Influence of Serotonin on the Synthesis of Striatal Neuropeptides

Grant Type
Grant Year
Institution Location
Institution Organization Name
Rutgers University
Investigators Name
Riley, Leigh, PhD

The interaction of serotonin and dopamine in the neostriatum is an important line of investigation since both Tourette Syndrome (treated with drugs affecting dopamine) and obsessive compulsive disorder (treated with drugs affecting serotonin) can occur in some families. To address this issue we have asked two questions: Do serotonin levels alter the synthesis of striatal neurotransmitters? Are the effects of serotonin direct or mediated through the dopamine system? In the first year of this project we found that the uptake blocker zimelidine caused a transient increase in striatal levels of substance P peptide (SP) as well as the mRNA coding for the prohormone precursor of (SP), preprotachykinin (PPT). In animals whose nigral dopaminergic neurons were destroyed using the neurotoxin 6-OH-dopamine, zimelidine did not increase levels of PPT mRNA, suggesting an intact dopamine system is required for serotonin’s effect on SP biosynthesis. However, striatal levels of SP peptide were still elevated by zimelidine after 6-OHdopamine treatment suggesting a direct role of serotonin in some aspects of SP metabolism. For the second year of the project, we will continue to study how serotonin levels influence the synthesis of striatal peptide neurotransmitters. The same paradigm used to study the effect of serotonin on substance P biosynthesis will be used to study the response of a number of other neurotransmitters (dynorphin, enkephalin, neurotensin, somatostatin and neuropeptide Y) to pharmacological manipulations of serotonin –and to discriminate direct from indirect serotonin effects by using 6-OH-dopamine treated animals where both dopamine and serotonin are involved. Manipulations of dopamine neurotransmission are known to affect the levels of these peptide neurotransmitters synthesized in the striatum, but little or nothing is known about the effects that serotonin manipulations might have. Considering the complexity of the striatum, examination of the changes of only one neurotransmitter in response to altered serotonin neurotransmission is certainly an oversimplification. However, current RNA isolation techniques make it technically feasible to use Northern blot analysis to measure the levels of a number of mRNAs coding for neuropeptides in RNA isolated from the same animals. Thus, we will be able to examine how chronic serotonin uptake blocker treatment alters a larger proportion of the entire striatal neurotransmitter landscape. Leigh A. Riley, Ph.D. Rutgers University, Newark, NJ Award $20,000 – Fellowship (2nd yr.) Tourette Association of America Inc. – Research Grant Award 1991