PROJECT SUMMARY/ABSTRACT
Nicotine abuse and addiction represent a substantial burden to public health. Nicotine, an active alkaloid
in tobacco, is responsible for addiction to tobacco-containing products such as cigars, cigarettes, and vaporized
liquid e-cigarettes. Given the immense negative health impact of nicotine addiction as well as the recent surge
in popularity of nicotine-containing e-cigarettes, there is a great need for innovative research on the
neurobiological underpinnings of nicotine addiction and relapse. Nicotine produces cellular adaptations in brain
regions associated with drug reward, such as the nucleus accumbens (NA). However, the neurobehavioral
mechanisms underlying the development of addiction and relapse vulnerability are relatively unknown. Nucleus
accumbens core (NAcore) glutamatergic mechanisms are involved in nicotine relapse, including rapid, transient
potentiation of synaptic strength (measured as increased dendritic spine diameter and AMPA currents) and
accompanying glutamate receptor changes. Interestingly, nicotinic acetylcholine receptors (nAChRs),
specifically a7 and ß2-containing, mediate this rapid, transient nicotine relapse-associated plasticity within the
NAcore. The principal hypothesis of the proposed studies is that cue-induced glutamate release at prefrontal
cortex (PFC)-NA projections (specifically, the prelimbic (PL) subregion of the PFC, and the NAcore) activates
release of acetylcholine (ACh) from NA cholinergic interneurons (ChIs) that feeds forward to promote prolonged
glutamate release contributing to relapse of nicotine-seeking behavior. In this way, ChIs may modulate aberrant
glutamatergic signaling by exacerbating the signal and thus unlocking the transition from drug craving to seeking.
Due to the cue dependency of smoking behavior, exposure to nicotine-associated cues is a risk factor for relapse.
In the proposed studies, we will explore ChI-specific mechanisms modulating both cued nicotine reinstatement
and associated changes in synaptic plasticity, and perform a circuit-level analysis of neuronal interactions
underlying relapse vulnerability. In Specific Aim 1, we will examine the impact of ChI signaling on prefrontal
cortex glutamatergic projections into the accumbens core, and the impact of this subcircuit on cue-induced
nicotine seeking and ACh release. In Specific Aim 2, ChIs will be chemogenetically activated or inhibited within
the accumbens core and rapid, transient synaptic plasticity in medium spiny neurons (MSNs) associated with
nicotine seeking behavior will be measured. We predict that manipulation of ChIs will result in altered relapse-
associated synaptic plasticity in MSNs, which in turn will lead to alterations in nicotine seeking motivation. In both
aims, novel techniques will be utilized from multiple levels of analysis including optogenetics, chemogenetics,
microdialysis, behavior, and electrophysiology. In conclusion, findings from these investigations will extend to
future goals of defining the neural circuitry and neurobehavioral mechanisms underlying nicotine addiction-
related behaviors.