Accumbens cholinergic interneurons mediate cue-induced nicotine seeking and associated glutamatergic plasticity

Abstract

Nicotine, the primary addictive substance in tobacco, is widely abused. Relapse to cues associated with nicotine results in increased glutamate release within nucleus accumbens core (NAcore), modifying synaptic plasticity of medium spiny neurons (MSNs) which contributes to reinstatement of nicotine seeking. However, the role of cholinergic interneurons (ChIs) within the NAcore in mediating these neurobehavioral processes in unknown. ChIs represent less than 1% of the accumbens neuronal population yet are activated during drug seeking and reward-predicting events. Thus, we hypothesized that ChIs may play a significant role in mediating glutamatergic plasticity that underlies nicotine seeking behavior. Using chemogenetics transgenic rats that express Cre under the control of the choline acetyltransferase (ChAT) promoter, ChIs were bi-directionally manipulated prior to cueinduced reinstatement. Following nicotine self-administration and extinction training, ChIs were activated or inhibited prior to a cue reinstatement session. Following reinstatement, whole-cell electrophysiology from NAcore MSNs was used to assess changes in plasticity, measured via α amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) / N-Methyl-D-Aspartate (NMDA) (A/N) ratios. Chemogenetic inhibition of ChIs inhibited cued nicotine seeking and resulted in decreased A/N, whereas activation of ChIs had no effect, demonstrating that ChI inhibition prevents transient synaptic potentiation (t-SP) associated with cue-induced nicotine seeking. To assess potential underlying mechanisms, accumbens α 4 β 2 -and α 7 -containing nicotinic ACh receptors (nAChRs) were pharmacologically inhibited and MSN synaptic morphology was assessed following reinstatement.Inhibition of both nAChR subtypes prevented cue-induced nicotine seeking and t-SP (measured via changes in spine head diameter). Together, these results demonstrate that these neurons mediate cue-induced nicotine reinstatement and underlying synaptic plasticity within the NAcore.--250 words--3 Introduction:

Orbitofrontal cortex to dorsal striatum circuit is critical for incubation of oxycodone craving after forced abstinence

“…One possibility is through striatal cholinergic interneurons (ChIs), which have been major players in mediating striatal dopamine transmission (Cragg, 2006;Cachope and Cheer, 2014;Kosillo et al, 2016;Yorgason et al, 2017). Further support for this hypothesis comes from recent studies indicating that ChIs in striatum contribute to reward seeking (Collins et al, 2019;Cover et al, 2019), cocaine conditioning and extinction (Witten et al, 2010;Lee et al, 2016;Fleming et al, 2022), nicotine seeking (Leyrer-Jackson et al, 2021) and cognitive flexibility after cocaine exposure (Gangal et al, 2023).…”