The nigrostriatal dopamine (DA) system has been traditionally considered a homogeneous entity necessary for movement. Recent studies have shown that the striatum may be topographically organized in an anatomical and neurochemical manner. Furthermore, there has been some evidence that subregions of the caudate-putamen contribute differentially to a variety of DA-dependent behaviors. Previous studies have inferred a functional heterogeneity by observing sensorimotor alterations resulting from microinjections of drugs or lesions of specific striatal areas. However, they may be confounded by the risk of non-specific damage and chemical diffusion to surrounding regions. Although important, these studies do no directly address the dynamic relationship between in vivo subregional DA function and voluntary locomotor behavior in the unlesioned animal. The recent development of in vivo voltammetry has made it possible to study, in a relatively non-invasive and specific manner, DA release in discrete brain regions of awake, moving animals.
The specific aims of this proposal will investigate and characterize the neurochemical heterogeneity of 9 striatal subregions by observing in vivo DA release in response to specific dopaminergic drugs. DA content and turnover will also be measured in vitro by HPLC with electrochemical detection. In addition, a functional profile of these subregions will include DA release during voluntary circling and in response to specific manipulations of posture, speed and direction. To further assess a heterogeneity of the striatum, the nigrostriatal path of rat will be unilaterally lesioned with 6-hydroxydopamine. DA release and turnover and L-dopa will be measured within subregions during amphetamine and L-dopa-induced turning. The long term objectives of this research will be a higher level of sophistication and an improved understanding of the anatomical, neurochemical and functional relationships between striatal subregions during normal behavior and hopefully add insight into the pathophysiology of striatal dysfunctions such as Parkinson's Disease.
