Nicotine regulates activity of lateral habenula neurons via presynaptic and postsynaptic mechanisms

Abstract

There is much interest in brain regions that drive nicotine intake in smokers. Interestingly, both the rewarding and aversive effects of nicotine are probably critical for sustaining nicotine addiction. The medial and lateral habenular (LHb) nuclei play important roles in processing aversion, and recent work has focused on the critical involvement of the LHb in encoding and responding to aversive stimuli. Several neurotransmitter systems are implicated in nicotine’s actions, but very little is known about how nicotinic acetylcholine receptors (nAChRs) regulate LHb activity. Here we report in brain slices that activation of nAChRs depolarizes LHb cells and robustly increases firing, and also potentiates glutamate release in LHb. These effects were blocked by selective antagonists of α6-containing (α6*) nAChRs, and were absent in α6*-nAChR knockout mice. In addition, nicotine activates GABAergic inputs to LHb via α4β2-nAChRs, at lower concentrations but with more rapid desensitization relative to α6*-nAChRs. These results demonstrate the existence of diverse functional nAChR subtypes at presynaptic and postsynaptic sites in LHb, through which nicotine could facilitate or inhibit LHb neuronal activity and thus contribute to nicotine aversion or reward.

Acute and Chronic Nicotine Exposures Differentially Affect Central Serotonin 2A Receptor Function: Focus on the Lateral Habenula

“…Nicotine increases LHb neuron activity when acutely administered in vivo [26], depolarizing directly LHb neurons via postsynaptic α6-containing (α6*) nAChRs but also modulating GABA and GLU input onto LHb neurons [40]. The involvement of 5-HT inputs on the nicotine effect in the LHb is also probable.…”

“…through the lateral tail vein 640 µg/kg cumulative doses of TCB-2 or its vehicle. A total of eight doses (5,5,10,20,40,80,160 and 320 µg/kg), each dissolved in 100 µL of the vehicle were given at two-minute intervals.…”

The interaction of the Chrna5 D398N variant with developmental nicotine exposure

“…Changes in habenular nicotinic responses were not significant when broken out into components sensitive to lower and higher concentrations of ACh (LS and HS, respectively). Although current methods evaluate presynaptic responses, recently published work shows nicotine activates GABAergic inputs to the LHb, which then excite GABAergic neurons in the rostromedial tegmental nucleus (RMTg) that then in turn inhibit midbrain dopaminergic neurons . The data are interesting in light of current studies showing changes persisting in presynaptic dopamine release.…”

“…Motivation to self‐administer drugs of abuse, including nicotine, despite their noxious effects is mediated by adaptations of DA transmission specifically linked to cholinergic afferents that encode reinforcing stimuli . In what may serve as a “balance” to the rewarding properties of nicotine, the habenula‐interpeduncular nucleus (Hb‐IPN) pathway appears to play a role in aversive responses to nicotine . A clear role for this pathway in aversion is illustrated in Fowler et al who showed that α5 nicotinic subunit KO mice continue nicotine self‐administration at doses that wild‐type (WT) mice find aversive.…”

Mechanistic bases for the adverse interaction of nicotine and chronic pain

“…Of note, though nicotine is relatively selective for α4β2 nAChRs, it does have affinity for other subtypes, including α5-and α6-containing, as well as α7 nAChRs, which can also be present in the RVM [237,246,248,249]. Others investigating the actions of nicotine have suggested that its effects may be mediated partially [253,323] or only minimally by α4β2 nAChRs [324]. While actions at non-nAChRs are less likely, a few studies have shown functional activity of nicotine at 5-HT 3 Rs and NMDA receptors [325].…”