Haloperidol-induced morphological changes in striatum are associated with glutamate synapses

Charles K. Meshul, Regina K. Stallbaumer, Barry Taylor, Aaron Janowsky

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Sub-chronic treatment with the typical neuroleptic, haloperidol (0.5 mg/kg/d, s.c.), but not the atypical neuroleptic, clozapine (35 mg/kg/day, s.c.), causes an increase in synapses containing a perforated postsynaptic density (referred to as 'perforated' synapses) and in dopamine (DA) D2 receptors within the caudate nucleus [46]. To determine if there perforated synapses are glutamatergic, we systemically co-administered 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, and haloperidol. MK-801 blocked the haloperidol-induced increase into the striatal also attenuated the haloperidol-induced increase in perforated synapses. Post-embedding immuno-gold MK-801 into the striatum also attenuated the haloperidol-induced increase in perforated synapses. Post-embedding immuno-gold electron microscopy using antibodies to glutamate indicated that the gold particles were localized within striatal presynaptic nerve terminals that make contact with perforated postsynaptic densities. These findings support the hypothesis that the haloperidol-induced 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 high incidence of extrapyramidal side effects (EPS), and the lack of a synaptic change following administration of clozapine, known to have a low frequency of EPS, suggests that glutanate synapses play a role in the motoric side effects that are observed with typical neuroleptic drug treatment.

Original languageEnglish (US)
Pages (from-to)181-195
Number of pages15
JournalBrain Research
Issue number2
Publication statusPublished - Jun 20 1994



  • Electron microscopy
  • Extrapyramidal side effect
  • Glutamate antagonist
  • Glutamate immunocytochemistry
  • Perforated synapse

ASJC Scopus subject areas

  • Developmental Biology
  • Molecular Biology
  • Clinical Neurology
  • Neuroscience(all)

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