Upregulation of nAChRs and Changes in Excitability on VTA Dopamine and GABA Neurons Correlates to Changes in Nicotine-Reward-Related Behavior

Akers, Austin T.; Cooper, Skylar Y.; Baumgard, Zachary J.; Casinelli, Gabriella P.; Avelar, Alicia J.; Henderson, Brandon J.

doi:10.1523/eneuro.0189-20.2020

Cited by 17 publications

(31 citation statements)

References 30 publications

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“…We have previously shown that nicotine reward-related behavior correlates with the degree of α4-containing (α4*) and α4α6* nicotinic acetylcholine receptor (nAChR) upregulation. 10 We have also previously observed that pharmacological agents that enhance nicotine reward-related behavior also enhance nAChR upregulation. 11 Accordingly, we examined the impact of nicotine, morphine, and their combination on reward, reinforcement, and nAChR upregulation in the ventral tegmental area (VTA).…”

Section: Introductionmentioning

confidence: 90%

Morphine Exposure Reduces Nicotine-Induced Upregulation of Nicotinic Receptors and Decreases Volitional Nicotine Intake in a Mouse Model

Avelar

Cooper

Wright

et al. 2022

Nicotine &Amp; Tobacco Research

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Introduction Nicotine addiction remains a primary health concern as tobacco smoking remains the number one cause of preventable death in America. At the same time, America is still facing the threat of the opioid epidemic. While the prevalence of smoking combustible cigarettes or electronic nicotine delivery systems (ENDS) in the USA varies between 12–35%, the smoking rates among the opioid use disorder (OUD) population is 74-97% 1. We examined changes in brain reward mechanisms in which co-use of nicotine and opioids may result in enhanced reward and/or reinforcement. Methods Adult male and female α4-mCherryα6-GFP mice (C57BL/6J) were used in conditioned place preference (CPP) and microscopy assays to examine reward-related behavior and nicotinic acetylcholine receptor (nAChR) upregulation following treatments with saline, nicotine, morphine, or nicotine plus morphine. Following this, separate mice were trained in e-Vape® self-administration assays to examine morphine’s impact on nicotine reinforcement. Results We observed that nicotine and morphine co-exposure in a conditioned place preference (CPP) assay did not produce enhanced reward-related behavior when compared to nicotine or morphine alone. In parallel we observed co-exposure reduced nicotine-induced upregulation of nAChRs on ventral tegmental area (VTA) dopamine and GABA neurons. Additionally, we observed that concurrent morphine exposure reduced nicotine (plus menthol) vapor self-administration in male and female mice. Conclusions While nicotine use is high among OUD individuals, our CPP assays suggest co-exposure not only fails to enhance reward-related behavior but also reduces nicotine-induced changes in VTA neurobiology. Our self-administration assays suggest that morphine exposure during nicotine acquisition reduces nicotine reinforcement-related behavior. Implications While some may postulate that the co-use of opioids and nicotine may be driven by reward-related mechanisms, our data indicate that opioid exposure may hinder nicotine intake due to reduced upregulation of nAChRs critical for nicotine reward and reinforcement. Thus, the high co-use in OUD individuals may be a result of other mechanisms and this warrants further investigations into nicotine and opioid co-use.

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Section: Introductionmentioning

confidence: 90%

Morphine Exposure Reduces Nicotine-Induced Upregulation of Nicotinic Receptors and Decreases Volitional Nicotine Intake in a Mouse Model

Avelar

Cooper

Wright

et al. 2022

Nicotine &Amp; Tobacco Research

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“…In the IPN, chronic nicotine exposure results in increased α5 transcript levels only in females, while α7 transcript was increased only in males ( Correa et al, 2019 ). Another recent report utilized mice with fluorescently tagged α4 and α6 nAChR subunits to measure receptor expression in the VTA following nicotine conditioned place preference, finding no sex differences in the degree of α4 ∗ and α4α6 ∗ nAChR upregulation ( Akers et al, 2020 ).…”

Section: Sex Differences In Nicotinic Acetylcholine Receptor Expression and Regulationmentioning

confidence: 99%

Sex Differences in the Nicotinic Acetylcholine Receptor System of Rodents: Impacts on Nicotine and Alcohol Reward Behaviors

Moen

Lee

2021

Front. Neurosci.

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Alcohol and nicotine are the two most widely used and misused drugs around the world, and co-consumption of both substances is highly prevalent. Multiple lines of evidence show a profound effect of sex in many aspects of alcohol and nicotine reward, with women having more difficulty quitting smoking and showing a faster progression toward developing alcohol use disorder compared with men. Both alcohol and nicotine require neuronal nicotinic acetylcholine receptors (nAChRs) to elicit rewarding effects within the mesolimbic system, representing a shared molecular pathway that likely contributes to the frequent comorbidity of alcohol and nicotine dependence. However, the majority of preclinical studies on the mechanisms of alcohol and nicotine reward behaviors utilize only male rodents, and thus our understanding of alcohol and nicotine neuropharmacology relies heavily on male data. As preclinical research informs the development and refinement of therapies to help patients reduce drug consumption, it is critical to understand the way biological sex and sex hormones influence the rewarding properties of alcohol and nicotine. In this review, we summarize what is known about sex differences in rodent models of alcohol and nicotine reward behaviors with a focus on neuronal nAChRs, highlighting exciting areas for future research. Additionally, we discuss the way circulating sex hormones may interact with neuronal nAChRs to influence reward-related behavior.

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Section: Introductionmentioning

confidence: 99%

“…Nicotine mediates its psychoactive effect by acting on nicotinic acetylcholine receptors (nAChRs) in the brain. Within the mesolimbic circuit, including ventral tegmental area dopamine neuron projections to nucleus accumbens, activation of nAChRs contribute to the rewarding effect of nicotine ( Calabresi et al, 1989 ; Pontieri et al, 1996 ; Mansvelder and McGehee, 2000 ; Pons et al, 2008 ; Liu et al, 2012 ; Peng et al, 2017 ; Grieder et al, 2019 ; Akers et al, 2020 ). Conversely, the excitatory projection from medial habenula (MHb) to interpeduncular nucleus (IPN) has been identified as a key substrate on which nicotine actions contribute to nicotine aversion ( Salas et al, 2009 ; Fowler and Kenny, 2011 , 2014 ; Fowler et al, 2011 ; Frahm et al, 2011 , 2015 ; Antolin-Fontes et al, 2015 , 2020 ; Tuesta et al, 2017 ; Elayouby et al, 2021 ).…”

Section: Introductionmentioning

confidence: 99%

Disruption of VGLUT1 in Cholinergic Medial Habenula Projections Increases Nicotine Self-Administration

Souter

Chen

Zell

et al. 2021

eNeuro

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Cholinergic projections from the medial habenula (MHb) to the interpeduncular nucleus (IPN) have been studied for their complex contributions to nicotine addiction and have been implicated in nicotine reinforcement, aversion, and withdrawal. While it has been established that MHb cholinergic projections co-release glutamate, no direct evidence has demonstrated a role for this glutamate projection in nicotine consumption. In the present study, a novel floxed Slc17a7 (VGLUT1) mouse was generated and used to create conditional knockout (cKO) mice that lack VGLUT1 in MHb cholinergic neurons. Loss of Slc17a7 expression in ventral MHb cholinergic neurons was validated using fluorescent in situ hybridization, and immunohistochemistry was used to demonstrate a corresponding reduction of VGLUT1 protein in cholinergic terminals in the IPN. We also used optogenetics-assisted electrophysiology to evoke excitatory post-synaptic currents in IPN and observed a reduction of glutamatergic currents in the cKO, supporting the functional disruption of VGLUT1 in MHb to IPN synapses. cKO mice exhibited no gross phenotypic abnormalities and displayed normal thigmotaxis and locomotor behavior in the open-field assay. When trained to lever press for food, there was no difference between control and cKO. However, when tested in a nicotine self-administration procedure we found that the loss of VGLUT1-mediated glutamate co-release led to increased responding for nicotine. These findings indicate that glutamate co-release from ventral MHb cholinergic neurons opposes nicotine self-administration, and provide additional support for targeting this synapse to develop potential treatments for nicotine addiction.Significance statement: Excitatory projections from the medial habenula (MHb) to interpeduncular nucleus (IPN) have been studied for their role in mediating the aversive properties of nicotine and nicotine intake behaviors. Although these projections are known to corelease acetylcholine and glutamate, the present study is the first investigation of a function for 2 this glutamate signaling in nicotine consumption. We demonstrate that a loss of VGLUT1 from cholinergic MHb neurons promotes increased nicotine self-administration in mice. Thus, we outline a role for glutamate release from MHb cholinergic projections in mediating the aversive properties of nicotine, expanding our knowledge of the neurobiology underlying nicotine consumption and identifying a possible substrate for therapeutic intervention.

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Upregulation of nAChRs and Changes in Excitability on VTA Dopamine and GABA Neurons Correlates to Changes in Nicotine-Reward-Related Behavior

Abstract: Upregulation of nAChRs and changes in excitability on VTA dopamine and GABA neurons correlates to changes in nicotine-reward related behavior.

Cited by 17 publications

References 30 publications

Morphine Exposure Reduces Nicotine-Induced Upregulation of Nicotinic Receptors and Decreases Volitional Nicotine Intake in a Mouse Model

Morphine Exposure Reduces Nicotine-Induced Upregulation of Nicotinic Receptors and Decreases Volitional Nicotine Intake in a Mouse Model

Sex Differences in the Nicotinic Acetylcholine Receptor System of Rodents: Impacts on Nicotine and Alcohol Reward Behaviors

Disruption of VGLUT1 in Cholinergic Medial Habenula Projections Increases Nicotine Self-Administration

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