Nicotine Dependence Reveals Distinct Responses from Neurons and Their Resident Nicotinic Receptors in Medial Habenula

Abstract

Nicotinic acetylcholine receptors (nAChRs) are the molecular target of nicotine. nAChRs in the medial habenula (MHb) have recently been shown to play a role in nicotine dependence, but it is not clear which nAChR subtypes or MHb neuron types are most important. To identify MHb nAChRs and/or cell types that play a role in nicotine dependence, we studied these receptors and cells with brain slice electrophysiology using both acute and chronic nicotine application. Cells in the ventroinferior (MHbVI) and ventrolateral MHb (MHbVL) subregions expressed functional nAChRs with different pharmacology. Further, application of nicotine to cells in these subregions led to different action potential firing patterns. The latter result was correlated with a differing ability of nicotine to induce nAChR desensitization. Chronic nicotine caused functional upregulation of nAChRs selectively in MHbVI cells, but did not change nAChR function in MHbVL. Importantly, firing responses were also differentially altered in these subregions following chronic nicotine. MHbVI neurons treated chronically with nicotine exhibited enhanced basal pacemaker firing but a blunted nicotine-induced firing response. MHbVL neurons did not change their firing properties in response to chronic nicotine. Together, these results suggest that acute and chronic nicotine differentially affect nAChR function and output of cells in MHb subregions. Because the MHb extensively innervates the interpeduncular nucleus, an area critical for both affective and somatic signs of withdrawal, these results could reflect some of the neurophysiological changes thought to occur in the MHb to the interpeduncular nucleus circuit in human smokers.

Habenula cholinergic neurons regulate anxiety during nicotine withdrawal via nicotinic acetylcholine receptors

“…Regardless, these data indicate that heightened anxiety during nicotine withdrawal is mediated by increased α6/α4β2* nAChR signaling in MHb cholinergic neurons. Interestingly, the medial ventral MHb where upregulation of nAChRs occurs in nicotine-dependent mice projects to the ventral IPN including the IPN intermediate, which is activated during nicotine withdrawal, triggering anxiety (Grieder et al, 2014, Shih et al, 2014, Shih et al, 2015, Zhao-Shea et al, 2015). …”

Anxiety and Nicotine Dependence: Emerging Role of the Habenulo-Interpeduncular Axis

“…Long-term nicotine exposure causes an up-regulation of nAChR signaling, underlying the development of nicotine dependence and withdrawal [43–45]. Within the mHb-IPN circuit, nicotine differentially affects nAChR function and output of cells in specific sub-regions of the vmHb [46]. In particular, up-regulated α6/α4 nAChR signaling in mHb cholinergic/glutamatergic neurons underlies heightened anxiety during nicotine withdrawal (Figure 3) [31].…”

Development of photoactivatable drugs enables nicotinic optopharmacology

“…For pharmacological experiments involving animal models, sample sizes were selected based on prior similar studies 12,15 , and mice of the appropriate age (8-24 wks) were randomly (informal randomization) chosen for assignment to specific experimental groups. For some studies involving recordings from neurons derived from mice treated with nicotine or control drinking water, the experimenter was blind to the treatment during data collection.…”

“…Chronic nicotine treatment results in up-regulation of nAChR function in MHb neurons 15 , including ChAT(+) neurons ( Supplementary Fig. 4a-d), but it is unknown whether this up-regulation reflects a numerical increase in surface receptors or a shift in nAChR sensitivity.…”

“…Using a restricted field stop aperture ( Supplementary Fig. 2k), we constrained the light flash to different ventral MHb subregions 15 during current clamp recordings from neurons in the VI subregion (Fig. 1k).…”