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 bidirectionally manipulated before cue-induced reinstatement. Following nicotine self-administration and extinction, ChIs were activated or inhibited before a cue reinstatement session. Following reinstatement, whole-cell electrophysiology from NAcore MSNs was used to assess changes in plasticity, measured via AMPA/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.
Highlights
Tobacco use disorder is the leading preventable cause of death within the United States and represents a substantial burden to public health (Prochaska and Benowitz, 2016)
Through the use of chemogenetics, behavioral assessments, and electrophysiology the results presented here highlight the importance of the cholinergic circuitry within the nucleus accumbens core (NAcore) for mediating cue-induced nicotine seeking
The present results show that chemogenetic inhibition of NAcore cholinergic interneurons (ChIs) inhibited cue-induced nicotine-seeking behavior
Summary
Tobacco use disorder is the leading preventable cause of death within the United States and represents a substantial burden to public health (Prochaska and Benowitz, 2016). Nicotine has been shown to increase glutamatergic input onto dopaminergic neurons, as measured by changes in AMPA/NMDA (A/N) ratios, and has been found to potentiate GABAergic input onto local VTA inhibitory neurons. Together, these findings support that nicotine exposure enhances VTA dopaminergic excitability and dopamine release into target areas, including the nucleus accumbens (Mansvelder and McGehee, 2000; Brown et al, 2010; Grieder et al, 2012). Drugs of abuse including nicotine induce changes in glutamatergic homeostasis within the mesocorticolimbic brain circuitry (Kalivas, 2009), altering glutamatergic-MSN connectivity and associated synaptic plasticity within the accumbens. While prior studies have explored changes in MSN synaptic plasticity because of altered dopaminergic and glutamatergic signaling, current studies have yet to explore additional mechanisms driving changes in MSN synaptic plasticity, which may underlie nicotine-seeking behaviors
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