Modulation of the motor response to dopaminergic drugs in a parkinsonian model of combined dopaminergic and noradrenergic degeneration.
Besides dopaminergic deficiency, other neurotransmitter systems such as noradrenergic nuclei are affected in Parkinson's disease. Locus coeruleus degeneration might influence the response to dopamine replacement and the presence of long-term complications such as dyskinesias. In this scenario of noradrenergic and dopaminergic neurodegeneration, behavioural effects induced by dopaminergic-interacting drugs are incompletely known. We investigated whether noradrenergic lesion modulates the levodopa (l-DOPA) response and modifies the response to adenosine antagonists and its interaction with l-DOPA. We examined the motor behaviour induced by: 1) subthreshold doses of l-DOPA (2mg/kg, i.p.), 2) the adenosine-receptor antagonist caffeine (10mg/kg), and 3) the combination of l-DOPA (2mg/kg) and caffeine (10mg/kg). Each study was done in two experimental conditions: a) rats with unilateral 6-OHDA lesion and b) rats with a lesion of the nigrostriatal pathway (6-OHDA) combined with selective denervation of locus coeruleus-noradrenergic terminal fields by N-(2-chloroethyl)-N-ethyl-2-bromobenzylamine (DSP-4). While only 28% of the 6-OHDA-lesioned animals presented circling behaviour after l-DOPA challenge, all (100%) double-denervated animals rotated after the same l-DOPA dose (p<0.05). No statistical differences in the percentage of rotating animals were observed between single- and double-denervated rats after caffeine challenge. Combined l-DOPA-caffeine challenge produced rotational behaviour in all (100%) single- and double-denervated rats. No differences in total turns were observed between single- and double-denervated animals in each treatment condition. These findings suggest that additional noradrenergic denervation selectively decreases the motor threshold to l-DOPA treatment without modifying the magnitude or the pattern of the motor response to adenosinergic antagonism.
Pérez
Virgili
V
Laboratori de Neuropsicofarmacologia, Institut de Recerca de l'Hospital de la Santa Creu i de Sant Pau, Avgda. St. Antoni M(a) Claret, 167, 08025 Barcelona, Spain.
Sosti
Victoria
V
Rubio
Antonia
A
Barbanoj
Manel
M
Rodríguez-Alvarez
José
J
Kulisevsky
Jaime
J
D015102:3,4-Dihydroxyphenylacetic Acid / Q000378:metabolism; D058917:Adenosine A2 Receptor Antagonists; D018663:Adrenergic Agents; D000818:Animals; D000978:Antiparkinson Agents / Q000494:pharmacology*; D001522:Behavior, Animal / Q000187:drug effects; D001596:Benzylamines; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D002110:Caffeine / Q000494:pharmacology; D004298:Dopamine / Q000378:metabolism; D015259:Dopamine Agents / Q000494:pharmacology*; D006719:Homovanillic Acid / Q000378:metabolism; D007980:Levodopa / Q000494:pharmacology*; D008297:Male; D009043:Motor Activity / Q000187:drug effects*; D009498:Neurotoxins; D016627:Oxidopamine; D010302:Parkinson Disease, Secondary / Q000139:chemically induced / Q000188:drug therapy / Q000503:physiopathology*; D051381:Rats; D017207:Rats, Sprague-Dawley
D058917:Adenosine A2 Receptor Antagonists; D018663:Adrenergic Agents; D000978:Antiparkinson Agents; D001596:Benzylamines; D015259:Dopamine Agents; D009498:Neurotoxins; D015102:3,4-Dihydroxyphenylacetic Acid; D002110:Caffeine; D007980:Levodopa; D016627:Oxidopamine; C012102:DSP 4; D004298:Dopamine; D006719:Homovanillic Acid