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 cue-induced 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-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, 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.
Significance Statement The studies reported here are the first to address the role of cholinergic interneurons (ChIs) in cue-induced nicotine seeking and in nicotine-induced changes in synaptic plasticity within nucleus accumbens medium spiny neurons (MSNs). Chemogenetic inhibition of ChIs prevented cue-induced nicotine seeking and associated MSN plasticity. Additionally, these studies highlight the role of nicotinic acetylcholine receptors in mediating cue induced nicotine seeking and associated MSN morphology. 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 for mediating cue-induced nicotine seeking.
Footnotes
Authors report no conflict of interest.
This work was supported by the National Institutes of Health Grant DA036569, DA036569-S1, DA044479, DA046526, and DA045881 (to CDG) as well as F32AA027962-01 to JMLJ, DA042172 to MFO, NS097537 to JMN and the Arizona Alzheimer’s Consortium (to CDG). All authors have no disclosures to declare.
This is an open-access article distributed under the terms of the Creative Commons Attribution 4.0 International license, which permits unrestricted use, distribution and reproduction in any medium provided that the original work is properly attributed.
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