Increase
of hippocampal acetylcholine turnover rate and
the stretching-yawning syndrome elicited by
alpha-MSH and ACTH
PL. Wood, D Malthe-Sorenssen, DL. Cheney, E.
Costa
National Institute of mental
Health, Whashington
ACTH and alpha-MSH are pituitary hormones,
whose secretion is regulated by hypothalarnic
releasing factors. In addition to their
localization. in pituitary, high concentrations
of ACTH and alpha-MSH have been detected in the
circumventricular organs and diencephalon.
More moderate concentrations have been found
in the limbic system. Since the ACTH and
alpha-MSH content of these brain areas usually
is unaffected by hypophysectomy, it has been
suggested that both peptides are synthesized in
brain areas where they rmy function as
neuromodulators.
In support of a neuramodulatory role are
experients showing that when these peptides are
given intraventricularly or parenterally they
also elicit pronounced behavioral, effects.
Parenteral. administration of alpha-MSH, ACTH-24
and protected ACTH4-9 (met (02) 4, D-Lys8, Phe9
ACTH4-9) prevents the extinction of conditioned
avoidance responses in rodents. In rats,
intraventricular (i.v.t.) or intracisternal
injections elicit a behavioral repertoire
consisting of grooming behavior followed by
the stretching and yawning syndrame
(SYS).
Since the SYS is antagonized by
anticholinergic drugs, we decided to study
whether in the rat the ACh turnover rate (TRAch)
of various brain areas is changed during the SYS
elicited by alpha-MSH and ACTHl-24. We found
that alpha-MSH and ACTHl-24, but not the
protected ACTH4-9 increase the hippocanipal
TRACh. The time course and dose dependency of
this biochemical response and of the SYS appear
to coincide.[...]
DISCUSSION
Various experimentai approaches have been
utilized to define the sites of action of
alpha-MSH and ACTH in causing the SYS. Although
the molecular mechanisms which participate in
the SYS have never been elucidated it appears
that the brain cholinergic neurons are operative
because anticholinergic agents block the
SYS.
Additional actions elicited by these
polypeptides have been considered as possible
factors to explain the changes in TRACh of
hippocampus. For example, peripherally
administered alpha-MSH decreases blood flow in
several neocortical areas, and it increases the
cAMP content and the serotonin turnover rate of
occipital cortex. However, it is hard to relate
a selective change in hippocampal TRACh as due
to a change in blood flow. While lesion
experiments have established that the dorsal
hippocampus and the parafascicular nuclei of the
thalamus are essential for the inhibition of the
extinction of conditioned avoidance responses
elicited by these polypeptides given
parenterally, the ventral hippocampus appears to
be implicated in the expression of grooming and
of the SYS elicited by ACTHl-24 given i.v.t..
Thus, this report suggests that an intact limbic
system is required for the expression of the SYS
elicited by the tow polypeptides.
Our data not only support such an inference
but also indicate that the cholinergic system of
the hippocampus participates in the SYS induced
by alphaMSH and ACTH. However, our results fail
to explain whether the polypeptides trigger the
SYS response because they act on specific
receptors located on the septal-hippocampal
cholinergic neurons or they act on other sites
to trigger the SYS which in turn elicit the
increase in the TRACh of the hippocampus.
ACTH4-9, a fragment of ACTH1-24 which is
extremely active in the conditioned avoidance
test of DeWied but which fails to elicit
grooming or the SYS, also fails to increase
hippocampal TRAch. Thus, this fragment not only
has a-MSH activity which is 1/1000 that of
alpha-MSH, but it fails to mimic other
biological activities of alpha-MSH. Although
ACTH4-9 is taken up by the septum after i.v.t.
injection, it fails to increase the hippocampal
TRAch suggesting that a specific reoeptor that
responds; to ACTH-24 but not to ACTH4-9 may
participate in the regulation of hippocampal
TRACh. One might infer that this receptor may
not be identical to that which is operative in
eliciting the behaviorai actions reported by
DeWied for ACTH4-9.
The site where alpha-MSH and ACTH act to
increase hippocampal TRACh remains to be
established. Electrophysiological studies have
shown that both ACTHl-24 and ACTH4-9 deamase the
frequency of the theta rhythm (4-8 Hz) in the
hippocampal EEG. Sinœ we have found that
ACTH4-9 fails to change the TRAch of hippocanpus
we infer that the ACTH4-9 reduces the frequency
of the theta rhythm by a mechanism other than
that which is operative to increase hippocampal
TRAch.
In summary, our data suggest, that the
pituitary peptides alpha-MSH and ACTHl-24 in
doses that cause the SYS accelerate the TRAch of
hippocampus selectively. The dose and time
relationship of the two responses are in good
agreement. Although the present experiments
indicate an interaction between alphaMSH and
ACTH with the synaptic input that regulates the
septal-hippocampal cholinergic neurons, they
fail to document wihether this interaction
reflects a trans-synaptic regulation.
