PNU-96391A (OSU6162) antagonizes the development of behavioral sensitization induced by dopamine agonists in a rat model for Parkinson's disease.
PNU-96391A is a weak dopamine (DA) D(2) receptor antagonist with behavioral stabilizing properties. Previous experiments revealed that PNU-96391A antagonizes the expression of L-DOPA induced behavioral sensitization (dyskinesias) in lesioned primates without inducing akinesia or reducing the anti-Parkinsonian efficacy of L-DOPA. This study evaluated the ability of PNU-96391A to block the development of DA agonist-induced behavioral sensitization in rats with unilateral 6-OH-DA lesions of the median forebrain bundle. Repeated twice daily treatment with L-DOPA and the decarboxylase inhibitor benserazide (15 and 5 mg/kg, IP, respectively), or quinpirole (D(2)/D(3) agonist, 0.1 mg/kg, SC) increased the contralateral rotations measured on day 7 and 14 as compared to day 1. PNU-96391A (10-60 mg/kg, SC, bid.) antagonized the development of behavioral sensitization induced by both agonists. The basal activity of L-DOPA was not affected while a reduction of quinpirole-induced rotations was observed after 30-60 mg/kg, SC of PNU-96391A. Neurochemical analyses confirmed >99 % reductions of striatal DA levels, unilaterally. Concomitant treatment with PNU-96391A and L-DOPA did not affect plasma levels of PNU-96391A indicating that the effects observed are not related to pharmacokinetic interactions. These results suggest that PNU-96391A could be therapeutically useful to prevent the development of behavioral sensitization induced by DA agonists.
Nichols
N F
NF
Neurobiology Research, Pharmacia Corporation, Kalamazoo, MI 49001, USA.
Cimini
M G
MG
Haas
J V
JV
Staton
B A
BA
Tedroff
J
J
Svensson
K A
KA
D000818:Animals; D000978:Antiparkinson Agents / Q000494:pharmacology; D001522:Behavior, Animal / Q000187:drug effects*; D001923:Brain Chemistry / Q000187:drug effects; D004298:Dopamine / Q000378:metabolism; D018491:Dopamine Agonists / Q000494:pharmacology*; D018492:Dopamine Antagonists / Q000494:pharmacology*; D065127:Dopamine D2 Receptor Antagonists; D006719:Homovanillic Acid / Q000378:metabolism; D007980:Levodopa / Q000378:metabolism / Q000494:pharmacology; D008297:Male; D008474:Medial Forebrain Bundle / Q000502:physiology; D016627:Oxidopamine; D010302:Parkinson Disease, Secondary / Q000139:chemically induced / Q000378:metabolism / Q000523:psychology*; D010880:Piperidines / Q000494:pharmacology*; D019257:Quinpirole / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D013239:Stereotyped Behavior / Q000187:drug effects; D013563:Sympathectomy, Chemical; D013565:Sympatholytics
D000978:Antiparkinson Agents; D018491:Dopamine Agonists; D018492:Dopamine Antagonists; D065127:Dopamine D2 Receptor Antagonists; D010880:Piperidines; D013565:Sympatholytics; C109513:OSU 6162; D019257:Quinpirole; D007980:Levodopa; D016627:Oxidopamine; D004298:Dopamine; D006719:Homovanillic Acid