Role of
adrenergic neuronal activity in the yawning
induced by tacrine and NIK-247 in
rats
Kimura H, Yamada K, Nagashima M, Matsumoto
S, Ishii Y, Yoshida S, Fujii K, Furukawa T
Department of phamacology, Fukuoka
University, Japan
Behavioral studies have shown that
physostigmine, an anticholinesterase
agent, and pilocarpine, a muscarinic
receptor agonist, induce yawning behavior
that is abolished by scopolamine, a muscarinic
receptor antagonist. The yawning induced by
dopamine receptor agonists such as apomorphine
and talipexole (B-HT 920) is also compIetely
inhibited by scopolamine. On the basis of these
results, it bas been proposed that
cholinergic neuronal
activity is indispensably involved in eliciting
yawning behavior.
9-Amino-1,2,3,4-tetrahydroacridine
(tacrine (THA)) is proposed to be a
potent, centrally acting cholinesterase
inhibitor.
9-Amino-2,3,5,6,7,8-hexahydro-IH-cyclopenta(b)-quinoline
monohydrate HCI (NIK-247) has also been reported
to exert inhibitory effects on cholinesterase.
These cholinesterase inhibitors are found to
improve cognitive functions at different phases
of the learning and memory processes in animals
and have been clinically developed as potential
cognitive improvers. However, there is little
documentation on yawning and acetylcholine
content in animals treated with tacrine or
NIK-247.
The potential functional role of
adrenaline-containing neuronal systems was
suggested in some of the earliest research on
brain catecholamines. The earlier hypothesis
that adrenaline is a neurotransmitter candidate
in the brain were validated by detailed studies
of the distribution of brain neurons containing
phenylethanolamine N-methyltransferase (PNMT)
and their close correlation with the regional
distribution of enzymatic activity and
adrenaline content. As inhibitors of PNMT were
reported to decrease adrenaline formation
without affecting dopamine and noradrenaline
levels, several lines of investigation with the
inhibitors subsequently suggested that brain
adrenaline may be involved in cerebral
cardiovascular, neuroendocrine, and behavioral
regulation. Recently, we reported that
administration of various beta-adrenoceptor
antagonists such as pindolol, propranolol,
and indenolol increased the yawning responses
induced by treatment with apomorphine,
talipexole, physostigmine, or pilocarpine,
suggesting that alpha adrenoceptor blockade
facilitates the occurrence of yawning; induced
by dopaminergic and cholinergic agonists. Thus,
central beta-adrenoceptors relating to
central adrenergic neuronal systems might be
involved in the regulation of yawning
responses.
The present experiments were therefore
performed to investigate whether or not tacrine
and NIK-247 elicit yawning that may possibly be
regulated by central adrenergic neurons via
beta-adrenoceptor activities in rats.
[...]
Discussion : Previous experiments
have shown that physostigmine and pilocarpine
elicit yawning and this behavior is blocked by
muscarnic but not dopamine receptor antagonists.
On the other hand, the yawning induced by
dopamine D2 receptor agonists is antagonized by
both dopamine and muscarinic receptor
antagonists, implying that dopamine receptor
agonist-induced yawning can result from a
consequent activation of cholinergic neurons.
From such findings, it has been proposed that
a dopaminergic-cholinergic-linked neuronal
system may participate in inducing yawning.
In the present experiment, treatment with
tacrine or NIK247 evoked a yawning response to a
small extent. This yawning response was markedly
increased by a beta-adrenoceptor antagonist,
pindolol, which did not evoke yawning; when
given alone. Moreover, the yawning elicited by
tacrine or NIK-247 given alone or in combination
with pindolol was inhibited by scopolamine, a
muscarinic receptor antagonist, but not by
mecamylamine, a nicotinic receptor antagonist,
and spiperone, a dopamine receptor antagonist.
The present results suggest that tacrine and
NIK-247 were able to elicit yawning via
muscarinic receptor activation, as our
previous experiments with physostigmine-induced
yawning. On the other hand, the dopamine D2
receptor agonist, talipexole, also elicited
yawning, which was increased by pindolol, as
previously reported. Accordingly, the
stimulation of muscarinic receptors is
obligatory for the induction of yawning and
central beta-adrenoceptor activity may regulate
the occurrence of yawning induced by
anticholinesterase agents and dopamine D2
receptor agonists.
A previous experiment showed that the
dopamine D1/ D2 receptor agonist, apomorphine,
induced yawning that was enhanced by pindolol,
propranolol, indenolol, and alprenolol, which
block central beta-adrenoceptors, but not by the
peripheral beta-adrenoceptor antagonists,
carteolol and atenolol, suggesting that yawning
is enhanced by central beta-adrenoceptor
blockade but not by peripheral blockade.
Pindolol is also known to have serotonin (5-HT)
receptor blocking actions in addition to
beta-adrenoceptor antagonistic properties.
However, the yawning induced by talipexole was
increased by pretreatment with pindolol but was
unaffected by either metergoline, a potent
antagonist of 5-HT, and 5-HT2 receptors, or
ketanserin, a specific antagonist of 5-HT2
recepters. Moreover, we found that various
beta-adrenoceptor antagonists, which have no
5-HT receptor antagonistic properties, also
increased the yawning induced by dopamine
receptor agonists. Accordingly, the 5-HT
receptor antagonistic property of pindolol may
not be related te the observed enhancement of
yawning responses by the drug.
Dopamine receptor agonists, locally applied
into the striatum, elicited yawning behavior,
and those administered systemically were
ineffective in evoking yawning after bilateral
lesions of the striatum. by 6-hydroxydoparnine.
Therefore, the striatum, is proposed te be
one of the important sites in the rat brain
areas involved in evoking yawning behavior.
In contrast with these reports, microinjection
of dopamine receptor agonists into the
paraventricular nucleus (PVN) of the
hypothalamus induced yawning behavior in
rats and electrolytic lesion of the hypothalamic
PVN prevented the drug induced yawning
responses, suggesting that the PVN is also the
brain area where dopamine receptor agonists act
for inducing yawning. However, a role of
cholinergic neuron activity in the PVN for
evoking yawning is still unknown. On the other
hand, high beta-adrenoceptor density was found
in the rat striatum . AccordingIy, in this
experiment acetylcholine content of the striatum
was measured after treatment with cholinesterase
inhibitors. The systemic administration of
tacrine or NIK-247 increased acetylcholine
content of the striatum, and this was
accompanied by a modest yawning response. These
results seem to be compatible with recent
findings that intraperitoneal injection of
tacrine increased acetylcholine content in
the striatum, cortex, and hippocampus in
rats. However, although pindolol increased the
yawning responses induced by tacrine or NIK-247
and the beta-adrenoceptor antagonist did not
alter basal acetylcholine content and failed to
enhance the increase of acetylcholine content in
the striatum induced by the two cholinesterase
inhibitors. Our previous experiments have also
shown that pretreatment with pindolol or
propranolol increased the yawning responses
induced by the direct muscarinic receptor
agonist, pilocarpine, suggesting that
beta-adrenoceptor antagonists may not affect the
synthesis and/or release of acetylcholine in the
brain areas involved in eliciting yawning
behavior. Furthermore, various beta-adrenoceptor
antagonists, including pindolol, did not change
the activity of acetylcholinesterase in the
brain. Taken together, it may be assumed that
central beta-adrenoceptors do not regulate the
activities of striatal cholinergic neurons.
According to expectation, in the present
experiment, the tacrine-induced yawning
responses were increased notably by LY-78335 and
UK- 1 187A. These drugs are reported to block
adrenaline synthesis without change of dopamine
and noradrenaline levels in the brain via the
inhibition of noradrenaline N-methyltransferase.
However, the dose-response curve of yawning to
PNMT inhibitors in combination with tacrine was
bell shaped. Similarly, the combined treatment
with pindolol and tacrine was shown te have
bell-shaped responses of yawning. Although the
real reason for showing a bell-shaped
dose-response curve is obscure at present, it is
a possibility that a high dose of PNMT
inhibitors or the beta-adrenoceptor antagonist
with the anticholinesterase agent produces
changes of the other neuronal activities that
inhibit the occurrence of yawning. Furthermore,
pretreatment with LY78335 or UK-1187A
facilitated talipexole-induced yawning.
Therefore, PNMT inhibitors as well as
0-adrenoceptor blockers seem to enhance yawning
responses via the inhibition of central
adrenergic neuronal activity.
The results suggest that the
beta-adrenoceptor blockade and inhibition of
central adrenaline synthesis facilitate the
occurrence of yawning induced by tacrine,
NIK-247, or talipexole and that the central
adrenergic neuronal systems may participate in
the regulation of yawning evoked by cholinergic
and dopaminergic agonists. However, further work
is warranted to clarify a neuronal circuit
between a dopaminergic-cholinergic-linked
neuronal system and an adrenergic neuronal
system involved in yawning behavior.
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