PET imaging of the mouse brain reveals a dynamic regulation of SERT density in a chronic stress model

The serotonin transporter (SERT, Slc6a4) plays an important role in the regulation of serotonergic neurotransmission and its aberrant expression has been linked to several psychiatric conditions. While SERT density has been proven to be amenable to in vivo quantitative evaluation by positron emission tomography (PET) in humans, this approach is in its infancy for rodents. Here we set out to evaluate the feasibility of using small-animal PET employing [(11)C]DASB ([(11)C]-3-amino-4-(2-dimethylaminomethyl-phenylsulfanyl)-benzonitrile) as a radiotracer to measure SERT density in designated areas of the mouse brain. Using Slc6a4(+/+), Slc6a4(+/−), and Slc6a4(−/−) mice as a genetic model of different SERT expression levels, we showed the feasibility of SERT imaging in the mouse brain with [(11)C]DASB-PET. The PET analysis was complemented by an evaluation of SERT protein expression using western blot, which revealed a highly significant correlation between in vivo and ex vivo measurements. [(11)C]DASB-PET was then applied to the examination of dynamic changes of SERT levels in different brain areas in the chronic corticosterone mouse model of chronic stress. The observed significant reduction in SERT density in corticosterone-treated mice was independently validated by and correlated with western blot analysis. This is the first demonstration of a quantitative in vivo evaluation of SERT density in subregions of the mouse brain using [(11)C]DASB-PET. The evidenced decrease in SERT density in response to chronic corticosterone treatment adds a new dimension to the complex involvement of SERT in the pathophysiology of stress-induced mental illnesses.