Hallucinogenic 5-hydroxytryptamine 2A receptor agonist effects in senescence-accelerated mice.
Many neuropharmacological agents modulate the activity and conformation of heptahelical G protein-coupled receptors and activate ligand-specific signaling pathways. The hallucinogenic chemical 1-2,5-dimethoxy-4-iodophenyl-2-aminopropane (DOI), a serotonin receptor 2A (5-HT2AR) agonist, evokes extracellular signal-regulated kinase 12 (ERK12) signaling and head-twitch behavior. We previously reported that the senescence accelerated-prone mouse 6 (SAMP6) exhibited altered emotional behavior and increased levels of a serotonin-biosynthesizing enzyme compared to the senescence accelerated-resistant mouse 1 (SAMR1) however, the mechanism underlying the relationship between specific receptor signaling and behavioral phenotypes was unclear. In this study, we performed head-twitch tests and examined the total and phosphorylated levels of ERK12 and cAMP-responsive element-binding protein (CREB) in the bilateral somatosensory cortex to assess the differences between SAMP6 and SAMR1 using DOI. Although DOI dose-dependently increased the head-twitch response in both strains, the responses of SAMP6 given 0.3 and 1.0 mgkg DOI were significantly greater than those of SAMR1 given DOI at the same doses. Although no dose-dependent increase in total ERK12 and total CREB expression was detected in response to DOI, the levels of phospho-ERK12 and -CREB increased in both strains. The phospho-ERK12 and -CREB levels in SAMP6 given 0.3 and 1.0 mgkg DOI were significantly higher than those in SAMR1 given DOI at the same doses. These results indicate that SAMP6 increases DOI-dependent ERK12-CREB signaling leading to more head-twitch responses than SAMR1, and that SAMP6 could provide a useful model for examining the relationship between 5-HT2AR regulatory signaling and behavioral phenotypes.