mise à jour du 7 août 2003
Life Sciences
1978; 22; 673-378
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.[...]
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.