Aleksandra Vicentic, Ph.D. - US grants

DESCRIPTION: (Applicant's 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.

Literature suggests that cellular plasticity within specific neuronal circuits underlies physiological and behavioral effects of psychomoter stimulation administration. Recent studies (Berke e al., 1998) demonstrated that acute cocaine administration induces a diverse st of previously undescribed gene fragments in striatum that were termed :anias" for activity and neurotransmitter-induced genes. The goal of this proposal is to extend these findings and to characterize "anias" for activity and neurotransmitter-induced genes. The goal of this proposal is to extend these findings and to characterize ania genes and their protein products. These studies may help elucidate additional mechanisms underlying cellular changes associated with psychomotor stimulant administration and identify potentially novel targets for psychotherapeutic medications. The following specific aims will be tested. Specific aim 1 will identify and analyze sequences of full-length cDNA clones for ania genes. The ania gene fragments (ania-1 through ania 12) have been supplied to us by Dr. Steve Hyman. We will screen a rat striatal cDNA library in order to isolate cDNA sequences. The sequences will be analyzed and amino acid sequences will be deducted to predict function of proteins encoded by ania genes. Specific aim 2 will determine the tissue distribution of ania gene expression. Because ania gene expression has been only explored in striatum (Berke et al., 1998), we will extend these findings by examining many neuroanatomical levels via in situ hybridization. Specific Aim 3 will attempt to synthesize fragments of proteins encoded by ania genes and prepare antibodies against these proteins. Immunocytochemical studies will be conducted to identify the best antibody and to examine the tissue distribution of ania protein products.