Behavioral and biochemical correlates of the dyskinetic potential of dopaminergic agonists in the 6-OHDA lesioned rat.
Prolonged treatment with L-DOPA induces highly disabling dyskinesia in Parkinson's disease (PD) patients. In contrast, dopaminergic agonists display variably dyskinetic outcome, depending on pharmacokinetic/pharmacodynamic profile. The present study was aimed at assessing behavioral and biochemical correlates of intense or mild dyskinesia displayed by the different dopamine (DA) receptors stimulation in a rat model of PD. The effect of subchronic stimulation of the D(1) receptor by SKF38393, and the D(2)/D(3) receptor by ropinirole was evaluated in unilaterally 6-hydroxyDA-lesioned rats. Sensitization of contralateral turning (SCT) behavior and abnormal involuntary movements (AIMs) were assessed as behavioral correlates of dyskinetic responses. Opioid peptides mRNA in the dorsolateral striatum (dlStr) and glutamic acid decarboxylase (GAD67) mRNA content in globus pallidus (GP), were evaluated as an index of neuroadaptive changes occurring in the direct and indirect basal ganglia pathways. Subchronic SKF38393 caused AIMs and SCT whereas ropinirole elicited SCT only, indicating that both drugs induced some dyskinetic response, albeit of different type. Peptides mRNA evaluation in dlStr, showed that SKF38393 subchronic treatment was associated to an overexpression of both dynorphin (DYN) and enkephalin (ENK) mRNAs, in the direct and indirect striatal pathway respectively. In contrast, a decrease in DYN mRNA levels only was observed after treatment with ropinirole. Analysis of GAD67 mRNA levels in the GP showed an increase after both D(1) and D(2)/D(3) agonist treatments. Results suggest that presence of SCT alone or SCT plus AIMs might represent correlates of the differential severity of dyskinetic movements induced by treatment with low (ropinirole) or high (SKF38393) dyskinetic potential. Neuroadaptive increases in opioid peptide expression in both direct and indirect striatal pathways were associated to the appearance of AIMs alone. In contrast, increase of GAD67 mRNA in the GP was associated to both behavioral responses (SCT and AIMs), suggesting that neuroadaptive changes in this area were unrelated to the difference in dyskinetic potential of drugs.
Carta
Anna R
AR
Department of Toxicology and Center of Excellence for Neurobiology of Addiction, University of Cagliari, Cagliari, Italy. acarta@unica.it
Frau
Lucia
L
Lucia
Frau
F
Pinna
Annalisa
A
Annalisa
Pinna
P
Pontis
Silvia
S
Silvia
Pontis
P
Simola
Nicola
N
Nicola
Simola
S
Schintu
Nicoletta
N
Nicoletta
Schintu
S
Morelli
Micaela
M
Micaela
Morelli
M
D015647:2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-benzazepine / Q000494:pharmacology; D000818:Animals; D000978:Antiparkinson Agents / Q000494:pharmacology* / Q000627:therapeutic use; D003342:Corpus Striatum / Q000187:drug effects* / Q000378:metabolism / Q000503:physiopathology; D004298:Dopamine / Q000378:metabolism*; D018491:Dopamine Agonists / Q000494:pharmacology* / Q000627:therapeutic use; D004399:Dynorphins / Q000378:metabolism; D004409:Dyskinesia, Drug-Induced / Q000378:metabolism / Q000503:physiopathology*; D004745:Enkephalins / Q000378:metabolism; D005968:Glutamate Decarboxylase / Q000187:drug effects / Q000378:metabolism; D007211:Indoles / Q000494:pharmacology; D008297:Male; D009043:Motor Activity / Q000187:drug effects / Q000502:physiology; D009434:Neural Pathways / Q000187:drug effects / Q000378:metabolism / Q000503:physiopathology; D018847:Opioid Peptides / Q000235:genetics; D016627:Oxidopamine; D020734:Parkinsonian Disorders / Q000139:chemically induced / Q000188:drug therapy* / Q000503:physiopathology; D012333:RNA, Messenger / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D011954:Receptors, Dopamine / Q000187:drug effects / Q000378:metabolism; D017447:Receptors, Dopamine D1 / Q000819:agonists / Q000378:metabolism; D017448:Receptors, Dopamine D2 / Q000819:agonists / Q000378:metabolism; D005680:gamma-Aminobutyric Acid / Q000096:biosynthesis
D000978:Antiparkinson Agents; D018491:Dopamine Agonists; D004745:Enkephalins; D007211:Indoles; D018847:Opioid Peptides; D012333:RNA, Messenger; D011954:Receptors, Dopamine; D017447:Receptors, Dopamine D1; D017448:Receptors, Dopamine D2; C046649:ropinirole; D005680:gamma-Aminobutyric Acid; D015647:2,3,4,5-Tetrahydro-7,8-dihydroxy-1-phenyl-1H-3-benzazepine; D004399:Dynorphins; D016627:Oxidopamine; D005968:Glutamate Decarboxylase; C402565:glutamate decarboxylase 1; D004298:Dopamine