Ivermectin increases striatal cholinergic activity to facilitate dopamine terminal function

Area of Science:

• Neuroscience
• Pharmacology

Background:

• Ivermectin (IVM) is an antiparasitic drug known to affect invertebrate ion channels.
• IVM also modulates vertebrate ion channels and shows preclinical promise for Parkinson's disease treatment, potentially by enhancing L-DOPA therapy.
• The precise mechanisms by which IVM influences dopamine terminal function are not fully understood.

Purpose of the Study:

• To investigate the pharmacological effects of Ivermectin on dopamine terminal function.
• To determine the role of purinergic P2X4 and nicotinic acetylcholine receptors in mediating IVM's effects on dopamine release.
• To elucidate how IVM influences dopamine release in the context of L-DOPA treatment.

Main Methods:

• Electrochemical detection was used to measure dopamine release in the dorsal striatum.
• Experiments involved inactivating P2X4 receptors and antagonizing nicotinic receptors to assess their role in IVM's effects.
• Cholinergic interneuron firing was monitored to evaluate IVM's impact on neuronal activity.
• Co-application of L-DOPA and IVM was performed to assess combined effects on dopamine release.

Main Results:

• Ivermectin significantly enhanced dopamine release in the dorsal striatum.
• IVM's effects on dopamine release were not dependent on P2X4 receptors but were blocked by nicotinic receptor antagonism.
• IVM enhanced striatal cholinergic interneuron firing.
• Combined L-DOPA and IVM treatment increased dopamine release, with a shift suggesting enhanced terminal excitability rather than increased vesicular content.

Conclusions:

• Ivermectin increases striatal dopamine release primarily by enhancing cholinergic activity that affects dopamine terminals.
• The mechanism involves increased terminal excitability rather than alterations in vesicular dopamine content.
• These findings highlight a novel role for IVM in modulating dopaminergic neurotransmission, with implications for Parkinson's disease research.