Differential expression of striatal synaptotagmin mRNA isoforms in hemiparkinsonian rats.
Synaptotagmins (Syts) constitute a multi-gene family of 15 putative membrane trafficking proteins. The expression of some of the Syts in the brain might be dopaminergically controlled and thus affected by dopamine depletion in Parkinson's disease. We used hemiparkinsonian rats to investigate the effects of chronic striatal dopamine depletion and the acute effects of antiparkinsonic drug L-DOPA or D1 agonist (+/-)-6-chloro-7,8-dihydroxy-3-allyl-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine hydrobromide (SKF82958) on the levels of striatal Syt I, II, IV, VI, VII, X, XI mRNA isoforms. On the 6-hydroxydopamine (6-OHDA)-lesioned side we observed a nearly total loss of tyrosine hydroxylase (TH), synaptotagmin I, Syt IV, Syt VII and Syt XI mRNA levels in the substantia nigra compacta (SNc). In dopamine-depleted striatum we also found a significant down-regulation Syt II and up-regulation of Syt X mRNA levels that could not be reversed by the acute treatment either with L-DOPA or SKF82958. By contrast, these two drugs induced an increase of Syt IV and Syt VII mRNA levels. A time-course study revealed the highest levels of Syt IV and VII mRNAs to occur at two hours and 12 hours after the treatment with SKF82958, respectively. D1 antagonist (+/-)-7-chloro-8-hydroxy-3-methyl-1-phenyl-2,3,4,5-tetrahydro-1H-3-benzazepine hydrochloride (SCH23390) but not D2 antagonist haloperidol prevented the L-DOPA-driven increase of Syt IV and VII mRNAs. These results imply that synaptic plasticity in response to chronic striatal dopamine depletion involves a complex pattern of changes in striatal Syt mRNA expression. The L-DOPA treatment does not reverse the changes in Syt II and Syt X gene expression, but recruits additional, D1 receptor-mediated changes in Syt IV and Syt VII gene expression. Whether these D1 receptor-mediated changes play a role in the alterations of synaptic transmission that results in the unwanted side effects of chronic L-DOPA treatment in Parkinson's disease remains to be determined.
Glavan
G
G
Brain Research Laboratory, Institute of Pathophysiology, Faculty of Medicine, University of Ljubljana, Zaloska 4, 1000 Ljubljana, Slovenia.
Zivin
M
M
D000818:Animals; D001058:Apomorphine / Q000494:pharmacology; D001522:Behavior, Animal / Q000187:drug effects / Q000502:physiology; D001552:Benzazepines / Q000008:administration & dosage / Q000494:pharmacology; D001921:Brain / Q000033:anatomy & histology / Q000378:metabolism; D003342:Corpus Striatum / Q000378:metabolism*; D004195:Disease Models, Animal; D018491:Dopamine Agonists / Q000494:pharmacology; D018492:Dopamine Antagonists / Q000008:administration & dosage; D004347:Drug Interactions; D005260:Female; D015870:Gene Expression / Q000187:drug effects / Q000502:physiology*; D005786:Gene Expression Regulation / Q000187:drug effects / Q000502:physiology*; D017403:In Situ Hybridization / Q000379:methods; D007980:Levodopa / Q000008:administration & dosage; D016627:Oxidopamine; D020734:Parkinsonian Disorders / Q000139:chemically induced / Q000188:drug therapy / Q000378:metabolism*; D020033:Protein Isoforms / Q000235:genetics; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D012399:Rotation; D013378:Substantia Nigra / Q000293:injuries / Q000378:metabolism; D050857:Synaptotagmins / Q000235:genetics / Q000378:metabolism*; D013997:Time Factors; D014446:Tyrosine 3-Monooxygenase / Q000235:genetics / Q000378:metabolism
D001552:Benzazepines; D018491:Dopamine Agonists; D018492:Dopamine Antagonists; D020033:Protein Isoforms; D012333:RNA, Messenger; D050857:Synaptotagmins; D007980:Levodopa; C071262:SK&F 82958; D016627:Oxidopamine; D014446:Tyrosine 3-Monooxygenase; D001058:Apomorphine