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

McKendrick, Greer; McDevitt, Dillon S.; Shafeek, Peter; Cottrill, Adam; Graziane, Nicholas

doi:10.3389/fnins.2022.972658

Cited by 6 publications

(7 citation statements)

References 132 publications

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“…Following oxycodone IVSA, measures of spontaneous withdrawal-related aggression and hyperalgesia have been reported 12 h after the last IVSA session 48 . Spontaneous SSW have also been observed following oral oxycodone intake in mice, when examined 24 h after the last oral intake session 49 .…”

Section: Discussionmentioning

confidence: 96%

Voluntary alcohol intake alters the motivation to seek intravenous oxycodone and neuronal activation during the reinstatement of oxycodone and sucrose seeking

Wilkinson,

Blount,

Davis

et al. 2023

Sci Rep

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Opioid-alcohol polysubstance use is prevalent and worsens treatment outcomes. Here we assessed whether co-consumption of oxycodone and alcohol influence the intake of one another, demand for oxycodone, and the neurocircuitry underlying cue-primed reinstatement of oxycodone-seeking. Male and female rats underwent oxycodone intravenous self-administration (IVSA) with homecage access to alcohol (20% v/v) and/or water immediately after the IVSA session. Next, economic demand for intravenous oxycodone was assessed while access to alcohol and/or water continued. Control rats self-administered sucrose followed by access to alcohol and/or water. Rats underwent a cue-primed reinstatement test and brains were processed for c-fos mRNA expression. While both sexes decreased oxycodone intake if they had access to alcohol, and decreased alcohol intake if they had access to oxycodone, only female oxycodone + alcohol rats exhibited decreased demand elasticity and increased cue-primed reinstatement. Alcohol consumption increased the number of basolateral and central amygdala neurons activated during sucrose and oxycodone reinstatement and the number of ventral and dorsal striatum neurons engaged by sucrose reinstatement. Nucleus accumbens shell dopamine 1 receptor expressing neurons displayed activation patterns consistent with oxycodone reinstatement. Thus, alcohol alters the motivation to seek oxycodone in a sex-dependent manner and the neural circuitry engaged by cue-primed reinstatement of sucrose and oxycodone-seeking.

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Section: Discussionmentioning

confidence: 96%

Voluntary alcohol intake alters the motivation to seek intravenous oxycodone and neuronal activation during the reinstatement of oxycodone and sucrose seeking

Wilkinson,

Blount,

Davis

et al. 2023

Sci Rep

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“…The dose and duration of oral oxycodone access are important differences when comparing results between oral oxycodone studies. Using different experimental protocols of oral oxycodone, other studies have reported that mice and rats escalate oral oxycodone intake across sessions (Zanni et al ., 2020; McKendrick et al ., 2022; Slivicki et al , 2023). For example, Zanni and co-workers (2020) had rats consume oxycodone orally for 22 weeks, whereas in the current study and in the study by Iyer et al .…”

Section: Discussionmentioning

confidence: 99%

“…For oral intake experiments, mice received drinking water with oxycodone (0.5 mg/ml) or drinking water without oxycodone in their home cage bottle for 10 consecutive days ( n = 12 per group, six males/six females). The concentration of oxycodone used in the drinking water was based on previous studies (Phillips et al ., 2020; McKendrick et al ., 2022; Slivicki et al ., 2023). No taste adulterants were added to the water or oxycodone solutions.…”

Section: Methodsmentioning

confidence: 99%

“…For oral intake, oxycodone hydrochloride (MilliporeSigma, Burlington, Massachusetts, USA) was dissolved in regular drinking water at a concentration of 0.5 mg/ml. This concentration has been previously used in volitional oral oxycodone models (Phillips et al ., 2020; McKendrick et al ., 2022; Slivicki et al ., 2023). For s.c. injections, oxycodone hydrochloride (MilliporeSigma) was dissolved in 0.9% sterile saline and administered s.c. (10 mg/kg) at a volume of 0.1 ml.…”

Section: Methodsmentioning

confidence: 99%

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Comparing withdrawal- and anxiety-like behaviors following oral and subcutaneous oxycodone administration in C57BL/6 mice

De Almeida,

Drinkuth,

Sartor

2024

Behavioural Pharmacology

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Excessive prescribing and misuse of prescription opioids, such as oxycodone, significantly contributed to the current opioid crisis. Although oxycodone is typically consumed orally by humans, parenteral routes of administration have primarily been used in preclinical models of oxycodone dependence. To address this issue, more recent studies have used oral self-administration procedures to study oxycodone seeking and withdrawal in rodents. Behavioral differences, however, following oral oxycodone intake versus parenteral oxycodone administration remain unclear. Thus, the goal of the current studies was to compare anxiety- and withdrawal-like behaviors using established opioid dependence models of either home cage oral intake of oxycodone (0.5 mg/ml) or repeated subcutaneous (s.c.) injections of oxycodone (10 mg/kg) in male and female mice. Here, mice received 10 days of oral or s.c. oxycodone administration, and following 72 h of forced abstinence, anxiety- and withdrawal-like behaviors were measured using elevated zero maze, open field, and naloxone-induced precipitated withdrawal procedures. Global withdrawal scores were increased to a similar degree following oral and s.c. oxycodone use, while both routes of oxycodone administration had minimal effects on anxiety-like behaviors. When examining individual withdrawal-like behaviors, mice receiving s.c. oxycodone exhibited more paw tremors and jumps during naloxone-induced precipitated withdrawal compared with oral oxycodone mice. These results indicate that both models of oxycodone administration are sufficient to elevate global withdrawal scores, but, when compared with oral consumption, s.c. oxycodone injections yielded more pronounced effects on some withdrawal-like behaviors.

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“…In addition, 1 ng of CTAP was used based on a previous publication ( Simmons and Self, 2009 ). For DREADD experiments, CNO (3 µm, 300 nl) was injected into the PVT at an infusion rate of 300 nl/min as we have shown that this concentration of CNO is sufficient to activate hM4D(Gi)-DREADDs ( McKendrick et al, 2022 ) and others have shown that 3 µm CNO is sufficient to activate hM4D(Gi)-DREADDs in the PVT ( Keyes et al, 2020 ).…”

Section: Methodsmentioning

confidence: 99%

The Paraventricular Thalamic Nucleus and Its Projections in Regulating Reward and Context Associations

McDevitt,

Wade,

McKendrick

et al. 2024

eNeuro

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The paraventricular thalamic nucleus (PVT) is a brain region that mediates aversive and reward-related behaviors as shown in animals exposed to fear conditioning, natural rewards, or drugs of abuse. However, it is unknown whether manipulations of the PVT, in the absence of external factors or stimuli (e.g., fear, natural rewards, or drugs of abuse) are sufficient to drive reward-related behaviors. Additionally, it is unknown whether drugs of abuse administered directly into the PVT are sufficient to drive reward-related behaviors. Here, using behavioral as well as pathway and cell-type specific approaches, we manipulate PVT activity as well as the PVT-to-nucleus accumbens shell (NAcSh) neurocircuit to explore reward phenotypes. First, whole-cell brain slice electrophysiology recordings on PVT neurons that project to the NAcSh showed that bath perfusion of morphine (10 μM) caused hyperpolarization of the resting membrane potential, increased rheobase, and decreased intrinsic membrane excitability. Additionally, we found that direct injections of morphine (50 ng) in the PVT of mice were sufficient to generate conditioned place preference (CPP) for the morphine-paired chamber. Mimicking the inhibitory effect of morphine, we employed a chemogenetic approach to inhibit PVT neurons that projected to the NAcSh and found that pairing the inhibition of these PVT neurons with a specific context evoked the acquisition of CPP. Lastly, using brain slice electrophysiology, we found that bath perfused morphine (10 μM) significantly reduced PVT excitatory synaptic transmission on both dopamine D1-receptor and D2-receptor expressing medium spiny neurons in the NAcSh, but that inhibiting PVT afferents in the NAcSh was not sufficient to evoke CPP. Together, these results provide valuable insights into the intricate interplay between the PVT and reward-related behaviors.Significance StatementThis study investigates the direct impact of paraventricular thalamic nucleus (PVT) inhibition on reward-related behaviors, employing manipulations related to drugs of abuse, specifically morphine, as well as employing chemogenetic approaches that replicate the inhibitory effects induced by morphine. Our findings reveal that morphine exerts an inhibitory effect on PVT neurons projecting to the nucleus accumbens shell (NAcSh). Furthermore, local administration of morphine within the PVT elicits reward-related behaviors, a response mimicked by the inhibition of PVT neurons projecting to the NAcSh. These results firmly establish the PVT as an integral component of a complex neurocircuit involved in the acquisition of associations with opioid-related contexts. Additionally, these results provide compelling evidence linking the inhibition of PVT neurons to reward processes.

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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

Cited by 6 publications

References 132 publications

Voluntary alcohol intake alters the motivation to seek intravenous oxycodone and neuronal activation during the reinstatement of oxycodone and sucrose seeking

Voluntary alcohol intake alters the motivation to seek intravenous oxycodone and neuronal activation during the reinstatement of oxycodone and sucrose seeking

Comparing withdrawal- and anxiety-like behaviors following oral and subcutaneous oxycodone administration in C57BL/6 mice

The Paraventricular Thalamic Nucleus and Its Projections in Regulating Reward and Context Associations

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