The long-term objectives of this proposal are: 1) To show that functional MRI (fMRI) can be used to spatially and temporally map drug-induced changes in neural activity in the rhesus monkey nigrostriatal system. 2) To use fMRI to gain further insight into the nigrostriatal adaptations which occur in parkinson's disease, and the effect of chronic levodopa treatment on those adaptations. To achieve the first objective we will use a rhesus model of Parkinson's disease to test the ability of an fMRI sequence to map R2* changes in the nigrostriatal system following the administration of the dopamine precursor levodopa. We will measure striatal dopamine levels under the same conditions using in vivo microdialysis to determine whether any nigrostriatal R2* changes observed are correlated with changes in local dopamine levels. To determine whether the R2* changes seen following levodopa administration are due to binding of newly synthesized dopamine to pre- and/or post-synaptic dopamine receptors, we will determine the effects of acute administration of dopamine receptor agonists on nigrostriatal R2* in normal and MPTP-treated monkeys. Comparison of the results of these two experiments will help us to determine whether nigrostriatal R2* changes induced by levodopa or dopamine receptor agonists arise from changes in neural activity. To achieve the second objective we will compare nigrostriatal R2* changes seen in unilaterally MPTP-lesioned monkeys chronically treated with levodopa, with the R2* changes seen in unilaterally MPTP-lesioned animals which were not treated with levodopa, and with the R2* changes seen in normal animals. These responses will be correlated with striatal dopamine levels measured by microdialysis.
The specific aims of the proposal are therefore: 1) To correlate levodopa-induced changes in R2* in normal and unilaterally MPTP-treated female rhesus monkeys with changes in nigrostriatal dopamine and dopamine metabolites measured in the same animals by in vivo microdialysis. 2) To examine the effects of pre- and post-synaptic dopamine receptor agonists on nigrostriatal R2* in normal and hemiparkisonian female rhesus monkeys. 3) To determine the levodopa- induced changes in R2* and striatal dopamine levels in unilaterally MPTP-treated female rhesus monkeys given chronic levodopa treatment.
| Andersen, Anders H; Zhang, Zhiming; Avison, Malcolm J et al. (2002) Automated segmentation of multispectral brain MR images. J Neurosci Methods 122:13-23 |
| Zhang, Z; Andersen, A H; Avison, M J et al. (2000) Functional MRI of apomorphine activation of the basal ganglia in awake rhesus monkeys. Brain Res 852:290-6 |
| Zhang, Z; Zhang, M; Ai, Y et al. (1999) MPTP-Induced pallidal lesions in rhesus monkeys. Exp Neurol 155:140-9 |
| Andersen, A H; Gash, D M; Avison, M J (1999) Principal component analysis of the dynamic response measured by fMRI: a generalized linear systems framework. Magn Reson Imaging 17:795-815 |
| Chen, Q; Andersen, A H; Zhang, Z et al. (1999) Functional MRI of basal ganglia responsiveness to levodopa in parkinsonian rhesus monkeys. Exp Neurol 158:63-75 |
