Stress Hormone Exposure Reduces mGluR5 Expression in the Nucleus Accumbens: Functional Implications for Interoceptive Sensitivity to Alcohol

Besheer, Joyce; Fisher, Kristen R.; Jaramillo, Anel A.; Frisbee, Suzanne; Cannady, Reginald

doi:10.1038/npp.2014.85

Cited by 24 publications

(50 citation statements)

References 78 publications

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“…The processes driving these adaptations need to be examined. Preclinical studies indicate that acute administration of corticosterone (27) and acute stress-induced increases in corticosterone (28) reduce the expression of mGluR5. However, PTSD seems to be associated with down-regulation of the glucocorticoid-related gene serum-and glucocorticoidregulated kinase 1 (SGK1) (29) and now, FKBP5.…”

Section: Discussionmentioning

confidence: 99%

Altered metabotropic glutamate receptor 5 markers in PTSD: In vivo and postmortem evidence

Holmes

Girgenti

Davis

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

110

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Posttraumatic stress disorder (PTSD) is a prevalent and highly disabling disorder, but there is currently no targeted pharmacological treatment for it. Dysfunction of the glutamate system has been implicated in trauma and stress psychopathology, resulting in a growing interest in modulation of the glutamate system for the treatment of PTSD. Specifically, the metabotropic glutamate receptor 5 (mGluR5) represents a promising treatment target. We used [18F]FPEB, a radioligand that binds to the mGluR5, and positron emission tomography (PET) to quantify in vivo mGluR5 availability in human PTSD vs. healthy control (HCs) subjects. In an independent sample of human postmortem tissue, we investigated expression of proteins that have a functional relationship with mGluR5 and glucocorticoids in PTSD. We observed significantly higher cortical mGluR5 availability in PTSD in vivo and positive correlations between mGluR5 availability and avoidance symptoms. In the postmortem sample, we observed up-regulation of SHANK1, a protein that anchors mGluR5 to the cell surface, as well as decreased expression of FKBP5, implicating aberrant glucocorticoid functioning in PTSD. Results of this study provide insight into molecular mechanisms underlying PTSD and suggest that mGluR5 may be a promising target for mechanism-based treatments aimed at mitigating this disorder.

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Section: Discussionmentioning

confidence: 99%

Altered metabotropic glutamate receptor 5 markers in PTSD: In vivo and postmortem evidence

Holmes

Girgenti

Davis

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

110

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“…Rats were trained using the same behavioral chambers and procedures as previous studies from this laboratory (Besheer et al 2012; Besheer et al 2014; Besheer et al 2009). Briefly, immediately following intragastric gavage (IG) administration of alcohol (1 g/kg) or water rats were placed in the chambers.…”

Section: Methodsmentioning

confidence: 99%

The role of varenicline on alcohol-primed self-administration and seeking behavior in rats

et al. 2015

Self Cite

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Rationale Varenicline, a smoking-cessation agent, may be useful in treating alcohol use disorders. An important consideration when studying factors that influence drinking/relapse is influence of the pharmacological effects of alcohol on these behaviors. Pre-exposure to alcohol (priming) can increase craving, drinking and seeking behaviors. Objectives The primary goal of this work was to determine the effects of varenicline on alcohol-primed self-administration and seeking behavior in male Long Evans rats. Methods First, we assessed whether varenicline (0, 0.3, 1, 3 mg/kg, IP) has alcohol-like discriminative stimulus effects and whether varenicline alters sensitivity to alcohol in rats trained to discriminate a moderate alcohol dose (1 g/kg, IG) vs. water. Second, animals trained to self-administer alcohol underwent assessments to test the effects of: (i) varenicline (0, 0.3, 1, 3 mg/kg, IP) on self-administration, (ii) alcohol priming (0, 0.3, 1 g/kg, IG) on self-administration and seeking behavior, (iii) varenicline (1 mg/kg) in combination with alcohol priming (1 g/kg) on these behaviors. Results Varenicline did not substitute for alcohol, but disrupted the expression of sensitivity to alcohol. Varenicline decreased self-administration, but only at a motor impairing dose (3 mg/kg). Alcohol priming decreased self-administration and seeking behavior. Varenicline (1 mg/kg) blocked this effect under self-administration conditions, but not seeking conditions, which effectively resulted in increased alcohol intake. Conclusions These findings suggest the importance of further behavioral and mechanistic studies to evaluate the use of varenicline in treating alcohol use disorders and its potential impact on drinking patterns in smokers using varenicline as a smoking cessation aid.

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“…Daily training sessions (Monday–Friday) were conducted as we previously described (Besheer et al, 2012, 2014; Cannady et al, 2011). Briefly, alcohol (1 g/kg) or water was administered IG and immediately afterward, rats were placed in the chambers.…”

Section: Methodsmentioning

confidence: 99%

“…Discriminative stimulus (interoceptive) effects of drugs are commonly indexed using drug discrimination procedures in both humans and animals. Using these procedures, we have demonstrated that following a 7-day period of exposure to the stress hormone CORT, rats show decreased sensitivity to the discriminative stimulus effects of both experimenter- and self-administered alcohol (e.g., decreased alcohol-appropriate responses; Besheer, Fisher, Grondin, Cannady, & Hodge, 2012; Besheer, Fisher, Jaramillo, Frisbee, & Cannady, 2014). Additionally, these CORT-induced behavioral adaptations are suggested to be related, in part, to glutamatergic neuroadaptations, and functional involvement of the Group I metabotropic glutamate receptor subtype 5 (mGluR5) has been determined (Besheer et al, 2014).…”

Section: Introductionmentioning

confidence: 99%

“…Using these procedures, we have demonstrated that following a 7-day period of exposure to the stress hormone CORT, rats show decreased sensitivity to the discriminative stimulus effects of both experimenter- and self-administered alcohol (e.g., decreased alcohol-appropriate responses; Besheer, Fisher, Grondin, Cannady, & Hodge, 2012; Besheer, Fisher, Jaramillo, Frisbee, & Cannady, 2014). Additionally, these CORT-induced behavioral adaptations are suggested to be related, in part, to glutamatergic neuroadaptations, and functional involvement of the Group I metabotropic glutamate receptor subtype 5 (mGluR5) has been determined (Besheer et al, 2014). Together, these findings have led to the suggestion that decreased sensitivity to alcohol following CORT exposure may be related to an underlying hyperglutamatergic state, as observed in other studies (Joëls, Sarabdjitsingh, & Karst, 2012).…”

Section: Introductionmentioning

confidence: 99%

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Activation of mGluR2/3 following stress hormone exposure restores sensitivity to alcohol in rats

Jaramillo

Randall

Frisbee

et al. 2015

Alcohol

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Sensitivity to the interoceptive effects of alcohol is blunted following a period of exposure to the stress hormone corticosterone (CORT), an effect that is suggested to be related, in part, to glutamatergic neuroadaptations. Group II metabotropic glutamate receptors (subtypes 2 and 3; mGluR2/3) modulate several drug- and alcohol-related behaviors, including the interoceptive (discriminative stimulus) effects of alcohol. Therefore, we sought to determine if manipulation of mGluR2/3 would restore sensitivity to the interoceptive effects of alcohol following CORT exposure. Using a two-lever drug discrimination task, male Long-Evans rats were trained to discriminate alcohol (1 g/kg, intragastric [IG]) vs. water. First, the effect of mGluR2/3 antagonism on the discriminative stimulus effects of alcohol was determined using LY341495 (0.3–3.0 mg/kg; intraperitoneal [IP]). Next, the effects of mGluR2/3 antagonism and activation were assessed in discrimination-trained animals exposed to CORT (300 μg/mL) in the home cage drinking water or water only, for 7 days. Following CORT exposure, decreased sensitivity to alcohol (1 g/kg) was observed. Pretreatment with the mGluR2/3 agonist LY379268 (1.0–3.0 mg/kg; IP), but not the mGluR2/3 antagonist (0.3–1.0 mg/kg; IP), restored sensitivity to alcohol. Additionally, in Water controls, mGluR2/3 antagonism and mGluR2/3 activation disrupted expression of the discriminative stimulus effects of alcohol. Together, these findings suggest that blunted sensitivity to the interoceptive effects of alcohol following an episode of heightened stress hormone levels may be due to adaptations in mGluR2/3-related systems. The ability of mGluR2/3 activation to restore sensitivity to alcohol under these conditions lends further support for the importance of these receptors under stress-related conditions.

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Stress Hormone Exposure Reduces mGluR5 Expression in the Nucleus Accumbens: Functional Implications for Interoceptive Sensitivity to Alcohol

Cited by 24 publications

References 78 publications

Altered metabotropic glutamate receptor 5 markers in PTSD: In vivo and postmortem evidence

Altered metabotropic glutamate receptor 5 markers in PTSD: In vivo and postmortem evidence

The role of varenicline on alcohol-primed self-administration and seeking behavior in rats

Activation of mGluR2/3 following stress hormone exposure restores sensitivity to alcohol in rats

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