| Description |
The site of decarboxylation of L-DOPA to dopamine (DA) in patients with Parkinson's disease is unknown. Projections from the raphe nucleus containing 5-hydroxytryptamine (5-HT) may contribute to the production of DA from L-DOPA since these cells are known to contain L-aromatic amino acid decarboxylase. To test this hypothesis, rats were given a unilateral injection of 6-hydroxy-dopamine (6OHDA; 8 (mu)g in 4 (mu)l) into the substantia nigra. Ten to 12 days later animals were given L-DOPA: carbidopa (100mg/kg: 10mg/kg) or vehicle every 12 hrs for 8 injections and sacrificed 1-2 hrs after the last injection. Tyrosine hydroxylase (TH) activities and DA levels in the ipsilateral neostriatum were reduced to less than 5% of control in lesioned animals. The contralateral striata were not affected and served as controls. L-DOPA treatment did not significantly increase the striatal DA levels in lesioned animals. Additional neostriatal lesions induced by the serotonin neurotoxin, 5,7-dihydroxytryptamine (DHT; 16 (mu)g), did not significantly decrease DA levels below those found in animals with the 6OHDA lesions alone. Due to the failure of L-DOPA to increase striatal DA in animals with extensive 6OHDA lesions, it is concluded that 5-HT terminals in the striatum do not contribute significantly to the production of DA from L-DOPA in Parkinson's disease. During the course of these experiments it became apparent that DHT was altering dopaminergic function. Unilateral injection of DHT into the rat neostriatum markedly reduced not only striatal tryptophan hydorxylase (TPH) activity but also striatal tyrosine hydroxylase (TH) activity and dopamine (DA) levels measured 10-15 days later. The decrease in striatal TH activity was dose-related over the range of 8 to 32 (mu)g DHT; a dose of 16 (mu)g reduced TH activity to 40-50% of control, DA levels to 38% of control and TPH activity to 5-15% of control. Pretreatment of animals with amfonelic acid (15mg/kg), a selective DA uptake inhibitor, significantly reduced the effect of DHT to striatal TH activity and DA levels without affecting the DHT-induced decrease in TPH activity. Striatal choline acetyltransferase and glutamic acid decarboxylase activities were not decreased by 16 (mu)g DHT. The results indicate that DHT can compromise dopaminergic function in the rat neostriatum by damaging DA terminals in addition to its established neurotoxic effects on serotonin and nonrepinephrine terminals. |
| OCR Text |
Show THE UNIVERSITY OF UTAH GRADUATE SCHOOL SUPERVISOR Y COMMITTEE APPROVAL of a dissertation submitted by Dane R. Liston I have read this dissertation and have fo nd it to be of satisfactory quality for a S,al degree. dO ).-'1--' 11'l Chairman, Supervisory Committee I have read this dissertation and have found_,:t to be Cj:,J �� �Jljtl I f satisfactory quality for a ����'�������-------Larry Member, Supervisory Committee I have read this dissertation and have found it to be of satisfactory quality for a doctoral degree. Date I J��} il ' I Harold H. Wolf Member, Supervisory Committee I have read this dissertation and have found it to be of satisfactory quality for a �/I�� doctoral degree. 1-2-2--8'1 Date Donald N. Franz Membet, Supervisory Committee I have read this dissertation and have found it to be of satisfactory quality for a doctoral degree. /-"w- PI ' Date A-. � U:� Bry /. {?7 . -! jJ �Q> , inkle . �.e. Member, Supervisory Committee THE UNIVERSITY OF UTAH GRADUATE SCHOOL FINAL READING APPROVAL To the Graduate Council of The University of Utah: I have read the dissertation of Dane R. Liston mlts final form and have found that (l) its format, citations, and bibliographic style are consistent and accepta ble� (2) its illustrative materials including figures, tables, and charts are in place; and (3) the final manuscript is satisfactory to the Supervisory Committee and is ready for submission to the Graduate School. Date Approved for the Major Department Ph. D. Chairman! Dean Approved for the Graduate Council ��A/�r James L. Clayton, Ph.D. Dean ot The Graduate School |
