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

The lateral habenula (LHb) balances reward and aversion by opposing activation of brain reward nuclei and is involved in the inhibition of responding for cocaine in a model of impulsive behavior. Previously, we reported that the suppression of cocaine seeking was prevented by LHb inactivation or nonselective antagonism of LHb mAChRs. Here, we investigate mAChR subtypes mediating the effects of endogenous acetylcholine in this model of impulsive drug seeking and define cellular mechanisms in which mAChRs alter LHb neuron activity. Using in vitro electrophysiology, we find that LHb neurons are depolarized or hyperpolarized by the cholinergic agonists oxotremorine-M (Oxo-M) and carbachol (CCh), and that mAChRs inhibit synaptic GABA and glutamatergic inputs to these cells similarly in male and female rats. Synaptic effects of CCh were blocked by the M-2-mAChR (M2R) antagonist AFDX-116 and not by pirenzepine, an M-1-mAChR (M1R) antagonist. Oxo-Mmediated depolarizing currents were also blocked by AFDX-116. Although M2R activation inhibited excitatory and inhibitory inputs to LHb neurons, the effect on excitation was greater, suggesting a shift in excitatory-inhibitory balance toward net inhibition. Activation of VTA inhibitory inputs to LHb neurons, via channelrhodopsin-2 expression, evoked IPSCs that were inhibited by M(2)Rs. Finally, we measured LHb-dependent operant response inhibition for cocaine and found it impaired by antagonism of M(2)Rs, and not M(1)Rs. In summary, we show that a cholinergic signal to LHb and activation of M,Its are critical to enable inhibition of responding for cocaine, and we define cellular mechanisms through which this may occur.

Automated summary

The lateral habenula (LHb) balances reward and aversion by opposing activation of brain reward nuclei and is involved in the inhibition of responding for cocaine in a model of impulsive behavior. Activation of cholinergic signal to LHb and M(2)Rs is critical for the inhibition of responding for cocaine, and the cellular mechanisms underlying this effect have been defined.