Levodopa replacement therapy alters enzyme activities in striatum and neuropeptide content in striatal output regions of 6-hydroxydopamine lesioned rats.
The effects of striatal dopamine denervation and levodopa replacement therapy on neuronal populations in the rat striatum were assessed by measurement of glutamic acid decarboxylase (GAD) and choline acetyltransferase (CAT) activities in the striatum, dynorphin and substance P concentrations in the substantia nigra, and enkephalin concentration in the globus pallidus. Rats with a unilateral 6-hydroxydopamine (6-OHDA) lesion of the nigrostriatal pathway were treated for 21 days with levodopa (100 mg/kg/day, i.p., with 25 mg/kg benserazide) on either an intermittent (b.i.d.) or continuous (osmotic pump infusion) regimen and sacrificed following a three day drug washout. In saline-treated control rats, striatal GAD activity and globus pallidus enkephalin content were elevated and nigral substance P content was reduced ipsilateral to the 6-OHDA lesion. Intermittent levodopa treatment further increased GAD activity, decreased CAT activity, restored substance P to control levels, markedly increased dynorphin content, and had no effect on enkephalin. In contrast, continuous levodopa elevated globus pallidus enkephalin beyond the levels occurring with denervation, but had no effect on any of the other neurochemical measures. These results indicate that striatal neuronal populations are differentially affected by chronic levodopa therapy and by the continuous or intermittent nature of the treatment regimen. With the exception of substance P, levodopa did not reverse the effects of the 6-OHDA lesion but, rather, either exacerbated the lesion-induced changes (e.g. GAD and enkephalin) or altered neurochemical markers which had been unaffected by the lesion (e.g. CAT and dynorphin).(ABSTRACT TRUNCATED AT 250 WORDS)
Engber
T M
TM
Experimental Therapeutics Branch, National Institute of Neurological Disorders and Stroke, Bethesda, MD 20892.
Susel
Z
Z
Kuo
S
S
Gerfen
C R
CR
Chase
T N
TN
D000818:Animals; D002795:Choline O-Acetyltransferase / Q000378:metabolism*; D003342:Corpus Striatum / Q000187:drug effects / Q000201:enzymology* / Q000473:pathology; D004334:Drug Administration Schedule; D004399:Dynorphins / Q000378:metabolism*; D004745:Enkephalins / Q000378:metabolism*; D007839:Functional Laterality; D005917:Globus Pallidus / Q000187:drug effects / Q000378:metabolism*; D005968:Glutamate Decarboxylase / Q000378:metabolism*; D007980:Levodopa / Q000008:administration & dosage / Q000494:pharmacology*; D008297:Male; D016627:Oxidopamine / Q000633:toxicity*; D051381:Rats; D011919:Rats, Inbred Strains; D013373:Substance P / Q000378:metabolism*; D013378:Substantia Nigra / Q000187:drug effects / Q000378:metabolism*
D004745:Enkephalins; D013373:Substance P; D007980:Levodopa; D004399:Dynorphins; D016627:Oxidopamine; D002795:Choline O-Acetyltransferase; D005968:Glutamate Decarboxylase