Combination of modified SHIRPA and pharmacological approach uncovers neuronal alteration in senescence-accelerated mouse prone 6 (SAMP6) strain

The senescence-accelerated mouse (SAM) is a murine model of aging that was developed from the AKR/J strain. We examined whether there are behavioral differences among SAM prone 6 (SAMP6; an established model of senile osteoporosis), SAM resistant 1 (SAMR1), and AKR/J, using a modified SmithKline/Harwell/Imperial College/Royal Hospital/Phenotype Assessment (SHIRPA) procedure and pharmacological tests. The modified SHIRPA, which is suitable for rapid and comprehensive phenotyping of transgenic and gene-targeted mice, revealed increased rearing, spontaneous activity, locomotor activity, tail elevation, head bobbing, and tail rattling behaviors of SAMP6 compared with SAMR1 and AKR/J. These phenotypes are consistent with alteration of the dopamine system in SAMP6. Adopting a pharmacological approach to examine dopamine signaling, we evaluated the locomotor activity of the mice after intraperitoneal administration of apomorphine, a subtype non-selective dopamine receptor agonist. Apomorphine at 1 mg/kg significantly increased the locomotor activity of SAMP6, but not SAMR1 or AKR/J. At 3 mg/kg, apomorphine significantly increased the locomotor activities of all three strains, but the increase in SAMP6 was still significantly greater than that in SAMR1 or AKR/J. These results indicate increased sensitivity of the dopamine receptor signaling pathway in SAMP6. Thus, alteration of dopamine receptor signal transduction appears to be one of the underlying mechanisms of the increased locomotor activity of SAMP6. The combination of modified SHIRPA and examination of drug threshold dose differences between strains appears to be an effective approach to extend the applicability of existing mouse models.