behavioral
effects induced by low doses of apomorphine. The
results indicate that pretreatment with LHRH
antagonized yawning and genital grooming
induced by apomorphine in rats.
Discussion
The present findings indicate that
exogenously administered LHRH antagonizes the
behavioral effects of low doses of apomorphine,
namely yawning and genital grooming.
These effects, which include hypomotility, are
considered to be due to an activation of DA
receptors in the CNS. There is evidence
suggesting that DA receptors mediating
yawning might be identified with
presynaptic DA autoreceptors. However, recent
reports postulate that DA receptors mediating
yawning are a special population of
postsynaptic DA receptors of the D2 type with a
high affinity for DA and apomorphine. Although
apomorphine is a mixed D1-D2 agonist its potency
for Dl receptors is only in the micromolar
range. Then the small doses of apomorphine that
were used in this study are likely to stimulate
selectively D2 receptors.
Yawning has been proposed to be a
reliable behavioral sign of DA agonistic action
of drugs. Furthermore, it has been suggested
that yawning could be useful in the
screening of drugs. 1f in a screening
observation a given substance induces
yawning in rats, which is blocked by DA
antagonists, there is a high probability that
the compound possesses DA receptor agonistic
properties. Consequently, if a given drug
abolishes apomorphine-induced yawning it
could be classified as a DA antagonist. In fact,
neuroleptics reduce yawning induced by
apomorphine and other putative DA receptor
agonists but do not abolish the yawning
induced by cholinergic drugs.
Yawning behavior and genital grooming
are also induced by protein hormones from the
pituitary, such as ACTH, alpha-MSH and oxytocin.
They have been postulated as mediators in the
behavioral effects of low doses of apomorphine.
Recently it has been reported that low doses of
prolactin injected systemically induce
yawning in male rats, maybe through the
release of small amounts of DA from the
striatum. On the other hand, hypophysectomy
inhibits yawning, penile erection and
genital grooming but not the hypomotility
induced by small doses of apomorphine,
suggesting that the lack of some pituitary
hormones alters the sensitivity of DA receptors
responsible for these effects, but not those
responsible for the reduction of motor activity.
Gonadal steroids seem to exert opposite effects
on apomorphine-induced yawning in male
rats. Whereas testosterone facilitates both
yawning and penile erection, castration
and exogenously administered estrogens
antagonize them. Besides, apomorphine is less
effective in inducing yawning in female
than in male rats. According to Serra et al.,
subsensitivity of DA receptors may explain the
reduction of this behavioral response observed
in males following estrogen treatment or in
normal female animals.
The present results show that the
hypothalamic hormone LHRH, as well as
hypophysectomy and castration, prevents
yawning and genital grooming induced by
apomorphine. We can speculate that LHRH is also
able to influence the effect of apomorphine by
inducing subsensitivity of DA receptors which
mediate these behaviors. The possibility that
LHRH modulates DA activity was suggested in
recent reports. The peptide antagonizes the
motor hyperactivity, rearing behavior and the
increase in the conditioned responses induced by
amphetamine and this antagonism is reverted by
L-DOPA, the precursor of DA synthesis. Besides,
there is biochemical evidence of an inhibitory
effect of LHRI-I upon DA synthesis. Thus, the
decrease in DA transmission should exert
inhibitory effects on apomorphine-induced
yawning. In fact, acute depletion of
brain DA by short-term reserpine or
alpha-methyltyrosine pretreatment reduces the
ability of D2 agonists to induce yawning.
Longoni et al. have postulated that D2 receptors
mediating yawning appear to be
functionally linked to Dl receptors in such a
way that endogenous DA by stimulating Dl
receptors plays a permissive role for the
expression of yawning induced by
postsynaptic D2 agonists.
Finally, the observation that LHRH does not
appear to block the hypomotility produced by low
doses of apomorphine (16) suggests that
hypomotility and yawning could be
mediated through the activation of different
kinds of high affinity D2 receptors, which are
probably located pre- and post synaptically,
respectively.
