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 is unknown. ChIs represent less than 1% of the accumbens neuronal population and 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 in transgenic rats expressing 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, 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-5methyl-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, relative to control animals, whereas activation of ChIs was unaltered, demonstrating that ChI inhibition may modulate plasticity underlying cue-induced nicotine seeking. These results demonstrate that ChI neurons play an important role in mediating cue-induced nicotine reinstatement and underlying synaptic plasticity within the NAcore.

Acute and chronic effects by nicotine on striatal neurotransmission and synaptic plasticity in the female rat brain

“…Estradiol treatment decreased striatal dopamine D2 receptor binding, and variations in dopamine levels and binding are seen in different phases of the estrous cycle in rats ( Bazzett and Becker, 1994 ; Al Sweidi et al, 2013 ). Still, there appears to be no estrous cycle dependent changes or sex differences when monitoring nicotine self-administration and reinstatement of nicotine-seeking ( Feltenstein et al, 2012 ; Leyrer-Jackson et al, 2021 ). In vivo spontaneous activity of dopamine neurons, as well as ex vivo intrinsic and synaptic properties, have also been reported to be similar in male and female rats ( Melis et al, 2013 ), even though there appears to be a sex difference with regards to tonic 2-AG signaling on to dopaminergic neurons ( Melis et al, 2013 ).…”

Cholinergic interneurons in the shell region of the nucleus accumbens regulate binge alcohol consumption: A chemogenetic and genetic lesion study

“…The chemogenetic technique has been widely used to understand the neurobiology of addiction, especially the role of selective neuronal populations in the NAc in nicotine and alcohol addiction (Leyrer‐Jackson et al., 2021; Strong et al., 2020). By introducing G protein‐coupled inhibitory (Gi) or excitatory (Gq) DREADD receptors into CINs through cre‐dependent viral vectors, we were able to control the activity of CINs in response to CNO (Ferguson et al., 2011).…”

Ovarian Hormones Regulate Nicotine Consumption and Accumbens Glutamatergic Plasticity in Female Rats

“…Our prior studies have examined plasticity during reinstatement of nicotine seeking in male rats, which is a protracted time point from nicotine self-administration ( Gipson et al, 2013b ; Namba et al, 2020 ; Leyrer-Jackson et al, 2021 ). In our first paper examining NAcore plasticity following nicotine self-administration, we found that initiated nicotine seeking in a cue-induced reinstatement model potentiated NAcore MSNs, which then collapsed within 45 min (similar to when active lever pressing declined; Gipson et al, 2013a ).…”