Ablation of μ opioid receptor-expressing GABA neurons in rostromedial tegmental nucleus increases ethanol consumption and regulates ethanol-related behaviors

Fu, Rao; Chen, Xing; Zuo, Wanhong; Li, Jing; Kang, Seungwoo; Zhou, Li; Siegel, Allan; Bekker, Alex; Ye, Jiang Hong

doi:10.1016/j.neuropharm.2016.02.027

Cited by 29 publications

(19 citation statements)

References 56 publications

(74 reference statements)

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“…In fact, and after a period of conditioning, the mice spent significantly more time in the chamber paired with EtOH. These results are consistent with earlier studies, from our laboratory (Al Bahi and Dreyer 2014;Bahi et al 2014b) and from others, in which 2 g kg −1 EtOH elicited a robust CPP in both mice (Huang et al 2018;Marcus et al 2017;Xie et al 2019), and rats (Fu et al 2016;Okhuarobo et al 2018;Zuo et al 2017). Next, we found, in the 1st experiment, that repeated daily exposure to both conditioning chambers successfully extinguished this CPP.…”

Section: Discussionsupporting

confidence: 93%

Environmental enrichment decreases chronic psychosocial stress-impaired extinction and reinstatement of ethanol conditioned place preference in C57BL/6 male mice

Bahí

Dreyer

2019

Psychopharmacology

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Rationale During the last few decades, alcohol use disorders (AUD) have reached an epidemic prevalence, yet social influences on alcoholism have not been fully addressed. Several factors can modulate alcohol intake. On one hand, stress can reinforce ethanol-induced behaviors and be an important component in AUD and alcoholism. On the other hand, environmental enrich-ment (EE) has a neuroprotective role and prevents the development of excessive ethanol intake in rodents. However, studies showing the role of EE in chronic psychosocial stress-impaired ethanol-conditioned rewards are nonexistent. Aim The purpose of the current study is to explore the potential protective role of EE on extinction and reinstatement of ethanolconditioned place preference (EtOH-CPP) following chronic psychosocial stress. Methods In the first experiment and after the EtOH-CPP test, the mice were subjected to 15 days of chronic stress, then housed in a standard (SE) or enriched environment (EE) while EtOH-CPP extinction was achieved by repeated exposure to the CPP chambers without ethanol injection. In the second experiment and after the EtOH-CPP test, extinction was achieved as described above. Mice were then exposed to chronic stress for 2 weeks before being housed in a SE or EE. EtOH-CPP reinstatement was induced by a single exposure to the conditioning chambers. Results As expected, stress exposure increased anxiety-like behavior and reduced weight gain. More importantly, we found that EE significantly shortened chronic stress-delayed extinction and decreased the reinstatement of EtOH-CPP. Conclusion These results support the hypothesis that EE reduces the impact of alcohol-associated environmental stimuli, and hence it may be a general intervention for reducing cue-elicited craving and relapse in humans.

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Section: Discussionsupporting

confidence: 93%

Environmental enrichment decreases chronic psychosocial stress-impaired extinction and reinstatement of ethanol conditioned place preference in C57BL/6 male mice

Bahí

Dreyer

2019

Psychopharmacology

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“…A number of studies have implicated the RMTg in processing the aversive properties of drugs of abuse including stimulants [26,30,31,48,49], opiates [50][51][52], and alcohol [53]. In addition, loss of RMTg function is associated with increased voluntary ethanol intake [54][55][56], whereas pharmacological activation of the RMTg decreases ethanol preference and consumption [54]. More recently, acute exposure to low-dose ethanol was shown to increase cFos expression in RMTg-projecting LHb neurons [57].…”

Section: Discussionmentioning

confidence: 99%

Inhibition of the rostromedial tegmental nucleus reverses alcohol withdrawal-induced anxiety-like behavior

Glover

Starr

Chao

et al. 2019

Neuropsychopharmacol.

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Acute withdrawal from alcohol is associated with a number of unpleasant symptoms that play an important role in preventing recovery and long-term abstinence. Considerable research has focused on the role that neuropeptide systems and the amygdala play in mediating affective symptoms of acute withdrawal, but promising preclinical findings have not translated successfully into the clinic. The rostromedial tegmental nucleus (RMTg) has been implicated in both fear and anxiety. In addition, RMTg neurons exert inhibitory control over midbrain dopamine neurons, the activity of which are suppressed during acute withdrawal. Thus, we hypothesized that the RMTg may play a role in mediating symptoms of acute withdrawal. Using a chronic ethanol vapor exposure paradigm that renders rats physically dependent on ethanol, we observed significant withdrawal-induced enhancement of cFos expression in the RMTg. This was accompanied by a significant increase in somatic symptoms and a decrease in reward sensitivity as measured by intracranial self-stimulation (ICSS). Both measures followed a similar time course to RMTg cFos expression with peak symptom severity occurring 12 h following cessation of ethanol exposure. Heightened anxiety-like behavior was also observed in withdrawn rats at this same time point. RMTg inhibition had no effect on somatic signs of withdrawal or withdrawal-induced changes in reward sensitivity, but significantly attenuated withdrawal-induced anxiety-like behavior. Together, these data demonstrate that the RMTg plays a distinct role in the negative affective state associated with acute withdrawal and may therefore be critically involved in the neurobiological mechanisms that promote relapse during early stages of recovery.

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“…In agreement with this, the cFos results presented here likely reflect enhanced RMTg and LHb cell firing following presentation of a cue predicting the aversive properties of EtOH or LiCl and suggest that these regions may play a role in signaling the aversive properties of drugs including EtOH. Interestingly, recent work has shown increased EtOH intake following muscimol inhibition (Fu et al., ) or dermorphin–saporin ablation of mu‐opioid‐expressing neurons within the RMTg (Fu et al., ) suggesting that activity within the RMTg plays a key role in the propensity to drink. In light of the present findings, these data suggest that the RMTg may be critical for signaling the aversive properties of EtOH, which may function to limit intake.…”

Section: Discussionmentioning

confidence: 99%

Role for the Rostromedial Tegmental Nucleus in Signaling the Aversive Properties of Alcohol

Glover

McDougle

Siegel

et al. 2016

Alcoholism Clin & Exp Res

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Background While the rewarding effects of alcohol contribute significantly to its addictive potential, it is becoming increasingly appreciated that alcohol’s aversive properties also play an important role in the propensity to drink. Despite this, the neurobiological mechanism for alcohol’s aversive actions is not well understood. The rostromedial tegmental nucleus (RMTg) was recently characterized for its involvement in aversive signaling and has been shown to encode the aversive properties of cocaine, yet its involvement in alcohol’s aversive actions have not been elucidated. Methods Adult male and female Long-Evans rats underwent conditioned taste aversion (CTA) procedures where exposure to a novel saccharin solution was paired with i.p. administration of saline, lithium chloride (LiCl), or ethanol (EtOH). Control rats underwent the same paradigm except that drug and saccharin exposure were explicitly unpaired. Saccharin consumption was measured on test day in the absence of drug administration and rats were sacrificed 90–105 min following access to saccharin. Brains were subsequently harvested and processed for cFos immunohistochemistry. The number of cFos labeled neurons was counted in the RMTg and the lateral habenula (LHb) – a region that sends prominent glutamatergic input to the RMTg. Results In rats that received paired drug and saccharin exposure, EtOH and LiCl induced significant CTA compared to saline to a similar degree in males and females. Both EtOH- and LiCl-induced CTA significantly enhanced cFos expression in the RMTg and LHb but not the hippocampus. Similar to behavioral measures, no significant effect of sex on CTA-induced cFos expression was observed. cFos expression in both the RMTg and LHb was significantly correlated to CTA magnitude with greater cFos being associated with more pronounced CTA. In addition, cFos expression in the RMTg was positively correlated with LHb cFos. Conclusions These data suggest that the RMTg and LHb are involved in the expression of CTA and are consistent with previous work implicating the RMTg in aversive signaling. Furthermore, increased cFos expression in the RMTg following EtOH-induced CTA suggests that this region plays a role in signaling alcohol’s aversive properties.

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Ablation of μ opioid receptor-expressing GABA neurons in rostromedial tegmental nucleus increases ethanol consumption and regulates ethanol-related behaviors

Cited by 29 publications

References 56 publications

Environmental enrichment decreases chronic psychosocial stress-impaired extinction and reinstatement of ethanol conditioned place preference in C57BL/6 male mice

Environmental enrichment decreases chronic psychosocial stress-impaired extinction and reinstatement of ethanol conditioned place preference in C57BL/6 male mice

Inhibition of the rostromedial tegmental nucleus reverses alcohol withdrawal-induced anxiety-like behavior

Role for the Rostromedial Tegmental Nucleus in Signaling the Aversive Properties of Alcohol

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