Modulation of the locomotor activating effects of the noncompetitive NMDA receptor antagonist MK801 by dopamine D2/3 receptor agonists in mice.
The noncompetitive NMDA receptor antagonist MK801 (dizocilpine) produces behavioral stimulation mediated, in part, through indirect activation of the dopamine (DA) system. Previous reports indicate that D2/3 agonists inhibit MK801-induced stereotypies; however, it is unclear if these agonists also attenuate MK801-induced locomotion. As such, the ability of the D2/3 agonists, quinelorane and quinpirole, and the partial D3 agonist, BP897, to attenuate the locomotor activating effects of MK801 was examined in mice. MK801 (0.1-1.0 mg/kg) produced a biphasic effect on total distance traveled with the intermediate dose of 0.3 mg/kg producing the greatest stimulation. The increase in MK801-induced total distance traveled was attenuated by the coadministration of quinelorane and quinpirole at doses that alone had no effect on activity. Similarly, the partial D3 agonist, BP897, blocked the effects of MK801. The D3-preferring antagonist, nafadotride, reversed the attenuation of quinelorane and partially reversed the attenuation of quinpirole. The D2-preferring antagonist, eticlopride, reversed the attenuating effects of quinelorane, but was not effective against quinpirole. Nafadotride and eticlopride were ineffective against the attenuating effects of BP897 on MK801-induced locomotion. Because BP897 is a partial agonist it was tested against quinelorane/MK801 and quinpirole/MK801 combinations. BP897 reversed the attenuating effects of quinelorane, but not those of quinpirole on MK801's effects. These results demonstrate that the DA system, through D2/3 receptor activation, modulates the locomotor activating effects produced by noncompetitive NMDA receptor blockade.
Cook
Charles D
CD
Department of Pharmacology and Toxicology, Virginia Commonwealth University, 410 North 12th Street, PO BOX 980613, Richmond, VA 23298-0613, USA. ccook@hsc.vcu.edu
Newman
Jennifer L
JL
Winfree
Jennifer C
JC
Beardsley
Patrick M
PM
D000818:Animals; D016291:Dizocilpine Maleate / Q000037:antagonists & inhibitors* / Q000494:pharmacology*; D018491:Dopamine Agonists / Q000494:pharmacology*; D018492:Dopamine Antagonists / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology*; D008297:Male; D051379:Mice; D009043:Motor Activity / Q000187:drug effects*; D009281:Naphthalenes / Q000494:pharmacology; D010879:Piperazines / Q000494:pharmacology; D011759:Pyrrolidines / Q000494:pharmacology; D011804:Quinolines / Q000037:antagonists & inhibitors / Q000494:pharmacology; D019257:Quinpirole / Q000037:antagonists & inhibitors / Q000494:pharmacology; D017448:Receptors, Dopamine D2 / Q000819:agonists*; D050637:Receptors, Dopamine D3; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors*; D012457:Salicylamides / Q000494:pharmacology; D013239:Stereotyped Behavior / Q000187:drug effects
D018491:Dopamine Agonists; D018492:Dopamine Antagonists; C493594:Drd3 protein, mouse; D018691:Excitatory Amino Acid Antagonists; D009281:Naphthalenes; D010879:Piperazines; D011759:Pyrrolidines; D011804:Quinolines; D017448:Receptors, Dopamine D2; D050637:Receptors, Dopamine D3; D016194:Receptors, N-Methyl-D-Aspartate; D012457:Salicylamides; D019257:Quinpirole; C120565:BP 897; D016291:Dizocilpine Maleate; C045989:eticlopride; C097285:nafadotride; C047726:quinelorane