Effects of YM-14673, a new thyrotropin-releasing hormone analogue, on impaired learning of passive avoidance in mice.

The effects of YM-14673(N alpha-([(S)-4-oxo-2-azetidinyl] carbonyl)-L-histidyl-L-prolinamide dihydrate), a new thyrotropin-releasing hormone analogue, on impaired passive avoidance responses, were studied in mice in comparison with those of the thyrotropin-releasing hormone and its analogue DN-1417. In a test trial 24 hr after training, the latency in entering into a darkened compartment from an illuminated one was shortened by scopolamine and cycloheximide treatment. The shortened latency was prolonged in both models when YM-14673, thyrotropin-releasing hormone and DN-1417, in doses without effect on spontaneous movement and pain response by the hot plate method, were administered before training. This prolongation of shortened latency by the thyrotropin-releasing hormone and its analogues in cycloheximide-treated mice was antagonized by scopolamine but not by haloperidol. YM-14673 was about 10 times more potent than the thyrotropin-releasing hormone and DN-1417 in improving the impaired learning behavior. The shortened latency of step-through was ameliorated in scopolamine-treated mice when YM-14673 was administered immediately after training but not before testing. These results suggest that YM-14673, in addition to the thyrotropin-releasing hormone and DN-1417, facilitates the cerebral functioning, presumably by activating the cholinergic system.