EFFECTS OF SUBCHRONIC CLOZAPINE AND HALOPERIDOL ON STRIATAL GLUTAMATERGIC SYNAPSES

Subchronic treatment with haloperidol increases the number of asymmetr ic glutamate synapses associated with a perforated postsynaptic densit y in the striatum. To characterize these synaptic changes further, the effects of subchronic (28 days) administration of an atypical antipsy chotic, clozapine (30 mg/kg, s.c.), or a typical antipsychotic, halope ridol (0.5 mg/kg, s.c.), on the binding of [H-3]MK-801 to the NMDA rec eptor-linked ion channel complex and on the in situ hybridization of r iboprobes for NMDAR2A and 2B subunits and splice variants of the NMDAR 1 subunit were examined in striatal preparations from rats. The densit y of striatal glutamate immunogold labeling associated with nerve term inals of all asymmetric synapses and the immunoreactivity of those asy mmetric synapses associated with a perforated postsynaptic density wer e also examined by electron microscopy. Subchronic neuroleptic adminis tration had no effect on [H-3] MK-801 binding to striatal membrane pre parations. Both drugs increased glutamate immunogold labeling in nerve terminals of all asymmetric synapses, but only haloperidol increased the density of glutamate immunoreactivity within nerve terminals of as ymmetric synapses containing a perforated postsynaptic density. Wherea s subchronic administration of clozapine, but not haloperidol, resulte d in a significant increase in the hybridization of a riboprobe that l abels all splice variants of the NMDAR1 subunit, both drugs significan tly decreased the abundance of NMDAR1 subunit mRNA containing a 63-bas e insert. Neither drug altered mRNA for the 2A subunit, but clozapine significantly increased hybridization of a probe for the 2B subunit. T he data suggest that some neurofeptic effects may be mediated by gluta matergic systems and that typical and atypical antipsychotics can have varying effects on the density of glutamate in presynaptic terminals and on the expression of specific NMDA receptor splice variant mRNAs. Alternatively, NMDAR1 subunit splice variants may differentially respo nd to interactions with glutamate.