NS-3, a TRH-analog, reverses memory disruption by stimulating cholinergic and noradrenergic systems

The effects of a TRH-analog, N[[(3R,6R)-6-methyl-5-oxo-3-thiomorpholinyl]carbonyl]-L-histidyl-L - prolinamide tetrahydrate (NS-3, CG3703, montirelin hydrate) were compared with those of physostigmine on learning and memory disruption in the passive avoidance response (PAR) induced by either electrolytic lesion of the nucleus basalis magnocellularis (NBM) or by treatment with the noradrenergic neurotoxin, N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine (DSP4) in rats. a) In NBM-lesioned rats, both NS-3 and physostigmine significantly reversed disruption of memory consolidation examined 15 min after the training session when these drugs were injected IP immediately after the training session. In addition, reversal by NS-3 (0.1 mg/kg) of the disruption of memory was observed even in the retention test conducted 24 h after the training session. b) NS-3 (0.5 mg/kg) significantly reversed the disruption of memory retrieval, when the drug was administered 15 min before the test session. c) DSP4 (50 mg/kg IP) caused memory disruption when the retention tests were conducted between 1 and 48 h after the acquisition session. NS-3 (0.1 mg/kg), but not physostigmine, significantly reversed the disruption of memory induced by DSP4 treatment. These findings suggest that the consistent antiamnestic action of NS-3 is due to the enhancement of both central cholinergic and noradrenergic systems, possibly via facilitation of the release of these transmitters.