Stress Hormone Exposure Reduces MGluR5 Expression in the Nucleus Accumbens: Functional Implications for Interoceptive Sensitivity to Alcohol

Overview

Journal Neuropsychopharmacology

Date 2014 Apr 10

PMID 24713611

Citations 20

Authors

Joyce Besheer

Kristen R Fisher

Anel A Jaramillo

Suzanne Frisbee

Reginald Cannady

Affiliations

Soon will be listed here.

Abstract

Escalations in alcohol drinking associated with experiencing stressful life events and chronic life stressors may be related to altered sensitivity to the interoceptive/subjective effects of alcohol. Indeed, through the use of drug discrimination methods, rats show decreased sensitivity to the discriminative stimulus (interoceptive) effects of alcohol following exposure to the stress hormone corticosterone (CORT). This exposure produces heightened elevations in plasma CORT levels (eg, as may be experienced by an individual during stressful episodes). We hypothesized that decreased sensitivity to alcohol may be related, in part, to changes in metabotropic glutamate receptors-subtype 5 (mGluR5) in the nucleus accumbens, as these receptors in this brain region are known to regulate the discriminative stimulus effects of alcohol. In the accumbens, we found reduced mGluR5 expression (immunohistochemistry and Western blot) and decreased neural activation (as measured by c-Fos immunohistochemistry) in response to a moderate alcohol dose (1 g/kg) following CORT exposure (7 days). The functional role of these CORT-induced adaptations in relation to the discriminative stimulus effects of alcohol was confirmed, as both the systemic administration of 3-Cyano-N-(1,3-diphenyl-1H-pyrazol-5-yl)benzamide (CDPPB) an mGluR5 positive allosteric modulator and the intra-accumbens administration of (R,S)-2-Amino-2-(2-chloro-5-hydroxyphenyl)acetic acid sodium salt (CHPG) an mGluR5 agonist restored sensitivity to alcohol in discrimination-trained rats. These results suggest that activation of mGluR5 may alleviate the functional impact of the CORT-induced downregulation of mGluR5 in relation to sensitivity to alcohol. Understanding the contribution of such neuroadaptations to the interoceptive effects of alcohol may enrich our understanding of potential changes in subjective sensitivity to alcohol during stressful episodes.

Citing Articles

mGlu and mGlu receptor negative allosteric modulators attenuate the interoceptive effects of alcohol in male and female rats.

Tyler R, Van Voorhies K, Blough B, Landavazo A, Besheer J Pharmacol Biochem Behav. 2024; 239():173767.

PMID: 38608960 PMC: 11090252. DOI: 10.1016/j.pbb.2024.173767.

Predator odor (TMT) exposure potentiates interoceptive sensitivity to alcohol and increases GABAergic gene expression in the anterior insular cortex and nucleus accumbens in male rats.

Tyler R, Bluitt M, Van Voorhies K, Ornelas L, Weinberg B, Besheer J Alcohol. 2022; 104:1-11.

PMID: 36150613 PMC: 9733390. DOI: 10.1016/j.alcohol.2022.07.002.

Interoception and alcohol: Mechanisms, networks, and implications.

Lovelock D, Tyler R, Besheer J Neuropharmacology. 2021; 200:108807.

PMID: 34562442 PMC: 8541934. DOI: 10.1016/j.neuropharm.2021.108807.

Low-dose alcohol: Interoceptive and molecular effects and the role of dentate gyrus in rats.

Randall P, Lovelock D, VanVoorhies K, Agan V, Kash T, Besheer J Addict Biol. 2020; 26(3):e12965.

PMID: 33015936 PMC: 8019682. DOI: 10.1111/adb.12965.

The synthetically produced predator odor 2,5-dihydro-2,4,5-trimethylthiazoline increases alcohol self-administration and alters basolateral amygdala response to alcohol in rats.

Makhijani V, Franklin J, Van Voorhies K, Fortino B, Besheer J Psychopharmacology (Berl). 2020; 238(1):67-82.

PMID: 32978649 PMC: 7796942. DOI: 10.1007/s00213-020-05659-w.

References

Stolerman I . Drugs of abuse: behavioural principles, methods and terms. Trends Pharmacol Sci. 1992; 13(5):170-6. DOI: 10.1016/0165-6147(92)90059-f. View

Krystal J, Mathew S, DSouza D, Garakani A, Gunduz-Bruce H, Charney D . Potential psychiatric applications of metabotropic glutamate receptor agonists and antagonists. CNS Drugs. 2010; 24(8):669-93. DOI: 10.2165/11533230-000000000-00000. View

Liu F, Grauer S, Kelley C, Navarra R, Graf R, Zhang G . ADX47273 [S-(4-fluoro-phenyl)-{3-[3-(4-fluoro-phenyl)-[1,2,4]-oxadiazol-5-yl]-piperidin-1-yl}-methanone]: a novel metabotropic glutamate receptor 5-selective positive allosteric modulator with preclinical antipsychotic-like and procognitive.... J Pharmacol Exp Ther. 2008; 327(3):827-39. DOI: 10.1124/jpet.108.136580. View

Pin J, Galvez T, Prezeau L . Evolution, structure, and activation mechanism of family 3/C G-protein-coupled receptors. Pharmacol Ther. 2003; 98(3):325-54. DOI: 10.1016/s0163-7258(03)00038-x. View

Bachtell R, Wang Y, Freeman P, Risinger F, Ryabinin A . Alcohol drinking produces brain region-selective changes in expression of inducible transcription factors. Brain Res. 1999; 847(2):157-65. DOI: 10.1016/s0006-8993(99)02019-3. View

Clifton N, Morisot N, Girardon S, Millan M, Loiseau F . Enhancement of social novelty discrimination by positive allosteric modulators at metabotropic glutamate 5 receptors: adolescent administration prevents adult-onset deficits induced by neonatal treatment with phencyclidine. Psychopharmacology (Berl). 2012; 225(3):579-94. DOI: 10.1007/s00213-012-2845-3. View

Cotman C, Monaghan D . Anatomical organization of excitatory amino acid receptors and their properties. Adv Exp Med Biol. 1986; 203:237-52. DOI: 10.1007/978-1-4684-7971-3_18. View

Cozzoli D, Courson J, Caruana A, Miller B, Greentree D, Thompson A . Nucleus accumbens mGluR5-associated signaling regulates binge alcohol drinking under drinking-in-the-dark procedures. Alcohol Clin Exp Res. 2012; 36(9):1623-33. PMC: 3382009. DOI: 10.1111/j.1530-0277.2012.01776.x. View

Besheer J, Grondin J, Salling M, Spanos M, Stevenson R, Hodge C . Interoceptive effects of alcohol require mGlu5 receptor activity in the nucleus accumbens. J Neurosci. 2009; 29(30):9582-91. PMC: 2845172. DOI: 10.1523/JNEUROSCI.2366-09.2009. View

10.

Venero C, Borrell J . Rapid glucocorticoid effects on excitatory amino acid levels in the hippocampus: a microdialysis study in freely moving rats. Eur J Neurosci. 1999; 11(7):2465-73. DOI: 10.1046/j.1460-9568.1999.00668.x. View

11.

Olive M . Metabotropic glutamate receptor ligands as potential therapeutics for addiction. Curr Drug Abuse Rev. 2009; 2(1):83-98. PMC: 2717506. DOI: 10.2174/1874473710902010083. View

12.

Schotanus S, Chergui K . Dopamine D1 receptors and group I metabotropic glutamate receptors contribute to the induction of long-term potentiation in the nucleus accumbens. Neuropharmacology. 2008; 54(5):837-44. DOI: 10.1016/j.neuropharm.2007.12.012. View

13.

Besheer J, Stevenson R, Hodge C . mGlu5 receptors are involved in the discriminative stimulus effects of self-administered ethanol in rats. Eur J Pharmacol. 2006; 551(1-3):71-5. PMC: 1676072. DOI: 10.1016/j.ejphar.2006.08.071. View

14.

Childs E, OConnor S, de Wit H . Bidirectional interactions between acute psychosocial stress and acute intravenous alcohol in healthy men. Alcohol Clin Exp Res. 2011; 35(10):1794-803. PMC: 3183385. DOI: 10.1111/j.1530-0277.2011.01522.x. View

15.

Kinney G, OBrien J, Lemaire W, Burno M, Bickel D, Clements M . A novel selective positive allosteric modulator of metabotropic glutamate receptor subtype 5 has in vivo activity and antipsychotic-like effects in rat behavioral models. J Pharmacol Exp Ther. 2004; 313(1):199-206. DOI: 10.1124/jpet.104.079244. View

16.

Besheer J, Fisher K, Lindsay T, Cannady R . Transient increase in alcohol self-administration following a period of chronic exposure to corticosterone. Neuropharmacology. 2013; 72:139-47. PMC: 3696398. DOI: 10.1016/j.neuropharm.2013.04.036. View

17.

Sinclair C, Cleva R, Hood L, Olive M, Gass J . mGluR5 receptors in the basolateral amygdala and nucleus accumbens regulate cue-induced reinstatement of ethanol-seeking behavior. Pharmacol Biochem Behav. 2012; 101(3):329-35. PMC: 3310253. DOI: 10.1016/j.pbb.2012.01.014. View

18.

Fowler S, Walker J, Klakotskaia D, Will M, Serfozo P, Simonyi A . Effects of a metabotropic glutamate receptor 5 positive allosteric modulator, CDPPB, on spatial learning task performance in rodents. Neurobiol Learn Mem. 2012; 99:25-31. DOI: 10.1016/j.nlm.2012.10.010. View

19.

Besheer J, Fisher K, Grondin J, Cannady R, Hodge C . The effects of repeated corticosterone exposure on the interoceptive effects of alcohol in rats. Psychopharmacology (Berl). 2011; 220(4):809-22. PMC: 3422726. DOI: 10.1007/s00213-011-2533-8. View

20.

Brakeman P, Lanahan A, OBrien R, Roche K, Barnes C, Huganir R . Homer: a protein that selectively binds metabotropic glutamate receptors. Nature. 1997; 386(6622):284-8. DOI: 10.1038/386284a0. View