Article

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

Research Service, VA Medical Center, Portland, OR 97201.
Brain Research (Impact Factor: 2.84). 07/1994; 648(2):181-95. DOI: 10.1016/0006-8993(94)91117-7
Source: PubMed

ABSTRACT

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.

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    • "K. Meshul and M. J. Low, unpublished observations). Using transgenic mice expressing enhanced GFP (EGFP) under control of the Pomc promoter (Cowley et al., 2001), axon terminals from POMC neurons were identified by pre-embedding immunohistochemistry and electron microscopy following the methods of Meshul and McGinty (Meshul et al., 1994, 1999; Meshul and McGinty, 2000). POMC neurons were identified using primary antisera to GFP or ACTH and visualized using biotinylated secondary antibodies and an avidin-coupled DAB reaction product, whereas GABA and glutamate were detected at EGFP- and ACTH-positive synaptic terminals with immunogold-coupled antibodies. "
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    • "The differences between the experimental groups were analyzed using the Student's t-test. The specificity of the immunolabeling for the glutamate antibody was previously established by incubating the antibody overnight with 3 mM glutamate (Meshul et al., 1994). This mixture was then applied to the sections as detailed above, with the final results showing a lack of tissue immunolabeling. "
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    Preview · Article · Dec 2005 · Synapse
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    • "The differences between treatment groups were analyzed using a one-way ANOVA and significant main effects were further characterized using the Fisher post-hoc test for comparison of multiple means. The specificity of the immunolabeling for the glutamate antibody was previously established by incubating the antibody overnight with 3 mM glutamate (Meshul et al., 1994). This mixture was then applied to the sections as detailed above. "
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