Effect of NS-3, a thyrotropin-releasing hormone analog, on in vivo acetylcholine release in rat brain: regional differences and its sites of action.

The effects of thyrotropin-releasing hormone (TRH) and its analog, NS-3 [CG-3703: (3R,6R)-6-methyl-5-oxo-3-thiomorpholinylcarbonyl-L-histidyl- prolinamide tetrahydrate], on acetylcholine (ACh) release were examined in the rat brain by using in vivo microdialysis, and possible sites of action of NS-3 were subsequently examined. Both NS-3 (0.1 and 0.3 mg/kg i.v.) and TRH (3 mg/kg i.v.) produced an increase in the ACh release from the cerebral cortex and hippocampus but not from the striatum, although the action of NS-3 was much longer in duration than that of TRH. The ACh-releasing action of NS-3 was more marked in the hippocampus than in the cerebral cortex. Application of NS-3 (0.1-10 microM) via a dialysis probe into the nucleus basalis Meynert but not into the cortex caused a rapid and significant increase in cortical ACh release. Similarly, hippocampal ACh release was elevated by NS-3 (1 microM) perfused into the medial septum-diagonal band but not into the hippocampus. These findings suggest that NS-3 produces regionally specific enhancement of ACh release in the rat brain, and such effects of NS-3 are far more potent and longer in duration than those of TRH. In addition, the nucleus basalis Meynert and medial septum-diagonal band may be the respective sites of action of NS-3 in enhancing cortical and hippocampal ACh release.