Abstract
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 [11C]DASB ([11C]-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 [11C]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. [11C]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 [11C]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.
Highlights
The serotonergic neurotransmitter system comprises a diffuse neuronal network that is involved in the control of several fundamental brain functions, including the regulation of mood[1,2,3], sleep/wake rhythms[4,5], aggression[6], appetite[7,8], learning and memory, and reward[9,10,11]
Positron emission tomography (PET) is one of these methods, which can measure the kinetics of radiolabeled molecules in virtually all tissues of the body in a minimally invasive manner
In the present study we set out to examine dynamic changes in SERT density in the mouse brain using PET imaging with [11C]DASB in a mouse model of chronic stress based upon long-term treatment with CORT
Summary
The serotonergic neurotransmitter system comprises a diffuse neuronal network that is involved in the control of several fundamental brain functions, including the regulation of mood[1,2,3], sleep/wake rhythms[4,5], aggression[6], appetite[7,8], learning and memory, and reward[9,10,11]. Alterations in serotonergic neurotransmission are implicated in a wide range of mental illnesses, from mood and anxiety to substance abuse disorders[12,13]. Over the last four decades, its important role as a major regulatory element of the 5-HT system has made SERT an attractive drug target for the development of psychoactive medications. With the availability of a constantly increasing toolbox of radiotracers that bind to a wide array of different molecular target structures, PET holds great potential to monitor disease progression and treatment response. In the last two decades, the development of small-animal PET technology has allowed the examination of humans and rodents in comparable paradigms, allowing for a minimally invasive in vivo investigation of neural circuitries and molecular targets in longitudinal studies in patients and experimental animals. The implementation of SERT-PET imaging in the translational neurosciences using animal models is a challenging task, as reflected in the difficulties to obtain accurate quantitative parameters of SERT binding in the mouse brain using a PET-based approach[27]
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