The mode
of action of bromocriptine following
pretreatment with reserpine and
alpha-methyl-p-tyrosine in rats
Ushijima I, Mizuki Y, Yamada M.
Department of
Neuropsychiatry, Yamaguchi University, School of
Medicine
Ube, Japan.
Abstract
The ability of bromocriptine (BRC), a
selective dopamine D-2 receptor agonist, to
induce yawning responses was studied in rats
pretreated with reserpine and
alpha-methyl-p-tyrosine (alpha-MPT). BRC (1 20
mg/kg IP) evoked yawning responses, which were
pronounced at 2.5 mg/kg and characterized by the
head moving downward. Higher doses of BRC (5 20
mg/kg) dose-dependently delayed the onset and
peak time of yawning.
A low dose of the selective D-1 dopamine
receptor agonist SK&F38393 did not induce
yawning but enhanced the BRC-induced response.
Pretreatment with reserpine (1 and 5 mg/kg SC),
alpha-MPT (100 and 300 mg/kg IP) and reserpine
(1 mg/kg) plus alpha-MPT (100 mg/kg) was able to
significantly reduce BRC-induced yawning. The
inhibitory effects were prevented by a low dose
of SK&F38393 (0.5 mg/kg IP). In particular,
combined treatment with reserpine (5 mg/kg) and
BRC (10 and 20 mg/kg) elicited upright fighting
and jumping behaviors which were inhibited by
haloperidol (1 mg/kg IP), a non-selective D-1
and D-2 receptor antagonist, SCH23390 (0.05
mg/kg SC). a selective D-1 receptor antagonist,
or sulpiride (20 mg/kg IP), a potent D-2
receptor antagonist, and were potentiated by
SK&F38393 (0.5 mg/kg).
SCH23390 (0.05 mg/kg) decreased BRC-induced
yawning and the apomorphine (low doses)-induced
potentiation of BRC yawning, and prevented the
apomorphine (high doses)-induced reduction of
BRC yawning. SCH23390 also inhibited
apomorphine-induced stereotypy and BRC-induced
potentiation of apomorphine stereotypy. .
Furthermore, haloperidol (0.02 and 1.0 mg/kg
IP), sulpiride (20 mg/kg IP) or scopolamine (0.5
mg/kg IP) inhibited BRC-induced yawning, but
prazosin (1.0 and 3.0 mg/kg IP), an Œ-1
receptor antagonist, did not affect this
behavior
These results suggest that BRC-induced
yawning may be mediated via presynaptic
dopaminergic neuron activity and that BRC, in
addition to the stimulation of dopamine 4J-2
receptors, appears to require endogenous
dopamine or receptor activation by another
dopamine agonist (D-1 agonist) for the induction
of yawning, stereotypy and upright lighting
responses. The ability of dopamine agonists to
induce these behaviors seems to depend apon the
potency and ratio of D-2 versus D-1 receptor
activity.
Bromocriptine (BRC) has been used to treat
patients with Parkinson's disease (Lieberman et
al. 1976) and hyperprolactinemic amenorrhoea
(Bergh et al. 1978). BRC evokes head twitches in
cats (Gonzalez-Lima et al. 1984), as well as
repeated episodes of penile erection and yawning
(Protais et al. 1983). Biochemical studies have
demonstrated that BRC has both agonist and
antagonist properties at preand postsynaptic
dopaminergic neurons, and that it decreases
synaptosomal tyrosine hydroxylase activity
(Goldstein et al. 1978; Spano and Trabucchi
1978). Furthermore, BRC acts like a dopamine D-2
agonist and inhibits dopamine-stimulated
synthesis of cyclic adenosine
3',S'-monophosphate (cyclic AMP) (Trabucchi et
al. 1978).
The dopamine agonist apomorphine exerts a
biphasic action, in that low doses result in an
activation of dopamine autoreceptors, thereby
producing an inhibition of dopamine release and
decreased dopamine synthesis (Carlsson 1975;
Trabucchi et al. 1975). Decreased tonic
dopaminergic transmission consequently induces
yawning (Yamada and Furukawa 1980, 1981). On the
other hand, high doses of apomorphine appear to
act by stimulating postsynaptic dopamine
receptors, producing stereotypy and
hyperlocomotion, and suppressing yawning (Groves
et al. 1975; Yamada and Furukawa 1980,
1981).
A presynaptic dopamine autoreceptor
belonging to the D-2 type seems to be
responsible for the sedative response to low
doses of apomorphine (Gessa et a!. 1985).
(-)-Sulpiride, which has been hypothesized to
have higher affinity for the presynaptic than
the postsynaptic D-2 receptor (Robertson and
MacDonald 1985), could antagonize apomorphine
sedation by preferential blockade of dopamine
autoreceptors. BRC cannot be considered a
directly acting agonist like apomorphine, since
reserpine and -MPT inhibit or completely abolish
most of the behavioral effects induced by BRC
(Johnson et al. 1976).
Jenkins and Jackson (1985) reported that
BRC, in behavioral terms, has no effect per se
at the postsynaptic dopamine receptor and that
BRC requires either endogenous dopamine or the
administration of an exogenous agonist such as
apomorphine for the expression of its effects.
Recently, it was shown that SCH23390, a
selective D-l receptor blocker (Hyttel 1983),
prevents apomorphine-induced yawning in normal
and reserpinized rats, suggesting that dopamine
receptors mediating yawning may not only be
classified as D-2 receptors, but also as D-1
receptors (Morelli et al. 1986). The present
studies were designed to clarify the neuronal
mechanisms involved in BRC-induced yawning, and
ro understand the influences of dopamine D2
receptor sensitvity and tyrosine hydroxylase
activity.
Discussion
It has been reported that yawning occurred
in rats after administration of relatively small
doses of various dopamine agonists which are
known to stimulate dopamine receptors either
directly (apomorphine) or indirectly
(amphetamine, nomifensine) (Mogilnicka and
Klimek 1977; Yamada and Furukawa 1980). Since
low and high doses of haloperidol, sulpiride (a
selective dopamine D-2 antagonist) and
scopolamine inhibit BRC-induced yawning, a
dopaminergic-cholinergic link is thought to be
involved in BRCinduced yawning. As was the case
with apomorphine-induced yawning, BRC-induced
yawning may also be mediated by cholinergic
activation secondary to the inhibition of
dopamine transmission. Furthermore, BRC-induced
yawning is characterized by the head moving
downward, which is similar to the effects
produced by apomorphine (Ushijima et al. 1985).
The neuronal mechanism involved in BRC yawning
seems to be similar to that of low doses of
apomorphine.
In this study, the ability of reserpine and
-MPT to potentiate yawning at high doses of BRC
is a reflection of an overall shift to the right
of the inverted U doseresponse curve for
BRC-induced yawning which, in turn, might be due
to receptor blockade produced by the dopamine
depletion. Reserpine plus -MPT completely
inhibited BRC-induced yawning. The prevention of
BRC-induced yawning by reserpine, as well as by
-MPT, suggests that intact neurotransmitter
function (dopamine, noradrenaline) is necessary
for the action of BRC to appear. Noradrenergic
stimulation, however, has to be excluded because
a noradrenergic antagonist, prazosin, did not
abolish BRC-induced yawning.
A low dose of SK&F38393 (0.5 mg/kg), a
dopamine D-1 agonist, prevented the inhibition
of BRCinduced yawning by reserpine, -MPT or
reserpine plus -MPT.- On the other hand, the
yawning and stereotyped behaviors induced by
apomorphine, a dopamine receptor (both D-1 and
D-2 receptors) agonist are markedly potentiated
by pretreatment with reserpine, -MPT or
reserpine plus cc-MPT (Morelli et al. 1986;
Ushijima et al. 1987; Kishimoto et al.
unpublished observation). The mode of action of
BRC is different from that of apomorphine. BRC,
but not apomorphine, appears to require
endogenous dopamine or receptor activation, by
another dopamine agonist (D-1 agonist) for the
induction of yawning.
While SK&F38393 or BRC alone does not
induce stereotyped behavior, combined treatment
with BRC (2.5-20 mg/kg) and high doses of
SK&F38393 (5 and 10 mg/kg) is followed by
stereotyped behaviors such as sniffing, licking
and biting in a dose-dependent manner (Ushijima
et al. 1988). Most recently, Arnt et al. (1987)
has reported that D-1 receptors are functionally
relevant, since SK&F38393 facilitates the
expression of oral stereotyped behavior (licking
and biting) after combination with quinpirole, a
D-2 agonist. Furthermore, it appears that D-1
receptors also contribute to the yawning
response, since this action of BRC alone is
partially offset by SCH23390.
Indeed, it appears that in most cases,
SCH23390 can reduce the apomorphine (low
doses)induced potentiation of BRC yawning and
BRC-induced potentiation of apomorphine
stereotypy. Conversely, SCH23390 can prevent the
apomorphine (high doses) induced reduction of
BRC yawning. These results suggest that dopamine
receptors mediating stereotypy as well as
yawning may include not only D-1 but probably
also D-2 receptors. It is probable that yawning
is produced by relatively weaker stimulation of
D-l and D-2 receptors, whereas stereotypy is due
to stronger stimulation of these receptors. The
ability of dopamine agonists to induce yawning
and stereotypy seems to be based on the ratio
and potency of D-2 versus D-1 receptor
stimulation.
When high doses of BRC (10 and 20 mg/kg)
were administered after a high dose of reserpine
(5 mg/kg), paroxysmal, violent upright lighting
and sudden jumping behavior appeared in addition
to typical behavioral symptoms such as
stereotypy and hyperlocomotion. The episodic
behaviors were inhibited by dopamine receptor
antagonists (either D-1, D-2 or non-specific
dopamine receptor antagonist), suggesting that
dopaminergic activation (both D-1 and D-2
receptor activation) was involved in the
behaviors. It is likely that newly synthetized
dopamine, released in the synaptic cleft, may be
sufficient to induce these symptoms
approximately 24 h after reserpine treatment,
partly because supersensitivity has probably
developed at postsynaptic dopamine receptors.
L-Dopa in combination with Ro4-4602, a
peripheral decarboxylase inhibitor and reserpine
has been reported to induce the bizarre
behaviors, which are reminiscent of certain
psychotic states seen in man, for which
neuroleptic, but not antianxiety drugs are the
drugs of choice (Benkert et al. 1973; Lammers
and Van Rossum 1968).
These results suggest that the mode of
action of BRC in producing yawning, stereotypy
and upright fighting responses requires both
ongoing dopamine synthesis and/or release in
addition its own (presumably D-2) receptor
stimulation, and seems to result in the potency
and ratio of D-2 versus D-1 receptor
activity.
-Ushijima I,
Mizuki Y, Yamada M Multifocal sites of
action involved in dopaminergic-cholinergic
neuronal interactions in yawning
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