Enhanced locomotor stimulation by NMDA receptor antagonists in alcohol-sensitive ANT rats

The ability of the antagonists for the N-methyl-D-aspartate (NMDA) type of glutamate receptor to modulate locomotor activity were compared in alcohol- sensitive (or alcohol-nontolerant, ANT) and alcohol-insensitive (or alcohol -tolerant, AT) rat lines. Both rat lines showed altered locomotor activity after acute injections of a competitive antagonist (LY235959), a glycine-si te antagonist (L-701,324), or noncompetitive antagonists [MK-801, phencycli dine (PCP), and ketamine] of the NMDA receptor, MK-801 at 0.5 mg/kg caused a strong increase in horizontal activity in both rat lines, the effect bein g significantly greater in the ANT rats. There was a subpopulation among AT rats that was almost completely unresponsive to MK-801. This insensitivity to MK-801 correlated with the lack of c-fos induction in the retrosplenial and cingulate cortices. Fos immunoreactive cells in these brain regions af ter MK-801 treatment were more numerous in ANT than AT rats, although c-fos induction in the inferior olivary nucleus was similar in all animals after MK-801. The ANT rats showed greater locomotor stimulation also after ketam ine and LY235959. while stimulation induced by PCP and depression induced b y L-701,324 did not differ between the rat lines. The data suggest that alt ered NMDA receptor-mediated processes may correlate with differences in inn ate alcohol sensitivity in the ANT/AT rat model. (C) 2001 Elsevier Science Inc. All rights reserved.