Prolonged nicotine exposure reduces aversion to the drug in mice by altering nicotinic transmission in the interpeduncular nucleus

Abstract

Nicotine intake is likely to result from a balance between the rewarding and aversive properties of the drug, yet the individual differences in neural activity that control aversion to nicotine and their adaptation during the addiction process remain largely unknown. Using a two-bottle choice experiment, we observed a high heterogeneity in nicotine-drinking profiles in isogenic adult male mice, with about half of the mice persisting in consuming nicotine even at high concentrations, whereas the other half durably stopped consumption. We found that nicotine intake was negatively correlated with nicotine-evoked currents in the interpeduncular nucleus (IPN), and that prolonged exposure to nicotine, by weakening this response, decreased aversion to the drug, and hence boosted consumption. Lastly, using knock-out mice and local gene re-expression, we causally identified β4-containing nicotinic acetylcholine receptors of IPN neurons as the molecular and cellular correlates of nicotine aversion. Collectively, our results identify the IPN as a substrate of individual variabilities and adaptations in nicotine consumption.

The interpeduncular nucleus blunts the rewarding effect of nicotine

“…[10][11][12][13] These competing reinforcing and aversive properties of nicotine, together with the feeling of satiety, are consistent with the observation that humans and laboratory rodents titrate their nicotine intake when high doses are available. 5,11,12,14 The aversive effect of high-dose nicotine involves the neural pathway projecting from the medial habenula (Mhb) to the interpeduncular nucleus (IPN). 5,10,11 Neurons belonging to this pathway express high densities of rare nAChR subunits, notably a3, a5 and β4.…”

“…These results are consistent with previous data obtained using the juxtacellular technique in neurons that were labelled and confirmed to be located in the IPN. 12 We then assessed the sensitivity of IPN neurons to a range of nicotine doses (7.5 to 60 µg/kg) and found that the effect of nicotine was dose-dependent, but that the polarity of the response (i.e., activation or inhibition) was not. Indeed, neurons that were activated by nicotine at 30 µg/kg were activated across all doses tested, and similarly, inhibited neurons maintained their inhibition at all doses (Figure 2D).…”

“…[15][16][17] In particular, the a3 and β4 subunits are almost absent in the VTA 18 and in other parts of the brain. 17,19 Knock-out mice lacking a5 11 or β4 12,20,21 consume more nicotine than wild-type (WT) mice, especially at high doses, and their consumption level is restored upon viral re-expression of these nAChR subunits in the Mhb 11,20 or IPN. 12,20,21 Similarly, knocking down a3 selectively in the Mhb or IPN 22 , or pharmacologically blocking a3β4 nAChRs in the IPN 23 , results in increased self-administration of nicotine in the rat.…”

“…17,19 Knock-out mice lacking a5 11 or β4 12,20,21 consume more nicotine than wild-type (WT) mice, especially at high doses, and their consumption level is restored upon viral re-expression of these nAChR subunits in the Mhb 11,20 or IPN. 12,20,21 Similarly, knocking down a3 selectively in the Mhb or IPN 22 , or pharmacologically blocking a3β4 nAChRs in the IPN 23 , results in increased self-administration of nicotine in the rat. Because the a3β4 nAChR has lower affinity for nicotine than the a4β2 nAChR 2,24 , one current hypothesis is that nicotine is rewarding at low doses because it activates primarily a4β2 receptors of the VTA, while it is aversive at high doses because only then does it activate a3β4 nAChRs of the MHb-IPN axis.…”

Nicotine in adolescence freezes dopamine circuits in an immature state

“…We propose that this may be one mechanism by which nicotine use in adolescence creates an enduring vulnerability to later nicotine use and addiction. An imbalance between the rewarding and aversive effects of nicotine has indeed been posited as a mechanism driving the transition from casual use to addiction 61,[90][91][92] .…”