Lateral habenula M2 muscarinic receptor control of neuronal activity and cocaine seeking behavior

Abstract

The lateral habenula (LHb) plays a central role in balancing reward and aversion by opposing the contributions of brain reward nuclei. Using a rat cocaine self-administration model, we previously found that LHb inhibition or non-selective blockade of LHb muscarinic acetylcholine receptors (mAChRs) led to persistent cocaine seeking despite its signaled unavailability. As understanding roles for the LHb and cholinergic signaling in behavioral control is important to psychiatric illness and addiction, we examine how mAChRs act on LHb neurons using in vitro electrophysiology. We find that different groups of LHb neurons are depolarized or hyperpolarized by the cholinergic agonist carbachol (CCh), and that CCh could inhibit GABAergic and glutamatergic synaptic inputs to these cells. Presynaptic CCh effects were reversed by the M2 mAChR (M2R) antagonist AFDX-116, but not by pirenzepine, an M1R antagonist. Contemporaneous measurement of CCh effects on synaptic inhibition and excitation in LHb neurons showed a smaller effect on inhibition, suggesting a net shift in synaptic integration toward greater inhibition by mAChRs. Synaptic currents elicited by light-activation of ventral tegmental area (VTA) axons in the LHb, following channelrhodopsin-2 transfection of VTA, were also inhibited by M2Rs, suggesting the VTA as at least one M2R-sensitive LHb afferent. Finally, Go-NoGo cocaine seeking studies showed that blockade of LHb M2Rs, and not M1Rs, triggered continued cocaine seeking. These data identify LHb M2Rs as a potential control point of LHb function that enables withholding responses for cocaine and define cellular mechanisms through which mAChRs modulate LHb activity.

Inhibition Within the Lateral Habenula—Implications for Affective Disorders

“…While the role of cholinergic signalling within the adjacent medial habenula in nicotine withdrawal and drug addiction has been relatively well-studied in recent years (Lee et al, 2019), a specific role for cholinergic signalling within the LHb has also recently started to become apparent (Zapata et al, 2017;Wolfe et al, 2021). In a manner similar to Kappa opioid receptor activation, cholinergic receptor activation appears to differentially excite or inhibit different populations of LHb neurons, while also suppressing both excitatory and inhibitory synaptic inputs; although this effect appears to more strongly suppress excitatory input hence resulting in an overall net shift towards increased inhibition (Wolfe et al, 2021).…”