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 1/2 (ERK1/2) 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 ERK1/2 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 mg/kg DOI were significantly greater than those of SAMR1 given DOI at the same doses. Although no dose-dependent increase in total ERK1/2 and total CREB expression was detected in response to DOI, the levels of phospho-ERK1/2 and -CREB increased in both strains. The phospho-ERK1/2 and -CREB levels in SAMP6 given 0.3 and 1.0 mg/kg DOI were significantly higher than those in SAMR1 given DOI at the same doses. These results indicate that SAMP6 increases DOI-dependent ERK1/2-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.
Niimi
Kimie
K
Brain Science and Life Technology Research Foundation, Itabashi, Tokyo, Japan.
Takahashi
Eiki
E
Itakura
Chitoshi
C
D000375:Aging; D019588:Aging, Premature; D000662:Amphetamines / Q000494:pharmacology*; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects / Q000502:physiology; D050882:CREB-Binding Protein / Q000378:metabolism; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D006213:Hallucinogens / Q000494:pharmacology*; D019416:Head Movements / Q000187:drug effects / Q000502:physiology; D008297:Male; D051379:Mice; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D010766:Phosphorylation; D058826:Serotonin 5-HT2 Receptor Agonists; D015398:Signal Transduction; D013003:Somatosensory Cortex / Q000187:drug effects* / Q000378:metabolism / Q000503:physiopathology
D000662:Amphetamines; D006213:Hallucinogens; D058826:Serotonin 5-HT2 Receptor Agonists; D050882:CREB-Binding Protein; C494364:Crebbp protein, mouse; D019950:Mitogen-Activated Protein Kinase 1; C015952:4-iodo-2,5-dimethoxyphenylisopropylamine