Anterior cingulate cortex is necessary for spontaneous opioid withdrawal and withdrawal-induced hyperalgesia in male mice

McDevitt, Dillon S.; McKendrick, Greer; Graziane, Nicholas

doi:10.1038/s41386-021-01118-y

Cited by 23 publications

(23 citation statements)

References 89 publications

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“…Thus, while they have not been placed in an extended abstinence paradigm they still likely exhibit nicotine and morphine withdrawal-related symptoms as both drugs produce withdrawal in early abstinence (in both humans and rodents). 40 , 41 While this is a possibility, there are several assays directed toward withdrawal that will need to be completed and are clearly lacking in this current work.…”

Section: Discussionmentioning

confidence: 99%

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: Discussionmentioning

confidence: 99%

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 this study, we first focused on L5 PyNs that had low membrane resistance (<100 M ), high capacitance (>150 pF), and predominate voltage sag, as these have been shown to project subcortically to the thalamus, tectum, brainstem, and spinal cord. We found this subtype of L5 PyN to be best described morphologically as "thick-tufted, " with HCN channelmediated current, large somas, and likely expressing dopamine D2 receptors McDevitt et al, 2021). We also examined VTA-projecting ACC neurons as well as L5 "thin-tufted" PyNs which had higher membrane resistance (>150 M ), lower capacitance (<100 pF), and no or a small voltage sag, which are putative dopamine D1 receptor expressing (Gee et al, 2012).…”

Section: Electrophysiologymentioning

confidence: 99%

“…Spontaneous opioid withdrawal was assessed using previously described methods (Papaleo and Contarino, 2006;Madayag et al, 2019;McDevitt et al, 2021). Briefly, 24-28 h after the final conditioning session, a time range used throughout this study, which encompasses the expression of significant spontaneous opioid withdrawal (Papaleo and Contarino, 2006;Madayag et al, 2019), mice were placed into a clear acrylic open field arena (37 cm × 23 cm × 15 cm) and examined for signs of somatic withdrawal during a 30-min period.…”

Section: Spontaneous Opioid Withdrawalmentioning

confidence: 99%

“…For IME experiments, we employed a commonly used current step protocol (Ishikawa et al, 2009; 10.3389/fnins.2022.972658 Roselli et al, 2020). The IME and rheobase protocols were conducted at unadjusted resting membrane potentials as previously performed in the ACC (McDevitt et al, 2021). Our current step protocol, consisting of 1 s steps ranging from −150 to +400 pA in 50 pA increments, was carried out with a 15 s intra-sweep interval.…”

Section: Electrophysiologymentioning

confidence: 99%

“…The number of action potentials observed at each current step was recorded. For experiments where CNO (3 µM) was bath applied, IME was measured first in the absence and then in presence of CNO, as performed previously (McDevitt et al, 2021). For rheobase experiments, a 2 s consistent-slope current injection ramp with a maximal current of 400 pA was performed, as previously described (Pati et al, 2020).…”

Section: Electrophysiologymentioning

confidence: 99%

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Anterior cingulate cortex and its projections to the ventral tegmental area regulate opioid withdrawal, the formation of opioid context associations and context-induced drug seeking

et al. 2022

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Clinical evidence suggests that there are correlations between activity within the anterior cingulate cortex (ACC) following re-exposure to drug-associated contexts and drug craving. However, there are limited data contributing to our understanding of ACC function at the cellular level during re-exposure to drug-context associations as well as whether the ACC is directly related to context-induced drug seeking. Here, we addressed this issue by employing our novel behavioral procedure capable of measuring the formation of drug-context associations as well as context-induced drug-seeking behavior in male mice (8–12 weeks of age) that orally self-administered oxycodone. We found that mice escalated oxycodone intake during the long-access training sessions and that conditioning with oxycodone was sufficient to evoke conditioned place preference (CPP) and drug-seeking behaviors. Additionally, we found that thick-tufted, but not thin-tufted pyramidal neurons (PyNs) in the ACC as well as ventral tegmental area (VTA)-projecting ACC neurons had increased intrinsic membrane excitability in mice that self-administered oxycodone compared to controls. Moreover, we found that global inhibition of the ACC or inhibition of VTA-projecting ACC neurons was sufficient to significantly reduce oxycodone-induced CPP, drug seeking, and spontaneous opioid withdrawal. These results demonstrate a direct role of ACC activity in mediating context-induced opioid seeking among other behaviors, including withdrawal, that are associated with the DSM-V criteria of opioid use disorder.

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Opioid withdrawal: role in addiction and neural mechanisms

Monroe

Radke

2023

Psychopharmacology

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Anterior cingulate cortex is necessary for spontaneous opioid withdrawal and withdrawal-induced hyperalgesia in male mice

Cited by 23 publications

References 89 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

Anterior cingulate cortex and its projections to the ventral tegmental area regulate opioid withdrawal, the formation of opioid context associations and context-induced drug seeking

Opioid withdrawal: role in addiction and neural mechanisms

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