Noradrenergic modulation of the motor response induced by long-term levodopa administration in Parkinsonian rats.
A decrease in noradrenergic activity in Parkinson's disease might play a critical role in long-term motor complications associated with chronic dopaminergic replacement. Using the rat model of parkinsonism with an additional noradrenergic degeneration induced by the N-(-2-chloroethyl)-N-ethyl-2-bromobenzylamine (DSP-4) toxin we evaluated whether the circling motor activity and dose-failure episodes induced by levodopa (L-DOPA) differ between single (6-OHDA) and double (6-OHDA + DSP-4) denervated animals challenged with a single daily dose of L-DOPA. While single-lesioned animals showed a sensitization-desensitization turning response with a significant increase on day 15 and a decrease on day 22, in double-lesioned animals, the turning activity was maximal from day 1 and did not decay on day 22. Double-lesioned rats exhibited significantly higher number of turns on days 15 and 22 and a significantly lower percentage of dose-failure episodes during treatment. Noradrenergic denervation appears to be associated with prolonged long-term dopaminergic sensitization. This type of response appears to be comparable to that in the clinical setting with intermittent L-DOPA administration where no desensitization occurs once the abnormal response is established.
Pérez
Virgili
V
Laboratori de Neuropsicofarmacologia, Institut de Recerca de l'Hospital de la Santa Creu i de Sant Pau, Avgda Sant Antoni Maria Claret, 167, Barcelona 08025, Spain.
Sosti
Victoria
V
Rubio
Antonia
A
Barbanoj
Manel
M
Gich
Ignasi
I
Rodríguez-Alvarez
José
J
Kulisevsky
Jaime
J
D000818:Animals; D000978:Antiparkinson Agents / Q000494:pharmacology; D001596:Benzylamines / Q000633:toxicity; D001921:Brain / Q000187:drug effects* / Q000378:metabolism* / Q000503:physiopathology; D004195:Disease Models, Animal; D004298:Dopamine / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D004347:Drug Interactions / Q000502:physiology; D007980:Levodopa / Q000494:pharmacology*; D008297:Male; D009068:Movement / Q000187:drug effects / Q000502:physiology; D009498:Neurotoxins / Q000633:toxicity; D009638:Norepinephrine / Q000378:metabolism*; D016627:Oxidopamine / Q000633:toxicity; D020734:Parkinsonian Disorders / Q000188:drug therapy* / Q000378:metabolism* / Q000503:physiopathology; D017729:Presynaptic Terminals / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D020127:Recovery of Function / Q000187:drug effects / Q000502:physiology; D009435:Synaptic Transmission / Q000187:drug effects / Q000502:physiology; D013995:Time; D016896:Treatment Outcome
D000978:Antiparkinson Agents; D001596:Benzylamines; D009498:Neurotoxins; D007980:Levodopa; D016627:Oxidopamine; C012102:DSP 4; D004298:Dopamine; D009638:Norepinephrine