Alterations in brain activation in response to prolonged morphine withdrawal-induced behavioral inflexibility in rats

Piao, Chengji; Liu, Tiane; L., L.; Ding, Xuekun; Wang, Xingyue; Chen, Xing; Duan, Ying; Song, Nan; Liang, Jing

doi:10.1007/s00213-017-4689-3

Cited by 9 publications

(5 citation statements)

References 52 publications

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“…Of the few studies conducted on single cell activity, heroin decreases AMPA/NMDA ratios in layer V pyramidal neurons ( Van den Oever et al, 2008 ), mainly through reductions in AMPA receptor activity and expression. Similarly, non-contingent morphine exposure reduces cellular excitability through reductions in mPFC AMPA GluA1 receptor expression and is also reflected in reductions in expression of the activity-related immediate early gene c-fos in this region ( Piao et al, 2017 ). Taken together, these studies highlight that, in general, opioids decrease prefrontal pyramidal cell excitability ( Hearing et al, 2012 ), yet their effects on pyramidal cell subtypes remain unknown.…”

Section: Introductionmentioning

confidence: 99%

Drugs of Abuse Differentially Alter the Neuronal Excitability of Prefrontal Layer V Pyramidal Cell Subtypes

Leyrer‐Jackson

Hood

Olive

2021

Front. Cell. Neurosci.

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The medial prefrontal cortex (mPFC) plays an important role in regulating executive functions including reward seeking, task flexibility, and compulsivity. Studies in humans have demonstrated that drugs of abuse, including heroin, cocaine, methamphetamine, and alcohol, alter prefrontal function resulting in the consequential loss of inhibitory control and increased compulsive behaviors, including drug seeking. Within the mPFC, layer V pyramidal cells, which are delineated into two major subtypes (type I and type II, which project to subcortical or commissurally to other cortical regions, respectively), serve as the major output cells which integrate information from other cortical and subcortical regions and mediate executive control. Preclinical studies examining changes in cellular physiology in the mPFC in response to drugs of abuse, especially in regard to layer V pyramidal subtypes, are relatively sparse. In the present study, we aimed to explore how heroin, cocaine, methamphetamine, ethanol, and 3,4-methylenedioxypyrovalerone (MDPV) alter the baseline cellular physiology and excitability properties of layer V pyramidal cell subtypes. Specifically, animals were exposed to experimenter delivered [intraperitoneal (i.p.)] heroin, cocaine, the cocaine-like synthetic cathinone MDPV, methamphetamine, ethanol, or saline as a control once daily for five consecutive days. On the fifth day, whole-cell physiology recordings were conducted from type I and type II layer V pyramidal cells in the mPFC. Changes in cellular excitability, including rheobase (i.e., the amount of injected current required to elicit action potentials), changes in input/output curves, as well as spiking characteristics induced by each substance, were assessed. We found that heroin, cocaine, methamphetamine, and MDPV decreased the excitability of type II cells, whereas ethanol increased the excitability of type I pyramidal cells. Together, these results suggest that heroin, cocaine, MDPV, and methamphetamine reduce mPFC commissural output by reducing type II excitability, while ethanol increases the excitability of type I cells targeting subcortical structures. Thus, separate classes of abused drugs differentially affect layer V pyramidal subtypes in the mPFC, which may ultimately give rise to compulsivity and inappropriate synaptic plasticity underlying substance use disorders.

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Section: Introductionmentioning

confidence: 99%

Drugs of Abuse Differentially Alter the Neuronal Excitability of Prefrontal Layer V Pyramidal Cell Subtypes

Leyrer‐Jackson

Hood

Olive

2021

Front. Cell. Neurosci.

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“…We and others have found similar effects within the prefrontal cortex, where heroin decreases the AMPA/NMDA ratios in layer V pyramidal neurons through reductions in AMPA receptor expression and activity ( Van den Oever et al, 2008 ) and decreases layer V pyramidal cell excitability of commissural projecting pyramidal neurons ( Leyrer-Jackson et al, 2021 ). Further, non-contingent morphine exposure has also been shown to reduce cellular excitability within the mPFC as reflected by reductions in activity-related immediate early gene c-fos expression ( Piao et al, 2017 ). Furthermore, heroin has been shown to increase GABAergic inhibition in the mPFC, therefore reducing pyramidal cell excitability ( Van den Oever et al, 2008 ).…”

Section: Discussionmentioning

confidence: 99%

Early Life Stress Promotes Heroin Seeking But Does Not Alter the Excitability of Insular Pyramidal Cells Targeting the Nucleus Accumbens

Leyrer‐Jackson

Overby

Nagy

et al. 2021

Front. Behav. Neurosci.

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A number of retrospective studies have demonstrated adverse childhood experiences are associated with increased vulnerability to substance use disorders, including opioid use disorders (OUDs). These adverse childhood experiences, also referred to as early life stress (ELS), can be modeled in laboratory animals by various paradigms including limited bedding and nesting (LBN) procedures. Studies using rodent models of ELS have been shown to recapitulate various aspects of OUDs, including relapse propensity and perseverance of drug-seeking behavior. In the current study, we utilized the LBN paradigm to explore potential effects on heroin self-administration, extinction, and relapse-like behaviors in male and female rats. We also utilized in vitro whole-cell electrophysiology to examine the effects of LBN and repeated heroin administration on the excitability of pyramidal neurons in the anterior insular cortex (AIC) projecting to the nucleus accumbens core (NAc), as recent studies suggest that this circuit may mediate various aspects of OUDs and may be compromised as a result of either ELS or OUDs. We observed that compared to control animals, rats exposed to LBN conditions during postnatal days 2–9 showed increased breakpoints for heroin self-administration under a progressive ratio schedule of reinforcement, impaired extinction of heroin-seeking behavior, and increased reinstatement of heroin-seeking behavior induced by heroin-associated cues. No effect of LBN rearing conditions were observed on the acquisition and maintenance of heroin self-administration, and no sex differences in heroin intake were observed. LBN and control reared animals showed no differences in the excitability of AIC-NAc pyramidal neurons, but animals treated with repeated heroin showed decreased excitability of these neurons through a significant increase in rheobase and reduction in action potentials induced by depolarizing currents. Together, these results suggest that ELS exposure produces exacerbations of heroin seeking behavior without parallel effects on AIC-NAc excitability, although heroin itself reduces the excitability of these neurons.

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“…Prior to each sucrose intake test (WD1 and WD2), rats were placed in a transparent plastic cylinder and continuously video recorded over a 30‐min observation period. Trained observers blind to the treatment scored withdrawal signs 48 , 49 (weighting factors shown in Figure 1G ). Withdrawal scores were averaged for each withdrawal interval (WD1 and WD2).…”

Section: Methodsmentioning

confidence: 99%

Differential effects of acute and prolonged morphine withdrawal on motivational and goal‐directed control over reward‐seeking behaviour

Halbout,

Hutson,

Agrawal

et al. 2024

Addiction Biology

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Opioid addiction is a relapsing disorder marked by uncontrolled drug use and reduced interest in normally rewarding activities. The current study investigated the impact of spontaneous withdrawal from chronic morphine exposure on emotional, motivational and cognitive processes involved in regulating the pursuit and consumption of food rewards in male rats. In Experiment 1, rats experiencing acute morphine withdrawal lost weight and displayed somatic signs of drug dependence. However, hedonically driven sucrose consumption was significantly elevated, suggesting intact and potentially heightened reward processing. In Experiment 2, rats undergoing acute morphine withdrawal displayed reduced motivation when performing an effortful response for palatable food reward. Subsequent reward devaluation testing revealed that acute withdrawal disrupted their ability to exert flexible goal‐directed control over reward seeking. Specifically, morphine‐withdrawn rats were impaired in using current reward value to select actions both when relying on prior action‐outcome learning and when given direct feedback about the consequences of their actions. In Experiment 3, rats tested after prolonged morphine withdrawal displayed heightened rather than diminished motivation for food rewards and retained their ability to engage in flexible goal‐directed action selection. However, brief re‐exposure to morphine was sufficient to impair motivation and disrupt goal‐directed action selection, though in this case, rats were only impaired in using reward value to select actions in the presence of morphine‐paired context cues and in the absence of response‐contingent feedback. We suggest that these opioid‐withdrawal induced deficits in motivation and goal‐directed control may contribute to addiction by interfering with the pursuit of adaptive alternatives to drug use.

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Alterations in brain activation in response to prolonged morphine withdrawal-induced behavioral inflexibility in rats

Abstract: Altogether, these data suggest that alterations in the function of the frontal cortex and its striatal connections during the late morphine withdrawal phase may underlie the disruption of inhibitory control in opioid dependence.

Cited by 9 publications

References 52 publications

Drugs of Abuse Differentially Alter the Neuronal Excitability of Prefrontal Layer V Pyramidal Cell Subtypes

Drugs of Abuse Differentially Alter the Neuronal Excitability of Prefrontal Layer V Pyramidal Cell Subtypes

Early Life Stress Promotes Heroin Seeking But Does Not Alter the Excitability of Insular Pyramidal Cells Targeting the Nucleus Accumbens

Differential effects of acute and prolonged morphine withdrawal on motivational and goal‐directed control over reward‐seeking behaviour

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