Haloperidol-induced morphological changes in striatum are associated with glutamate synapses.
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 these 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 in striatal perforated synapses, but not the haloperidol-induced increase in DA D2 receptors. Injection of 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 glutamate synapses play a role in the motoric side effects that are observed with typical neuroleptic drug treatment.
Meshul
C K
CK
Research Service, VA Medical Center, Portland, OR 97201.
Stallbaumer
R K
RK
Taylor
B
B
Janowsky
A
A
D000818:Animals; D001552:Benzazepines / Q000494:pharmacology; D016291:Dizocilpine Maleate / Q000008:administration & dosage / Q000494:pharmacology; D018698:Glutamic Acid / Q000502:physiology*; D006220:Haloperidol / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D007150:Immunohistochemistry; D007267:Injections; D008297:Male; D008854:Microscopy, Electron; D017072:Neostriatum / Q000033:anatomy & histology* / Q000187:drug effects / Q000648:ultrastructure; D011869:Radioligand Assay; D051381:Rats; D017207:Rats, Sprague-Dawley; D017447:Receptors, Dopamine D1 / Q000187:drug effects; D017448:Receptors, Dopamine D2 / Q000187:drug effects; D016194:Receptors, N-Methyl-D-Aspartate / Q000037:antagonists & inhibitors / Q000187:drug effects; D013569:Synapses / Q000187:drug effects*
D001552:Benzazepines; D017447:Receptors, Dopamine D1; D017448:Receptors, Dopamine D2; D016194:Receptors, N-Methyl-D-Aspartate; D018698:Glutamic Acid; D016291:Dizocilpine Maleate; D006220:Haloperidol