Nicotine-induced dopamine release in the nucleus accumbens is inhibited by the novel AMPA antagonist ZK200775 and the NMDA antagonist CGP39551.
BACKGROUND
Accumulated data suggest that N-methyl-D-aspartate (NMDA) receptors are involved in the reinforcing properties of nicotine. However, less is known about the role of alpha-amino-3-hydroxy-5-methyl-4-isoxazoleproprionate (AMPA) receptors in this context.


OBJECTIVE
To study the effect of the novel systemically administered AMPA receptor antagonist ZK200775 ([1,2,3,4-tetrahydro-7-morpholinyl-2,3-dioxo-6-(fluoromethyl) quinoxalin-1-yl] methylphosphonate) on nicotine-induced dopamine (DA) release in the nucleus accumbens (NAcc) and nicotine-stimulated locomotor activity (LMA) and particularly the relative role of NMDA and AMPA receptors in nicotine-stimulated DA release and LMA.


METHODS
Male Wistar rats were administered ZK200775, CGP39551 or NBQX 30 min prior to nicotine and DA release and LMA was measured using in vivo microdialysis or photocell equipped activity boxes. Glutamate-produced neurotoxicity in cultured brain cells and binding assays were performed to determine the glutamate receptor subtype selectivity and affinity to nicotine receptors of ZK200775, respectively.


RESULTS
ZK200775 (3.0 but not 1.5 or 6.0 mg/kg) significantly decreased the nicotine-induced (0.6 mg/kg) DA release in the NAcc and nicotine-stimulated LMA. ZK200775 (1.5, 3.0, 6.0 mg/kg) alone influenced neither DA release nor LMA. ZK200775 showed 34-fold selectivity for AMPA receptors compared to NMDA receptors and no affinity to nicotine receptors. The NMDA receptor antagonist CGP39551 (10 mg/kg) significantly decreased both the nicotine-induced DA release and nicotine-stimulated LMA whereas the AMPA receptor antagonist NBQX (10 mg/kg) had no effect. Notably, CGP39551 and ZK200775 (3.0 mg/kg) displayed a different pattern in inhibition of nicotine-induced DA release.


CONCLUSIONS
Both NMDA- and AMPA receptors are involved in nicotine's dependence-producing properties, although in a spatiotemporally differential manner.
Kosowski
Alexander R
AR
Department of Clinical Neuroscience, Division of Drug Dependence Research, Karolinska Institutet, Building L4:00, 171 76, Stockholm, Sweden.
Cebers
Gvido
G
Cebere
Aleta
A
Swanhagen
Ann-Charlott
AC
Liljequist
Sture
S
D015763:2-Amino-5-phosphonovalerate / Q000031:analogs & derivatives* / Q000494:pharmacology*; D000818:Animals; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D002531:Cerebellum / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D004298:Dopamine / Q000096:biosynthesis*; D008297:Male; D017551:Microdialysis; D009043:Motor Activity / Q000187:drug effects; D009538:Nicotine / Q000494:pharmacology*; D009714:Nucleus Accumbens / Q000187:drug effects* / Q000378:metabolism; D063065:Organophosphonates / Q000494:pharmacology*; D011810:Quinoxalines / Q000494:pharmacology*; D011869:Radioligand Assay; D051381:Rats; D017207:Rats, Sprague-Dawley; D017208:Rats, Wistar; D018091:Receptors, AMPA / Q000037:antagonists & inhibitors*; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors*; D011978:Receptors, Nicotinic / Q000187:drug effects / Q000378:metabolism; D013997:Time Factors
D063065:Organophosphonates; D011810:Quinoxalines; D018091:Receptors, AMPA; D016194:Receptors, N-Methyl-D-Aspartate; D011978:Receptors, Nicotinic; C064540:CGP 39551; D009538:Nicotine; D015763:2-Amino-5-phosphonovalerate; C114423:ZK 200775; D004298:Dopamine