Regulation of Brain Serotonin Transporters

Vicentic, Aleksandra

Abstract

Selective serotonin reuptake inhibitors (SSRIs) such as paroxetine (Paxil) are being increasingly administered to children, despite the paucity of data on their effects prior to maturation. SSRIs target brain 5-HT transporters which differ in density in immature versus adult brain. These data suggest different intracellular transporter kinetics (production and degradation) in immature brain. Thus, SSRIs given prior to maturation are likely to produce changes in 5-HT transporter density which h are different from those produced when SSRIs are administered to adults. Hypothesis: Brain 5-HT transporters in immature versus mature rates will differ with respect to turnover kinetics and regulation by treatment with SSRIs.
Specific Aim (1) to determine regional differences in the rates of serotonin transporter production and degradation in immature versus adult rats. We have identified age-dependent differences in 5-HT transporter density in discrete brain regions. Therefore, the proposed study will employ in vitro autoradiography to assess the kinetics of serotonin transporter turnover (i.e., rate constants of transporter production-r and degradation-k and the half-life or recovery t 1/2) in brain regions where 5-HT transporters are shown to be altered between immature and adult animals. Because densities (Bmax) of 5-HT transporter s are dependent on the rats of transporter turnover, age- dependent differences in transporter kinetics would indicate different responsiveness of 5-Ht transporter to regulation by SSRIs.
Specific Aim (2) To determine the immediate and long-term effects of administration of paroxetine (Paxil) on brain 5-HT transporter density between immature and adult rats. The responsiveness of 5-HT transporters of regulation by SSRIs has generally been evaluated only in adult animals. These studies will use in vitro autoradiography to determine the differences between immature and adult rats in the ability of paroxetine to alter 5-HT transporter densities in discrete brain regions. In addition, the long-term impact of the changes in immature animals will be determined by evaluating 5-Ht transporter densities in adult rats which were treated with paroxetine prior to maturation.