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 considerable heterogeneity in nicotine-drinking profiles in isogenic adult male mice, with about half of the mice persisting in nicotine consumption even at high concentrations, whereas the other half stopped consuming. 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 identified β4-containing nicotinic acetylcholine receptors of IPN neurons as molecular and cellular correlates of nicotine aversion. Collectively, our results identify the IPN as a substrate for individual variabilities and adaptations in nicotine consumption.

The interpeduncular nucleus blunts the rewarding effect of nicotine

“…MPEG 4 Ch treatment markedly decreased the amplitude of the response to nicotine in β4E61C mice (> 60%), but had no effect in WT mice (Figure 1D). This result confirms that β4-containing nAChRs are the main receptor subtypes in the IPN, 12 and that the engineered E61C mutation is required for MPEG 4 Ch-induced nAChR antagonism.…”

“…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…”

“…10–13 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…”

“…15–17 In particular, the α3 and β4 subunits are almost absent in the VTA 18 and in other parts of the brain. 17,19 Knock-out mice lacking α5 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 α3 selectively in the Mhb or IPN 22 , or pharmacologically blocking α3β4 nAChRs in the IPN 23 , results in increased self-administration of nicotine in the rat.…”

“…17,19 Knock-out mice lacking α5 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 α3 selectively in the Mhb or IPN 22 , or pharmacologically blocking α3β4 nAChRs in the IPN 23 , results in increased self-administration of nicotine in the rat. Because the α3β4 nAChR has lower affinity for nicotine than the α4β2 nAChR 2,24 , one current hypothesis is that nicotine is rewarding at low doses because it activates primarily α4β2 receptors of the VTA, while it is aversive at high doses because only then does it activate α3β4 nAChRs of the MHb-IPN axis.…”