α3* Nicotinic Acetylcholine Receptors in the Habenula-Interpeduncular Nucleus Circuit Regulate Nicotine Intake

Abstract

Allelic variation in CHRNA3, the gene encoding the a3 nicotinic acetylcholine receptor (nAChR) subunit, increases vulnerability to tobacco dependence and smoking-related diseases, but little is known about the role for a3-containing (a3p) nAChRs in regulating the addiction-related behavioral or physiological actions of nicotine. a3p nAChRs are densely expressed by medial habenula (mHb) neurons, which project almost exclusively to the interpeduncular nucleus (IPn) and are known to regulate nicotine avoidance behaviors. We found that Chrna3 tm1.1Hwrt hypomorphic mice, which express constitutively low levels of a3p nAChRs, self-administer greater quantities of nicotine (0.4 mg kg 21 per infusion) than their wild-type littermates. Microinfusion of a lentivirus vector to express a short-hairpin RNA into the mHb or IPn to knock-down Chrna3 transcripts markedly increased nicotine self-administration behavior in rats (0.01-0.18 mg kg 21 per infusion). Using whole-cell recordings, we found that the a3b4p nAChR-selective antagonist a-conotoxin AuIB almost completely abolished nicotine-evoked currents in mHb neurons. By contrast, the a3b2p nAChR-selective antagonist a-conotoxin MII only partially attenuated these currents. Finally, micro-infusion of a-conotoxin AuIB (10 lM) but not a-conotoxin MII (10 lM) into the IPn in rats increased nicotine self-administration behavior. Together, these data suggest that a3b4p nAChRs regulate the stimulatory effects of nicotine on the mHb-IPn circuit and thereby regulate nicotine avoidance behaviors. These findings provide mechanistic insights into how CHRNA3 risk alleles can increase the risk of tobacco dependence and smoking-related diseases in human smokers.

Disruption of VGLUT1 in cholinergic medial habenula projections increases nicotine self-administration

“…More recently, targeted knock-down of a3 nAChR subunit in either MHb or IPN was shown to produce similar increases in nicotine intake [24]. Global overexpression of β4 nAChR subunit led to increased nicotine aversion, an effect reversed by selective expression of a5 nAChR subunit in MHb [21].…”

“…Additionally, overexpression of b4 nAChR subunit leads to enhanced MHb activity and a strong aversive response to nicotine, which can be abolished by disruption of the a5 nAChR subunit in MHb [21]. More recently, it has been shown that knockdown of the a3 nAChR subunit in either the MHb or IPN increases nicotine intake in rats [24]. These data together suggest that nAChRs containing the a5, a3, and b4 subunits mediate aversive signaling in the MHb-IPN.…”

“…Within the mesolimbic circuit, including ventral tegmental area dopaminergic projections to nucleus accumbens, activation of nAChRs contribute to the rewarding effect of nicotine [7][8][9][10][11][12][13][14]. Conversely, the excitatory projection from medial habenula (MHb) to interpeduncular nucleus (IPN) has been identified as a key substrate upon which nicotine actions contribute to nicotine aversion [15][16][17][18][19][20][21][22][23][24].…”

Protein profiling in the habenula after chronic (–)‐menthol exposure in mice

“…The habenula has high levels of nAChR expression and one of the brain regions with the greatest (>30% of total) levels of non‐α4β2 nAChRs in the brain (Whiteaker, Jimenez, et al, 2000). These non‐α4β2 nAChRs, notably α3*, α5*, and β4* nAChRs, are involved with withdrawal symptoms and nicotine intake, and are highly expressed in the habenula (Elayouby et al, 2021; Velasquez et al, 2014). Several studies have characterized the functional implications of reduced nAChR signaling from the habenula.…”

Multidimensional Intersection of Nicotine, Gene Expression, and Behavior

“…In contrast, mice with overexpression of the β4 nAChR gene exhibit a strong aversion to nicotine (Frahm et al, 2011). Finally, knockdown of the α3 nAChR subunit in the MHb or IPN increases nicotine intake at higher doses, a behavioral effect also found with the infusion of the α3β4 antagonist, a-conotoxin AuIB, into the IPN (Elayouby et al, 2021). Interestingly, the α3β4-containing nAChR has further been implicated in the physical signs of nicotine withdrawal (Jackson et al, 2013), which may involve altered GABAergic signaling in the IPN (Zhao-Shea et al, 2013).…”