HALOPERIDOL-INDUCED MORPHOLOGICAL-CHANGES IN STRIATUM ARE ASSOCIATED WITH GLUTAMATE SYNAPSES

Sub-chronic treatment with the typical neuroleptic, haloperidol (0.5 m g/kg/d, s.c.), but not the atypical neuroleptic, clozapine (35 mg/kg/d ay, s.c.) causes an increase in synapses containing a perforated posts ynaptic density (referred to as 'perforated' synapses) and in dopamine (DA) D-2 receptors within the caudate nucleus [46]. To determine if t hese perforated synapses are glutamatergic, we systemically co-adminis tered MK-801 (0.3 mg/kg/day for 2 weeks), a non-competitive antagonist at the N-methyl-D-aspartate (NMDA) receptor-associated ion channel, a nd haloperidol. MK-801 blocked the haloperidol-induced increase in str iatal perforated synapses, but not the haloperidol-induced increase in DA D-2 receptors. Injection of MK-801 into the striatum also attenuat ed the haloperidol-induced increase in perforated synapses. Post-embed ding immune-gold electron microscopy using antibodies to glutamate ind icated that the gold particles were localized within striatal presynap tic nerve terminals that make contact with perforated postsynaptic den sities. These findings support the hypothesis that the haloperidol-ind uced increase in perforated synapses is regulated by the NMDA subtype of excitatory glutamate receptor. The increase in perforated synapses following administration of haloperidol, which is associated with a hi gh incidence of extrapyramidal side effects (EPS), and the lack of a s ynaptic change following administration of clozapine, known to have a low frequency of EPS, suggests that glutamate synapses play a role in the motoric side effects that are observed with typical neuroleptic dr ug treatment.