Striatal output markers do not alter in response to circling behaviour in 6-OHDA lesioned rats produced by acute or chronic administration of the monoamine uptake inhibitor BTS 74 398.
The monoamine uptake inhibitor BTS 74 398 induces ipsilateral circling in 6-hydroxydopamine (6-OHDA) lesioned rats without induction of abnormal motor behaviours associated with L-dopa administration. We examined whether this was reflected in the expression of peptide mRNA in the direct and indirect striatal output pathways.6-OHDA lesioning of the nigrostriatal pathway increased striatal expression of PPE-A mRNA and decreased levels of PPT mRNA with PPE-B mRNA expression remaining unchanged. Acute L-dopa administration normalised PPE-A mRNA and elevated PPT mRNA while PPE-B mRNA expression remained unchanged. Acute administration of BTS 74 398 did not alter striatal peptide mRNA levels. Following chronic treatment with L-dopa, PPE-A mRNA expression in the lesioned striatum continued to be normalised and PPT mRNA was increased compared to the intact side. PPE-B mRNA expression was also markedly increased relative to the non-lesioned striatum. Chronic BTS 74 398 administration did not alter mRNA expression in the 6-OHDA lesioned striatum although small increases in PPT mRNA expression in the intact and sham lesioned striatum were observed. The failure of BTS 74 398 to induce changes in striatal neuropeptide mRNA correlated with its failure to induce abnormal motor behaviours or behavioural sensitisation but does not explain how it produces a reversal of motor deficits. An action in another area of the brain appears likely and may explain the subsequent failure of BTS 74 398 and related compounds to exert anti-parkinsonian actions in man.
Lane
E L
EL
Neurodegenerative Disease Research Centre, School of Health and Biomedical Sciences, King's College, London, UK. laneel@cf.ac.uk
Cheetham
S
S
Jenner
P
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D018663:Adrenergic Agents / Q000633:toxicity; D000818:Animals; D000978:Antiparkinson Agents / Q000008:administration & dosage*; D001522:Behavior, Animal / Q000187:drug effects; D002722:Chlorobenzenes / Q000008:administration & dosage*; D003342:Corpus Striatum / Q000187:drug effects* / Q000378:metabolism; D003503:Cyclobutanes / Q000008:administration & dosage*; D004399:Dynorphins / Q000096:biosynthesis / Q000187:drug effects; D004745:Enkephalins / Q000096:biosynthesis / Q000187:drug effects; D015870:Gene Expression / Q000187:drug effects; D017403:In Situ Hybridization; D007980:Levodopa / Q000008:administration & dosage; D008297:Male; D009043:Motor Activity / Q000187:drug effects*; D016627:Oxidopamine / Q000633:toxicity; D020734:Parkinsonian Disorders / Q000188:drug therapy*; D012333:RNA, Messenger / Q000032:analysis; D051381:Rats; D017208:Rats, Wistar; D013373:Substance P / Q000096:biosynthesis / Q000187:drug effects; D013995:Time
D018663:Adrenergic Agents; D000978:Antiparkinson Agents; C488846:BTS 74 398; D002722:Chlorobenzenes; D003503:Cyclobutanes; D004745:Enkephalins; D012333:RNA, Messenger; D013373:Substance P; D007980:Levodopa; D004399:Dynorphins; D016627:Oxidopamine