Dyskinetic potential of dopamine agonists is associated with different striatonigral/striatopallidal zif-268 expression.
In the dopamine-depleted striatum, an altered post-synaptic signalling of efferent neurons might underline the onset of variable dyskinetic responses to dopaminergic agonists. We have previously shown that a subchronic treatment with the D1 agonist SKF-38393 and the D2 agonist ropinirole induces a dyskinetic response of high and low intensities respectively, in 6-hydroxydopamine-lesioned rats. Here, zif-268 mRNA expression was evaluated in striatonigral and striatopallidal neurons to assess a neurochemical marker of these different dyskinetic responses upon drug administration. Acute and subchronic SKF-38393 (3mg/kg) increased zif-268 expression per neuron in the striatonigral pathway, albeit the number of neurons displaying high early-gene levels was reduced by the subchronic treatment. Zif-268 mRNA in striatopallidal neurons was not affected by SKF-38393 treatments. In contrast, ropinirole (5mg/kg) did not alter zif-268 mRNA in striatonigral neurons acutely, whereas ropinirole decreased zif-268 mRNA subchronically. Both acute and subchronic ropinirole decreased zif-268 levels in the striatopallidal pathway. The differential expression of zif-268 in striatonigral and striatopallidal neurons might provide a biochemical correlate of the dyskinetic outcome displayed by SKF-38393 and ropinirole treatments, suggesting that evaluation of neuronal responses upon drug administration provides a tool for the preclinical characterization of dyskinetic potential beyond behavioural tests.
Carta
Anna R
AR
Department of Toxicology, University of Cagliari, Cagliari, Italy; Centre of Excellence for Studies on Neurobiology of Addiction, Cagliari, Italy. acarta@unica.it
Frau
Lucia
L
Pinna
Annalisa
A
Morelli
Micaela
M
D015647:2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-benzazepine / Q000009:adverse effects; D000818:Animals; D003342:Corpus Striatum / Q000187:drug effects* / Q000378:metabolism; D018491:Dopamine Agonists / Q000009:adverse effects*; D004409:Dyskinesia, Drug-Induced / Q000209:etiology / Q000378:metabolism*; D051766:Early Growth Response Protein 1 / Q000096:biosynthesis* / Q000235:genetics; D005917:Globus Pallidus / Q000187:drug effects / Q000378:metabolism; D007211:Indoles / Q000009:adverse effects; D008297:Male; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D016627:Oxidopamine; D010302:Parkinson Disease, Secondary / Q000209:etiology / Q000378:metabolism; D012333:RNA, Messenger / Q000096:biosynthesis; D051381:Rats; D017207:Rats, Sprague-Dawley; D017447:Receptors, Dopamine D1 / Q000819:agonists; D017448:Receptors, Dopamine D2 / Q000819:agonists; D050637:Receptors, Dopamine D3 / Q000378:metabolism; D013378:Substantia Nigra / Q000187:drug effects* / Q000378:metabolism
D018491:Dopamine Agonists; D051766:Early Growth Response Protein 1; C486110:Egr1 protein, rat; D007211:Indoles; D012333:RNA, Messenger; D017447:Receptors, Dopamine D1; D017448:Receptors, Dopamine D2; D050637:Receptors, Dopamine D3; C046649:ropinirole; D015647:2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-benzazepine; D016627:Oxidopamine