A prominent theory of the pathophysiology of Tourette Syndrome (TS) is based on abnormal function of monoaminergic (e.g. dopaminergic, serotonergic, and noradrenergic) pathways in basal ganglia. The abnormality may lie within the neurochemistry of the """"""""primary"""""""" monoaminergic systems themselves or that of """"""""secondary"""""""" systems (e.g.) gonadal steroid receptors or oxytoxin and vasopressin pathways that project to basal ganglia), which regulate the basal ganglia or their monoamine afferents. Monoamines have been implicated in TS by metabolic abnormalities, increased dopamine transporter binding, and effective treatment with dopamine receptor blockers. However, gonadal steroids and their peptidergic effector systems also may be involved, since male to female ratios are disproportionate, changes in steroid hormone levels alter tic severity, and androgen antagonist were efficacious in preliminary trials. Moreover, steroid hormones and oxytocin and vasopressin pathways have distinct sex differences, have distinct ontogenic events that could account for the chldhood onet of TS, and regulate monoaminergic circuits and related locomotor and limbic behaviors. The goal of this research proposal is to determine if there are neurochemical alterations in either of these primary and secondary circuits that could cause the pathophysiology of TS. The specific neurochemicals to be studied will be the plasma membrane transporters for dopamine (DAT), sertonin (SERT), and norepinephrine (NET), and the vesicular monoamine transporter (VMAT2), gonadal steroid receptors (androgen (AR) and estrogen (ER)), and receptors for oxytocin (OT-R), and vasopressin (V1a). The specific techniques to be used include immunocytoghemistry quantitative immunoautoradiography, quantitative immunoautoradiography, quantitative counting methods, and quantitative radioligand binding autoradiography in postmortem TS brain tissue. Our transporter analysis will focus on the respective monoaminergic neurons in brainstem and their terminal fields in basal ganaglia, whereas the steroid receptor and neuropeptide receptor analyses will focus on parvocellular oxytocin and vasopressin neurons in paraventricular nucleus of hypothalamus and bed nucleus of stria terminalis/medial amygdala complex, and their terminal fields in brainstem monoamine cell groups and basal ganglia. The findings of this study will help elucidate the neurochemical changes that occur in TS and might suggest novel therapeutic strategies.
