Effects of a sustained release formulation of thyrotropin-releasing hormone on behavioral abnormalities in senescence-accelerated mice.

Effects of a sustained release formulation of thyrotropin-releasing hormone (TRH-SR) on reduced anxiety-like behavior and learning impairment in senescence-accelerated mice (SAM) were examined. SAMP8/Ta (SAMP8) mice showing age-related emotional changes as well as learning and memory impairments, and SAMR1TA (SAMR1) mice exhibiting normal aging were used at 8 months of age. Subcutaneous injection of TRH-SR (2.8 mg/kg as free TRH) produced a sustained increase in immunoreactive plasma TRH levels up to about 4 weeks after dosing in SAMP8. TRH-SR antagonized the reduced neophobia to novel food in SAMP8 in a dose-dependent manner when tested 10 days but not 3 days after the injection. In the elevated plus-maze test, the SAMP8 control group treated with vehicle had significant increases in the number of entries into open arms and the time spent in open arms in comparison to SAMR1 mice. TRH-SR showed dose-dependent decreases in the number of entries into open arms, and reduced the time spent in open arms in SAMP8 mice. Furthermore, TRH-SR significantly improved the impairment of water maze learning in SAMP8 mice. In contrast, bolus administration of TRH had no significant effects on behavioral abnormalities in SAMP8 even at high doses, implying that long-term and continuous infusion of TRH may be important for amelioration of the behavioral abnormalities. These results suggest that TRH-SR may be useful for treatment of age-related emotional disorders and memory disturbance in dementia.