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Updated: Mar 15, 2026

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Haloperidol Selectively Remodels Striatal Indirect Pathway Circuits.

Luke E Sebel1, Steven M Graves1, C Savio Chan1

  • 1Department of Physiology, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA.

Neuropsychopharmacology : Official Publication of the American College of Neuropsychopharmacology
|September 1, 2016
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Summary

Typical antipsychotics, like haloperidol, take weeks to work by altering dopamine D2 receptor pathways in the brain. This study reveals slow circuit remodeling in spiny projection neurons (SPNs) that explains the delayed therapeutic effect.

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Area of Science:

  • Neuroscience
  • Pharmacology
  • Cellular Biology

Background:

  • Typical antipsychotics target dopamine D2 receptors to treat schizophrenia's positive symptoms.
  • The therapeutic latency of weeks for these drugs remains poorly understood.

Purpose of the Study:

  • To investigate the cellular and synaptic adaptations underlying the delayed therapeutic effects of antipsychotics.
  • To elucidate the role of spiny projection neurons (SPNs) in antipsychotic drug action.

Main Methods:

  • Ex vivo electrophysiology and anatomical analysis in transgenic mouse brain slices.
  • Chronic treatment with haloperidol and perphenazine.

Main Results:

  • Two weeks of haloperidol induced intrinsic and synaptic adaptations in indirect pathway SPNs (iSPNs).
  • Adaptations included reduced excitability and pruning of glutamatergic synapses.
  • Strengthening of a subset of excitatory corticostriatal synapses was also observed.

Conclusions:

  • Chronic antipsychotic treatment induces slow, homeostatic, and specific synaptic remodeling in iSPNs.
  • This remodeling of corticostriatal circuitry likely mediates the delayed therapeutic effects of neuroleptics.