Department of Neurobiology,
Clinical Research Institute of Montreal, 110
Pine Avenue West, Montreal 130, Quebec,
Canada.
Summary
Administration of zinc into the left lateral
ventricle of rats elicited yawning-stretching
behavior. Yawning and stretching was not
observed after injection of the metal ions
manganese, copper and cadmium. Intraventricular
injection of l-24-ACTH, synthetic n and B-LPH
also evoked yawning and stretching after a
latent period of 40-60 minutes. The
administration of L-glutamate and D, L-glycine
was ineffective in producing yawning-stretching
behavior.
Introduction
The observation that yawning and stretching
crises of muscular hypertonus (which can be
considered as an effect of the body to delay the
onset of sleep or to reinforce wakefulness after
sleep) are elicited by administration of
adreno-corticotrophic hormone (ACTH) and
melanocyte-stimulating hormone (MSH) into the
cerebrospinal fluid of mammals was first
reported by Ferrari (1). Further studies from
the same laboratory (2) revealed that this
peculiar behavior was induced only through the
administration of the component heptapeptide:
methionine-glutamate-histidine-phenylalanine-arginine-tryptophan-glycirte
(MetGlu-Hls-Phe-Arg-Try-Gly) common to both ACTH
and MSH. The site of action of ACTH and/or MSH
for these effects was thought to be in the
hypothalamus and probably involved its
connections with the descending and ascending
reticular formation of the brain stem, usually
considered responsible for yawning and
stretching (2, 3). Yawning and stretching
induced by ACTH was suppressed by
chlorpromazine, atropine and diethazine, drugs
known to act within the reticular formation
(2).
During a previous study (4) concerned with
the ability of certain metal ions to produce
clonic-tonic seizures in rats it was observed
that low doses of zinc, following injection into
the left lateral ventricle, evoked a peculiar
yawning-stretching syndrome in the treated
animals. The present communication reports the
results of experiments designed to elaborate
further the role of zinc and other metal ions in
the induction of the yawning-stretching
phenomenon. In addition, the role of certain
polypeptides in the initiation of this type of
behavior was further expanded and
confirmed.
Discussion
The mechanism of action of zinc in the
production of a yawning and stretching syndrome
is not resolved by the present experiments. It
would appear, however, that the behavioral
response elicited by zinc is specific for this
ion since copper and cadmium ions, both of which
have similar physical and chemical properties to
zinc (5), did not produce yawning and stretching
in rats so treated. Manganese ions were
similarly ineffective. Coupling of zinc with a
particular amino acid may be a possibility (6),
since both the content of ACTH and zinc have
been found to increase in the serum under stress
conditions (7). It is possible the "active"
component of the metal-hormone coupling could be
the zinc molecule. However amounts of zinc in
MSH and B-LPH sufficient to cause the special
behavior could not be detected, although large
amounts of zinc in 24-ACTH were found.
Additionally, the administration of L-glutamate
and D,L-glycine, amino acids also known to bind
zinc (8), did not cause yawning or
stretching.
Another possibility to consider is that zinc
is involved in the release of these peptides and
that the special patterns of behavior were
elicited as a result of the induced secretion of
such hormone (s). This possibility can probably
be ruled out since excessive grooming, yawning
and stretching from zinc were similar in mode,
but different in latency of onset and intensity
from those induced by the peptides. Indeed, as
previously stated, the latency of the induced
patterns was much shorter with zinc and the
intensity greater with the hormones.
An alternate possibility could be that zinc
is involved in the mechanism of hormone-receptor
interaction. Certain amino acids or peptides
have a greater affinity for specific trace
metals (6). On the other hand, it is known that
the affinity of various trace metals for
specific brain regions is not uniform and does
not necessarily correspond with the regional
concentration of a specific trace element
(Donaldson et al., unpublished observation). For
example, although the concentration of zinc is
highest in the hippocampus and hypothalamus, the
region with the highest affinity for exogenously
administered zinc is the medulla oblongata (9).
It is possible that a "functional" coupling
between certain hormones and a trace metal
exists and that the trace metal (here zinc)
could serve to orient the hormonal structure
towards specific, high affinity, regional
receptor sites in the brain.
The results of our studies with a-NS}! and
8124-ACTH are in agreement with those of Ferrari
and collaborators (1, 2). Because zinc has been
known to increase and prolong the action of ACTH
(10, 11, 12) and in view of our own results with
intraventricular injections of zinc, the zinc
content in these peptides was estimated and
found to be negligible with the exception of
8124-ACTH which contained elevated amounts of
the ion. Therefore, 8124-ACTH action in
provoking yawning and stretching may not relate
to its peptide structure but to its inherent
zinc content. However, the fact that
administration of 824-ACTH also caused this
peculiar behavior with the same intensity and
latency to that of MSH (a- and 8-), does
indicate that the mechanism involved may be
related to a structure common to all the
peptides. Such a structure as postulated by
Ferrari et al. (2) appears to be the amino acid
sequence: Met-Glu-His-Phe-Arg-Try-Gly. Our
studies thus repeat those of Ferrari et al. (2),
and add further confirmation through the results
obtained with 8-LPH (2,500 jig.), a fact
previously unreported.
B-LPH has to be given in higher quantity for
the same amount of the heptapeptide to have any
potential effect, because of the differences in
molecular weight between 8-MSH and 8-LPH. It is
indeed probable that physiologically 8-LPH
serves as a precursor to 8-MSH (13). It is
noteworthy that the action of the polypeptides
is of marked intensity, but of long latency; on
the other hand that of zinc is of short latency,
but of moderate intensity, therefore further
studies on the exact mode of action will have to
carried out.
