Haloperidol blocks voltage-activated Ca2+ channels in hippocampal neurones

Area of Science:

• Neuropharmacology
• Molecular Biology
• Cell Physiology

Background:

• Antipsychotic medications like haloperidol are crucial for treating neurological and psychiatric disorders.
• Understanding the precise molecular targets of these drugs is essential for optimizing their therapeutic use and minimizing side effects.
• Voltage-gated calcium channels play critical roles in neuronal function, including neurotransmitter release and excitability.

Purpose of the Study:

• To investigate the calcium (Ca2+) channel antagonist action of the antipsychotic drug haloperidol.
• To determine the selectivity and potency of haloperidol's effects on neuronal Ca2+ channels.
• To elucidate the mechanism by which haloperidol modulates Ca2+ channel activity.

Main Methods:

• Utilized Fura-2 loaded cultured rat hippocampal neurons to measure intracellular free Ca2+ ([Ca2+]i) changes.
• Employed whole-cell patch-clamp electrophysiology in voltage-clamped mouse hippocampal neurons to record Ba2+ currents (IBa).
• Assessed dose-dependent effects of haloperidol and characterized the reversibility and voltage-dependence of its action.

Main Results:

• Haloperidol dose-dependently attenuated K+-evoked increases in [Ca2+]i in rat neurons (IC50 = 7.8 ± 0.5 µM).
• Haloperidol reduced whole-cell IBa in mouse neurons with an IC50 of 15.6 ± 1.1 µM.
• The block of IBa by haloperidol was rapid, fully reversible, and more pronounced at depolarized membrane potentials.

Conclusions:

• Haloperidol exhibits non-selective blockade of neuronal voltage-gated Ca2+ channels.
• These effects occur at micromolar concentrations, suggesting a direct interaction with the channels.
• The findings provide insights into the potential mechanisms underlying haloperidol's therapeutic and side effects related to neuronal excitability.