Muscarinic Acetylcholine M₂ Receptors Regulate Lateral Habenula Neuron Activity and Control Cocaine Seeking Behavior

Area of Science:

• Neuroscience
• Molecular Biology
• Behavioral Science

Background:

• The lateral habenula (LHb) plays a crucial role in balancing reward and aversion, influencing motivated behaviors and impulse control.
• Dysfunction in the LHb is linked to psychiatric disorders and substance use disorders, including cocaine addiction.
• Previous research indicated that muscarinic acetylcholine receptors (mAChRs) in the LHb are involved in suppressing cocaine seeking.

Purpose of the Study:

• To investigate the specific subtypes of mAChRs that mediate the effects of acetylcholine in the LHb during impulsive cocaine seeking.
• To define the cellular mechanisms by which mAChRs alter LHb neuron activity.
• To determine the necessity of M2-mAChRs for LHb-dependent inhibition of cocaine seeking.

Main Methods:

• In vitro electrophysiology was used to examine the effects of cholinergic agonists (oxotremorine-M and carbachol) on LHb neuron activity and synaptic inputs.
• Specific mAChR subtype antagonists (AFDX-116 for M2R, pirenzepine for M1R) were employed to identify receptor involvement.
• Channelrhodopsin-2 was used to activate VTA inhibitory inputs to LHb neurons.
• LHb-dependent operant response inhibition for cocaine was measured in the presence of mAChR antagonists.

Main Results:

• Activation of mAChRs in LHb neurons modulated both excitatory and inhibitory synaptic inputs, with a greater effect on excitation, leading to net inhibition.
• Synaptic effects of carbachol and depolarizing currents induced by oxotremorine-M were primarily mediated by M2-mAChRs.
• Antagonism of M2-mAChRs, but not M1-mAChRs, impaired LHb-dependent inhibition of responding for cocaine.
• M2R activation inhibited inhibitory postsynaptic currents evoked by VTA inputs to LHb neurons.

Conclusions:

• Cholinergic signaling to the LHb and subsequent M2-mAChR activation are critical for enabling the inhibition of cocaine seeking.
• M2-mAChRs alter LHb neuron activity by modulating synaptic inputs, shifting the excitatory-inhibitory balance towards inhibition.
• LHb M2-mAChRs represent a potential therapeutic target for treating substance use disorders, particularly cocaine addiction.