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.
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References
Ardayfio P, Kim KS (2006). Anxiogenic-like effect of chronic corticosterone in the light-dark emergence task in mice. Behav Neurosci 120: 249–256.
Bachtell RK, Wang YM, Freeman P, Risinger FO, Ryabinin AE (1999). Alcohol drinking produces brain region-selective changes in expression of inducible transcription factors. Brain Res 847: 157–165.
Badiani A, Oates MM, Day HE, Watson SJ, Akil H, Robinson TE (1998). Amphetamine-induced behavior, dopamine release, and c-fos mRNA expression: modulation by environmental novelty. J Neurosci 18: 10579–10593.
Bagley J, Moghaddam B (1997). Temporal dynamics of glutamate efflux in the prefrontal cortex and in the hippocampus following repeated stress: effects of pretreatment with saline or diazepam. Neuroscience 77: 65–73.
Banks ML, Czoty PW, Nader MA (2007). The influence of reinforcing effects of cocaine on cocaine-induced increases in extinguished responding in cynomolgus monkeys. Psychopharmacology 192: 449–456.
Basar K, Sesia T, Groenewegen H, Steinbusch HW, Visser-Vandewalle V, Temel Y (2010). Nucleus accumbens and impulsivity. Prog Neurobiol 92: 533–557.
Becker HC, Lopez MF, Doremus-Fitzwater TL (2011). Effects of stress on alcohol drinking: a review of animal studies. Psychopharmacology 218: 131–156.
Besheer J, Fisher KR, Cannady R, Grondin JJ, Hodge CW (2012a). Intra-amygdala inhibition of ERK(1/2) potentiates the discriminative stimulus effects of alcohol. Behav Brain Res 228: 398–405.
Besheer J, Fisher KR, Grondin JJ, Cannady R, Hodge CW (2012b). The effects of repeated corticosterone exposure on the interoceptive effects of alcohol in rats. Psychopharmacology 220: 809–822.
Besheer J, Fisher KR, Lindsay TG, Cannady R (2013). Transient increase in alcohol self-administration following a period of chronic exposure to corticosterone. Neuropharmacology 72: 139–147.
Besheer J, Grondin JJ, Cannady R, Sharko AC, Faccidomo S, Hodge CW (2010). Metabotropic glutamate receptor 5 activity in the nucleus accumbens is required for the maintenance of ethanol self-administration in a rat genetic model of high alcohol intake. Biol Psychiatry 67: 812–822.
Besheer J, Grondin JJ, Salling MC, Spanos M, Stevenson RA, Hodge CW (2009). Interoceptive effects of alcohol require mGlu5 receptor activity in the nucleus accumbens. J Neurosci 29: 9582–9591.
Besheer J, Hodge CW (2005). Pharmacological and anatomical evidence for an interaction between mGluR5- and GABA(A) alpha1-containing receptors in the discriminative stimulus effects of ethanol. Neuropsychopharmacology 30: 747–757.
Besheer J, Schroeder JP, Stevenson RA, Hodge CW (2008). Ethanol-induced alterations of c-Fos immunoreactivity in specific limbic brain regions following ethanol discrimination training. Brain Res 1232: 124–131.
Besheer J, Stevenson RA, Hodge CW (2006). mGlu5 receptors are involved in the discriminative stimulus effects of self-administered ethanol in rats. Eur J Pharmacol 551: 71–75.
Brakeman PR, Lanahan AA, O'Brien R, Roche K, Barnes CA, Huganir RL et al (1997). Homer: a protein that selectively binds metabotropic glutamate receptors. Nature 386: 284–288.
Britt JP, Benaliouad F, McDevitt RA, Stuber GD, Wise RA, Bonci A (2012). Synaptic and behavioral profile of multiple glutamatergic inputs to the nucleus accumbens. Neuron 76: 790–803.
Campioni MR, Xu M, McGehee DS (2009). Stress-induced changes in nucleus accumbens glutamate synaptic plasticity. J Neurophysiol 101: 3192–3198.
Cannady R, Grondin JJ, Fisher KR, Hodge CW, Besheer J (2011). Activation of Group II metabotropic glutamate receptors inhibits the discriminative stimulus effects of alcohol via selective activity within the amygdala. Neuropsychopharmacology 36: 2328–2338.
Chaouloff F, Groc L (2011). Temporal modulation of hippocampal excitatory transmission by corticosteroids and stress. Front Neuroendocrinol 32: 25–42.
Childs E, O'Connor S, de Wit H (2011). Bidirectional interactions between acute psychosocial stress and acute intravenous alcohol in healthy men. Alcohol Clin Exp Res 35: 1794–1803.
Clifton NE, Morisot N, Girardon S, Millan MJ, Loiseau F (2013). 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 225: 579–594.
Cotman CW, Monaghan DT (1986). Anatomical organization of excitatory amino acid receptors and their properties. Adv Exp Med Biol 203: 237–252.
Cozzoli DK, Courson J, Caruana AL, Miller BW, Greentree DI, Thompson AB et al (2012). Nucleus accumbens mGluR5-associated signaling regulates binge alcohol drinking under drinking-in-the-dark procedures. Alcoholism, Clin Exp Res 36: 1623–1633.
D'Ascenzo M, Podda MV, Fellin T, Azzena GB, Haydon P, Grassi C (2009). Activation of mGluR5 induces spike afterdepolarization and enhanced excitability in medium spiny neurons of the nucleus accumbens by modulating persistent Na+ currents. J Physiol 587 (Pt 13): 3233–3250.
D'Souza MS, Markou A (2011). Metabotropic glutamate receptor 5 antagonist 2-methyl-6-(phenylethynyl)pyridine (MPEP) microinfusions into the nucleus accumbens shell or ventral tegmental area attenuate the reinforcing effects of nicotine in rats. Neuropharmacology 61: 1399–1405.
Fowler SW, Ramsey AK, Walker JM, Serfozo P, Olive MF, Schachtman TR et al (2011). Functional interaction of mGlu5 and NMDA receptors in aversive learning in rats. Neurobiol Learn Mem 95: 73–79.
Fowler SW, Walker JM, Klakotskaia D, Will MJ, Serfozo P, Simonyi A et al (2013). Effects of a metabotropic glutamate receptor 5 positive allosteric modulator, CDPPB, on spatial learning task performance in rodents. Neurobiol Learn Mem 99: 25–31.
Friedman DP, Aggleton JP, Saunders RC (2002). Comparison of hippocampal, amygdala, and perirhinal projections to the nucleus accumbens: combined anterograde and retrograde tracing study in the Macaque brain. J Comp Neurol 450: 345–365.
Garcia-Keller C, Martinez SA, Esparza MA, Bollati F, Kalivas PW, Cancela LM (2013). Cross-sensitization between cocaine and acute restraint stress is associated with sensitized dopamine but not glutamate release in the nucleus accumbens. Eur J Neurosci 37: 982–995.
Gass JT, Olive MF (2009). Positive allosteric modulation of mGluR5 receptors facilitates extinction of a cocaine contextual memory. Biol Psychiatry 65: 717–720.
Gourley SL, Taylor JR (2009). Recapitulation and reversal of a persistent depression-like syndrome in rodents. Curr Protoc Neurosci Chapter 9: Unit 9 32.
Grant KA (1999). Strategies for understanding the pharmacological effects of ethanol with drug discrimination procedures. Pharmacol Biochem Behav 64: 261–267.
Groenewegen HJ, Trimble M (2007). The ventral striatum as an interface between the limbic and motor systems. CNS Spectr 12: 887–892.
Hache G, Guiard BP, Le Dantec Y, Orvoen S, David DJ, Gardier AM et al (2012). Antinociceptive effects of fluoxetine in a mouse model of anxiety/depression. Neuroreport 23: 525–529.
Herman JP (1993). Regulation of adrenocorticosteroid receptor mRNA expression in the central nervous system. Cell Mol Neurobiol 13: 349–372.
Herman JP, Ostrander MM, Mueller NK, Figueiredo H (2005). Limbic system mechanisms of stress regulation: hypothalamo-pituitary-adrenocortical axis. Prog Neuropsychopharmacol Biol Psychiatry 29: 1201–1213.
Huang CC, Hsu KS (2012). Activation of NMDA receptors reduces metabotropic glutamate receptor-induced long-term depression in the nucleus accumbens via a CaMKII-dependent mechanism. Neuropharmacology 63: 1298–1307.
Iyo AH, Feyissa AM, Chandran A, Austin MC, Regunathan S, Karolewicz B (2010). Chronic corticosterone administration down-regulates metabotropic glutamate receptor 5 protein expression in the rat hippocampus. Neuroscience 169: 1567–1574.
Joca SR, Ferreira FR, Guimaraes FS (2007). Modulation of stress consequences by hippocampal monoaminergic, glutamatergic and nitrergic neurotransmitter systems. Stress 10: 227–249.
Kinney GG, O'Brien JA, Lemaire W, Burno M, Bickel DJ, Clements MK et al (2005). 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 313: 199–206.
Krystal JH, Mathew SJ, D'Souza DC, Garakani A, Gunduz-Bruce H, Charney DS (2010). Potential psychiatric applications of metabotropic glutamate receptor agonists and antagonists. CNS Drugs 24: 669–693.
Lemos JC, Wanat MJ, Smith JS, Reyes BA, Hollon NG, Van Bockstaele EJ et al (2012). Severe stress switches CRF action in the nucleus accumbens from appetitive to aversive. Nature 490: 402–406.
Liu F, Grauer S, Kelley C, Navarra R, Graf R, Zhang G et al (2008). 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 activities. J Pharmacol Exper Ther 327: 827–839.
McEwen BS (2007). Physiology and neurobiology of stress and adaptation: central role of the brain. Physiol Rev 87: 873–904.
McEwen BS, De Kloet ER, Rostene W (1986). Adrenal steroid receptors and actions in the nervous system. Physiol Rev 66: 1121–1188.
Mihindou C, Vouillac C, Koob GF, Ahmed SH (2011). Preclinical validation of a novel cocaine exposure therapy for relapse prevention. Biol Psychiatry 70: 593–598.
Moghaddam B (1993). Stress preferentially increases extraneuronal levels of excitatory amino acids in the prefrontal cortex: comparison to hippocampus and basal ganglia. J Neurochem 60: 1650–1657.
Morales-Medina JC, Sanchez F, Flores G, Dumont Y, Quirion R (2009). Morphological reorganization after repeated corticosterone administration in the hippocampus, nucleus accumbens and amygdala in the rat. J Chem Neuroanat 38: 266–272.
Moussawi K, Pacchioni A, Moran M, Olive MF, Gass JT, Lavin A et al (2009). N-Acetylcysteine reverses cocaine-induced metaplasticity. Nat Neurosci 12: 182–189.
Niswender CM, Conn PJ (2010). Metabotropic glutamate receptors: physiology, pharmacology, and disease. Annu Rev Pharmacol Toxicol 50: 295–322.
Olive MF (2009). Metabotropic glutamate receptor ligands as potential therapeutics for addiction. Curr Drug Abuse Rev 2: 83–98.
Paxinos G, Watson C (1998) The Rat Brain In Stereotaxic Coordinates 4th edn Academic Press: London.
Perrotti LI, Hadeishi Y, Ulery PG, Barrot M, Monteggia L, Duman RS et al (2004). Induction of deltaFosB in reward-related brain structures after chronic stress. J Neurosci 24: 10594–10602.
Phillipson OT, Griffiths AC (1985). The topographic order of inputs to nucleus accumbens in the rat. Neuroscience 16: 275–296.
Pin JP, Galvez T, Prezeau L (2003). Evolution, structure, and activation mechanism of family 3/C G-protein-coupled receptors. Pharmacol Ther 98: 325–354.
Popoli M, Yan Z, McEwen BS, Sanacora G (2012). The stressed synapse: the impact of stress and glucocorticoids on glutamate transmission. Nat Rev Neurosci 13: 22–37.
Rainer Q, Xia L, Guilloux JP, Gabriel C, Mocaer E, Hen R et al (2011). Beneficial behavioural and neurogenic effects of agomelatine in a model of depression/anxiety. Int J Neuropsychopharmacol 15: 1–15.
Reichel CM, Schwendt M, McGinty JF, Olive MF, See RE (2011). Loss of object recognition memory produced by extended access to methamphetamine self-administration is reversed by positive allosteric modulation of metabotropic glutamate receptor 5. Neuropsychopharmacology 36: 782–792.
Schenk S, Partridge B (1999). Cocaine-seeking produced by experimenter-administered drug injections: dose-effect relationships in rats. Psychopharmacology 147: 285–290.
Schotanus SM, Chergui K (2008). Dopamine D1 receptors and group I metabotropic glutamate receptors contribute to the induction of long-term potentiation in the nucleus accumbens. Neuropharmacology 54: 837–844.
Sequeira-Cordero A, Mora-Gallegos A, Cuenca-Berger P, Fornaguera-Trias J (2014). Individual differences in the forced swimming test and neurochemical kinetics in the rat brain. Physiol Behav 128C: 60–69.
Shaffer C, Guo ML, Fibuch EE, Mao LM, Wang JQ (2010). Regulation of group I metabotropic glutamate receptor expression in the rat striatum and prefrontal cortex in response to amphetamine in vivo. Brain Res 1326: 184–192.
Shoji H, Mizoguchi K (2010). Acute and repeated stress differentially regulates behavioral, endocrine, neural parameters relevant to emotional and stress response in young and aged rats. Behav Brain Res 211: 169–177.
Sinclair CM, Cleva RM, Hood LE, Olive MF, Gass JT (2012). mGluR5 receptors in the basolateral amygdala and nucleus accumbens regulate cue-induced reinstatement of ethanol-seeking behavior. Pharmacol Biochem Behav 101: 329–335.
Skorzewska A, Bidzinski A, Hamed A, Lehner M, Turzynska D, Sobolewska A et al (2007). Changes in hippocampal amino acid concentrations after chronic administration of corticosterone. Pharmacol Rep 59: 763–772.
Soderpalm AH, de Wit H (2002). Effects of stress and alcohol on subjective state in humans. Alcohol Clin Exp Res 26: 818–826.
Stauffer SR (2011). Progress toward positive allosteric modulators of the metabotropic glutamate receptor subtype 5 (mGlu(5)). ACS Chem Neurosci 2: 450–470.
Stefani MR, Moghaddam B (2010). Activation of type 5 metabotropic glutamate receptors attenuates deficits in cognitive flexibility induced by NMDA receptor blockade. Eur J Pharmacol 639: 26–32.
Stolerman I (1992). Drugs of abuse: behavioural principles, methods and terms. Trends Pharmacol Sci 13: 170–176.
Stolerman IP, Childs E, Ford MM, Grant KA (2011). Role of training dose in drug discrimination: a review. Behav Pharmacol 22: 415–429.
Szumlinski KK, Ary AW, Lominac KD (2008). Homers regulate drug-induced neuroplasticity: implications for addiction. Biochem Pharmacol 75: 112–133.
Tidey JW, Miczek KA (1997). Acquisition of cocaine self-administration after social stress: role of accumbens dopamine. Psychopharmacology 130: 203–212.
Tomita M, Katsuyama H, Watanabe Y, Shibaike Y, Yoshinari H, Tee JW et al (2013). c-Fos immunoreactivity of neural cells in intoxication due to high-dose methamphetamine. J Toxicol Sci 38: 671–678.
Vales K, Svoboda J, Benkovicova K, Bubenikova-Valesova V, Stuchlik A (2010). The difference in effect of mGlu2/3 and mGlu5 receptor agonists on cognitive impairment induced by MK-801. Eur J Pharmacol 639: 91–98.
Venero C, Borrell J (1999). Rapid glucocorticoid effects on excitatory amino acid levels in the hippocampus: a microdialysis study in freely moving rats. Eur J Neurosci 11: 2465–2473.
Wang W, Sun D, Pan B, Roberts CJ, Sun X, Hillard CJ et al (2010). Deficiency in endocannabinoid signaling in the nucleus accumbens induced by chronic unpredictable stress. Neuropsychopharmacology 35: 2249–2261.
Wieronska JM, Branski P, Szewczyk B, Palucha A, Papp M, Gruca P et al (2001). Changes in the expression of metabotropic glutamate receptor 5 (mGluR5) in the rat hippocampus in an animal model of depression. Polish J Pharmacol 53: 659–662.
Wise RA, Wang B, You ZB (2008). Cocaine serves as a peripheral interoceptive conditioned stimulus for central glutamate and dopamine release. PLoS One 3: e2846.
Witkin JM, Marek GJ, Johnson BG, Schoepp DD (2007). Metabotropic glutamate receptors in the control of mood disorders. CNS Neurol Disord Drug Targets 6: 87–100.
Xiao B, Tu JC, Worley PF (2000). Homer: a link between neural activity and glutamate receptor function. Curr Opin Neurobiol 10: 370–374.
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We thank Andrew Whang and Maria Masciello for help with various aspects of behavioral studies.
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Besheer, J., Fisher, K., Jaramillo, A. et al. Stress Hormone Exposure Reduces mGluR5 Expression in the Nucleus Accumbens: Functional Implications for Interoceptive Sensitivity to Alcohol. Neuropsychopharmacol 39, 2376–2386 (2014). https://doi.org/10.1038/npp.2014.85
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DOI: https://doi.org/10.1038/npp.2014.85
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