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

Area of Science:

• Neuroscience
• Pharmacology
• Cell Biology

Background:

• Typical neuroleptics, such as haloperidol, increase dopamine D2 receptors and perforated synapses in the caudate nucleus.
• Atypical neuroleptics, like clozapine, do not induce these synaptic changes.
• Perforated synapses are implicated in synaptic plasticity and neuronal communication.

Purpose of the Study:

• To investigate whether the haloperidol-induced increase in perforated synapses is mediated by glutamatergic pathways.
• To explore the role of N-methyl-D-aspartate (NMDA) receptors in this synaptic modification.
• To determine the potential link between glutamate synapses and neuroleptic-induced motor side effects.

Main Methods:

• Sub-chronic administration of haloperidol and clozapine in rodents.
• Systemic and intrastriatal co-administration of MK-801, an NMDA receptor antagonist, with haloperidol.
• Post-embedding immuno-gold electron microscopy to detect glutamate localization.

Main Results:

• MK-801 blocked the haloperidol-induced increase in striatal perforated synapses but not the increase in dopamine D2 receptors.
• Intrastriatal MK-801 injections also attenuated the increase in perforated synapses.
• Glutamate was localized in presynaptic terminals contacting perforated postsynaptic densities.

Conclusions:

• The haloperidol-induced increase in perforated synapses is regulated by NMDA receptor activity.
• Glutamatergic synapses likely play a role in the motor side effects associated with typical neuroleptic treatment.
• These findings differentiate the mechanisms of typical and atypical neuroleptics regarding synaptic changes and side effect profiles.