Does MK-801 discrimination constitute an animal model of schizophrenia useful for detecting atypical antipsychotics?

Two groups of female Wistar rats were trained to discriminate two doses (0.075 and 0.0375 mg/kg) of the noncompetitive NMDA antagonist MK-801 (dizocilpine) in a food-rewarded operant FR30 drug discrimination task. The atypical neuroleptic clozapine (2-6 mg/kg) produced only minimal antagonism (max. 32%) of the MK-801 cue at either training dose, and the "antagonist" effects were not clearly dose related. Furthermore, in the 0.075 mg/kg trained animals clozapine at 3 mg/kg failed to shift the MK-801 dose-response curve to the right. The alpha(1)-adrenoceptor antagonist prazosin (1-8 mg/kg) was also tested for antagonism of the 0.0375 mg/kg MK-801 cue, and again, only partial antagonism was seen (maximum 36%). Recently, it was suggested [4] that as the discriminative stimulus produced by MK-801 (0.075 mg/kg) was fully antagonized by clozapine at 3 mg/kg, but not by the typical neuroleptic haloperidol, this assay may be a useful screen for detecting atypical neuroleptics. It would seem, however, that this is not necessarily the case, and that the MK-801 discriminative cue may not be psychotomimetic. However, as this was a food rewarded rather than an avoidance paradigm that was used in the prior study [4], it may be that the drug discrimination procedure itself is a critical factor, although this hypothesis requires empirical testing. (C) 1999 Elsevier Science Inc.