Dopamine-mediated MK-801-induced elevation in food-based extinction responding in rats and associated changes in region-specific phosphorylated ERK.
BACKGROUND
The current study examined the effect of the noncompetitive N-methyl-D: -aspartate (NMDA) receptor antagonist (+)-5-methyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5,10-imine maleate (MK-801) on the extinction of food-based operant responding.


OBJECTIVE
Experiments were carried out to determine (1) the nature of the elevated responding when rats were under the influence of MK-801, (2) the effect of combined and separate D1- and D2-like dopaminergic antagonists (SCH 23390 and haloperidol) on this MK-801-induced behavioral effect and (3) the neural correlates on and off MK-801 using immunohistochemical localization of the phosphorylated forms of the extracellular signal-regulated kinase-1 and -2.


METHODS
Male Long Evans rats were trained using operant conditioning procedures then treated with the various compounds, and resultant extinction pressing was measured.


RESULTS
A moderate dose (0.1 mg/kg) of MK-801 produced a persistent, elevated lever pressing throughout the entire 30-min extinction session. When animals were pretreated with combined or separate dopamine (DA) D1- or D2-like receptor antagonists, extinction responding under MK-801 was significantly reduced. Examination of pERK1/2 labeling in MK-801-treated animals showed reduced staining in the infralimbic and piriform cortices and elevated staining in the nucleus accumbens compared with controls.


CONCLUSIONS
These data show that MK-801 elevates food-based extinction behavior that can be reduced by DA receptor antagonists. The disrupted extinction behavior may be mediated, in part, by disinhibition of corticostriatal circuits.
Holahan
Matthew R
MR
Department of Psychology, Institute of Neuroscience, Carleton University, 1125 Colonel By Drive, 337 Life Science Research Building, Ottawa, ON, K1S 5B6, Canada. matthew_holahan@carleton.ca
Clarke
Melanie J
MJ
Hines
Delaney D
DD
D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D003216:Conditioning, Operant / Q000187:drug effects; D016291:Dizocilpine Maleate / Q000494:pharmacology*; D004298:Dopamine / Q000378:metabolism*; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology*; D005108:Extinction, Psychological / Q000187:drug effects*; D005502:Food; D008297:Male; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D051381:Rats; D020318:Rats, Long-Evans
D018691:Excitatory Amino Acid Antagonists; D016291:Dizocilpine Maleate; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D004298:Dopamine