title: Modulation of the motor response to dopaminergic drugs in a parkinsonian model of combined dopaminergic and noradrenergic degeneration.
abstract: 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.
authors: 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.
authors: Virgili
authors: V
authors: Pérez
authors: Victoria
authors: V
authors: Sosti
authors: Antonia
authors: A
authors: Rubio
authors: Manel
authors: M
authors: Barbanoj
authors: José
authors: J
authors: Rodríguez-Alvarez
authors: Jaime
authors: J
authors: Kulisevsky
mesh_terms: 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
chemical_list: 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