with
reserpine and alpha-methyl-p-tyrosine in
rats
Ushijima I, Mizuki Y, Yamada M.
Department of
Neuropsychiatry, Yamaguchi University, Ube,
Japan
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 IF) 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 D-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 fighting
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.
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) (Mogiinicka 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
oc-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, oc-MPT or
reserpine plus x-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, x-MPT or
reserpine plus -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 (Sand 10mg/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)-in-
duced 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-1
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 fighting
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.
