This project involves neurochemical studies of the effects of glial-derived neurotrophic factor (GDNF), a novel dopaminotrophic molecule that promotes the survival of DA neurons, on DA neurons in the rat basal ganglia. The effects of GDNF will be studied by unilaterally infusing this growth factor into the substantia nigra of 6-OHDA lesioned rats, and into 6-OHDA-lesioned rats that have received fetal ventral mesencephalic brain grafts. In these animals, in vivo electrochemical and microdialysis measurements will be used to study the extracellular release and uptake of dopamine (DA) in tahe striatum and substantia nigra. These studies will examine the role of DA in athe neuronal circuits involved with motor behavior, and the compensatory neurochemical changes seen following the treatment of damaged DA neurons with GDNF. First, we will examine the extracellular regulation of potassium-evoked overflow of DA, the effects of nomifensine and GBR- 12909 on K+ - evoked overflow of DA, and the clearance/diffusion of DA in the striatum and substantia nigra of unilateral 6-OHDA-lesioned Fischer 344 rats that have been treated with vehicle or GDNF. High-speed (5-25 Hz) chronoamperometry and fast scan cyclic voltammetry recordings coupled with pressure ejection of drugs from micropipettes will be used to investigate the dynamics of DA release and uptake. Microdialysis studies of the extracellular regulation DA and potassium-evoked DA release will be studied. In addition, the effects of nomifensine or GBR-12909 on potassium-evoked overflow of DA in the striatum and substantia nigra will be used to further confirm the validity of the electrochemical studies, and to investigate changes in the metabolic regulation of DA ina the GDNF- treated animals. Secondly, high-speed electrochemical recordings will be performed in the substantia nigra and striatum of unanesthetized freely- moving rats. Normal rats and animals that have received unilateral 6- OHDA-lesions to the basal ganglia that have been treated with vehicle or GDNF will be studied. These studies will investigate the potential adverse effect of anesthesia ont the dynamic properties of normal DA neurons and damaged DA neurons following GDNF treatment. Third, in vivo electrochemical and microdialysis studies of DA release will be studied in 6-OHDA-lesioned rats that have received transplants of fetal ventral mesencephalon with and without treatment with GDNF. Finally, Project 1 will provide support for the in vivo electrochemical and HPLC-EC measures of DA and DA metabolites that are proposed in Projects 2,3,4, and 5.
| Bowenkamp, K E; David, D; Lapchak, P L et al. (1996) 6-hydroxydopamine induces the loss of the dopaminergic phenotype in substantia nigra neurons of the rat. A possible mechanism for restoration of the nigrostriatal circuit mediated by glial cell line-derived neurotrophic factor. Exp Brain Res 111:1-7 |
| Freed, C R (1986) The trained circling rat and in vivo electrochemistry: a behavioral model and a measurement method to study the dynamic role of dopamine in movement. Ann N Y Acad Sci 473:188-99 |
| Freed, C R; Yamamoto, B K (1985) Regional brain dopamine metabolism: a marker for the speed, direction, and posture of moving animals. Science 229:62-5 |
