Correlates of motivation and reward

National Institute On Drug Abuse

Investigators

Linked publications, trials & patents

Abstract

I am summarizing one of our ongoing projects: Nicotine administration into the supramammillary region (SuM) of the posterior hypothalamus produces reinforcing effects, as rats will self-administer nicotine into this region. Selective activation of SuM glutamatergic (Glu) neurons projecting to the medial septum (MS) also reinforces behavior and promotes dopamine release in the nucleus accumbens. However, the mechanisms by which nicotine acts in the SuM, and whether the SuM contributes to reinforcement from systemic nicotine, remain unclear. To address this, we developed a mouse model of intravenous (IV) nicotine self-administration. Under a fixed-ratio 5 schedule, mice self-administered 0, 10, and 30 µg/kg/infusion of nicotine at comparable levels but responded significantly less for 100 µg/kg. While this suggested an aversive effect at the higher dose, the self-administration pattern indicated otherwise: mice engaged in clustered bouts of lever pressing, followed by pauses after each infusion, consistent with intake regulation rather than simple avoidance. Using a progressive ratio 3 schedule, where lever-press requirements increased by 3 with each infusion, mice earned significantly more infusions of 25 µg/kg nicotine than saline, suggesting nicotine’s reinforcing effects. To probe the role of SuM neurons, we examined whether SuM Glu neurons projecting to the MS express nicotinic acetylcholine receptors (nAChRs) and respond to systemic nicotine. Retrograde tracing combined with RNAscope in situ hybridization revealed that ~95% of SuM→MS neurons expressed the β2 nAChR subunit, with 20–30% also expressing other subunits. Nearly all (95%) of these projection neurons were glutamatergic. Finally, fiber photometry in VGluT2-Cre mice expressing GCaMP showed that both experimenter-delivered and self-administered IV nicotine (30 and 100 µg/kg) produced time-locked calcium transients, suggesting that nicotine activates SuM Glu neurons. Together, these findings suggest that nicotine acts on β2-containing nAChRs in SuM Glu neurons, engaging SuM→MS neurons and their associated circuits that contribute to nicotine reinforcement.