In vivo neurochemical effects of the NR2B selective NMDA receptor antagonist CR 3394 in 6-hydroxydopamine lesioned rats.
Microdialysis in intact and denervated striatum of unilaterally 6-hydroxydopamine (6-OHDA) lesioned rats was used to investigate whether CR 3394, N-[2-(3,5-dimethyl-1-adamantyl)ethyl]acetamidine, an adamantane derivative with preferential selectivity for the NR2B subunit of the NMDA receptor, has dopamine releasing properties in vivo. We also investigated whether this NMDA antagonist can potentiate the effects of L-Dopa on extracellular dopamine in these animals. After systemic injection, there was no significant effect of CR 3394 on extracellular dopamine, at all doses studied (1, 5 and 20 mg/kg i.p.), in either intact or in denervated striatum. On the other hand, striatal perfusion with 100 microM of the compound elicited release of dopamine in intact, but not in denervated striatum. In denervated striatum of the 6-OHDA-lesioned rats, CR 3394 (5 mg/kg) significantly enhanced the dopamine release induced by L-Dopa administration (25 mg/kg i.p.) in combination with benserazide (10 mg/kg i.p.). In particular, the onset of action of L-Dopa was potentiated. However, when combined with a subthreshold dose of L-Dopa (5 mg/kg), the effects of CR 3394 were lost. We conclude that CR 3394, like other NR2B receptor antagonists, has dopamine releasing properties in vivo. It enhances the effects of suprathreshold doses of L-Dopa in the denervated striatum, but not of low doses of L-Dopa. Therefore, future studies are necessary to establish the potential of selective NR2B receptor antagonists as L-Dopa-sparing agents.
Sarre
Sophie
S
Department of Pharmaceutical Chemistry and Drug Analysis, Research Group Experimental Pharmacology, Vrije Universiteit Brussel, Laarbeeklaan 103, B1090 Brussels, Belgium. sophie.sarre@vub.ac.be
Lanza
Marco
M
Makovec
Francesco
F
Artusi
Roberto
R
Caselli
Gianfranco
G
Michotte
Yvette
Y
D015102:3,4-Dihydroxyphenylacetic Acid / Q000378:metabolism; D000218:Adamantane / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology; D000578:Amidines / Q000008:administration & dosage / Q000494:pharmacology*; D000818:Animals; D000978:Antiparkinson Agents / Q000008:administration & dosage / Q000494:pharmacology*; D001479:Basal Ganglia / Q000187:drug effects* / Q000378:metabolism; D003714:Denervation; D004298:Dopamine / Q000378:metabolism; D015259:Dopamine Agents / Q000008:administration & dosage / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004347:Drug Interactions; D018691:Excitatory Amino Acid Antagonists / Q000008:administration & dosage / Q000494:pharmacology*; D007274:Injections, Intraperitoneal; D007980:Levodopa / Q000008:administration & dosage / Q000494:pharmacology*; D008297:Male; D008474:Medial Forebrain Bundle / Q000187:drug effects / Q000378:metabolism; D017551:Microdialysis; D016627:Oxidopamine; D020734:Parkinsonian Disorders / Q000139:chemically induced / Q000188:drug therapy* / Q000378:metabolism; D010477:Perfusion; D051381:Rats; D017208:Rats, Wistar; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013997:Time Factors
D000578:Amidines; D000978:Antiparkinson Agents; D015259:Dopamine Agents; D018691:Excitatory Amino Acid Antagonists; C510385:N-(2-(3,5-dimethyl-1-adamantyl)ethyl)acetamidine; C121001:NR2B NMDA receptor; D016194:Receptors, N-Methyl-D-Aspartate; D015102:3,4-Dihydroxyphenylacetic Acid; D007980:Levodopa; D016627:Oxidopamine; D000218:Adamantane; D004298:Dopamine