EFFECTS OF SUSTAINED-RELEASE FORMULATION OF THYROTROPIN-RELEASING-HORMONE ON LEARNING IMPAIRMENTS CAUSED BY SCOPOLAMINE AND AF64A IN RODENTS

The effects of a sustained-release formulation of thyrotropin-releasin g hormone (TRH-SR) on learning impairments induced by scopolamine and a cholinergic neurotoxin, ethylcholine aziridinium ion (AF64A), were e xamined in rodents. Subcutaneous injection of TRH-SR (2.8 mg/kg as fre e TRH) produced a sustained increase in immunoreactive plasma TRH leve ls up to about 2 weeks after dosing in rats. TRH-SR (0.56 and 2.8 mg/k g) given subcutaneously 7 days before the acquisition trial markedly a meliorated scopolamine-induced amnesia in mice, as evaluated with a pa ssive avoidance task. Repeated administration of TRH for 7 days at dos es of 0.2-5 mg/kg s.c. elicited a dose-dependent recovery from amnesia induced by scopolamine, whereas only the group treated with 5 mg/kg/d ay showed a significant improvement. The rats with bilateral intracere broventricular injection of AF64A (3.75 nmol/brain) showed a significa nt impairment in the water maze task 2 weeks after surgery. TRH-SR (0. 56 and 2.8 mg/kg) also exhibited a dose-dependent ameliorating action on the deficit. These findings indicate that TRH-SR ameliorates learni ng impairments produced by scopolamine and AF64A, and suggest that con tinuous infusion of TRH may have a potent learning and memory improvin g action at low doses.