Dopamine-mediated MK-801-induced elevation in food-based extinction responding in rats and associated changes in region-specific phosphorylated ERK

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