Novelty-induced Hyperactivity and Suppressed Cocaine Induced Locomotor Activation in Mice Lacking Threonine 53 Phosphorylation of Dopamine Transporter

摘要: Dopamine (DA) transporter (DAT) is dynamically regulated by several protein kinases and the Thr53 phosphorylation of DAT (pT53-DAT) documented in heterologous cell models rat brain. However, role endogenous pT53-DAT living animals has never been addressed. Here we generated studied pT53-lacking mouse model (DAT-Ala53) CRISPR/Cas9 technology. DAT-Ala53 mice showed normal growth, body weight, temperature, grip strength, sucrose preference while was completely absent. hyperlocomotion, pronounced vertical exploratory behavior, stereotypy a novel environment compared to wild-type littermates (WT). displayed unaltered levels monoamines, glutamate, GABA striatum WT. There were also no significant differences between WT tyrosine hydroxylase (TH) phospho-TH levels, or total surface DA-transport kinetic parameters Vmax Km. Immunohistochemical colocalization analyses TH caudate-putamen nucleus accumbens revealed mice. Interestingly, cocaine's potency inhibit striatal DA transport cocaine-induced locomotor activation significantly reduced Also, ERK1/2 inhibitors failed uptake Collectively, our findings reveal that lacking display novelty-induced hyperactive phenotype despite having expression, kinetics DA-linked markers. The results lack renders resistant inhibition less susceptible cocaine cocaine-evoked stimulation.