Abstract
Rationale
Extracellular-signal regulated protein kinase (ERK1/2) is activated by ethanol in reward-related brain regions. Accordingly, systemic inhibition of ERK1/2 potentiates ethanol reinforcement. However, the brain region(s) that mediate this effect are unknown.
Objective
This study aims to pharmacologically inhibit ERK1/2 in the medial prefrontal cortex (PFC), nucleus accumbens (NAC), and amygdala (AMY) prior to ethanol or sucrose self-administration, and evaluate effects of operant ethanol self-administration on ERK1/2 phosphorylation (pERK1/2).
Methods
Male C57BL/6J mice were trained to lever press on a fixed-ratio-4 schedule of 9 % ethanol + 2 % sucrose (ethanol) or 2 % sucrose (sucrose) reinforcement. Mice were sacrificed immediately after the 30th self-administration session and pERK1/2 immunoreactivity was quantified in targeted brain regions. Additional groups of mice were injected with SL 327 (0–1.7 μg/side) in PFC, NAC, or AMY prior to self-administration.
Results
pERK1/2 immunoreactivity was significantly increased by operant ethanol (g/kg = 1.21 g/kg; BAC = 54.9 mg/dl) in the PFC, NAC (core and shell), and AMY (central nucleus) as compared to sucrose. Microinjection of SL 327 (1.7 μg) into the PFC selectively increased ethanol self-administration. Intra-NAC injection of SL 327 had no effect on ethanol- but suppressed sucrose-reinforced responding. Intra-AMY microinjection of SL 327 had no effect on either ethanol- or sucrose-reinforced responding. Locomotor activity was unaffected under all conditions.
Conclusions
Operant ethanol self-administration increases pERK1/2 activation in the PFC, NAC, and AMY. However, ERK1/2 activity only in the PFC mechanistically regulates ethanol self-administration. These data suggest that ethanol-induced activation of ERK1/2 in the PFC is a critical pharmacological effect that mediates the reinforcing properties of the drug.
Similar content being viewed by others
References
Adams JP, Sweatt JD (2002) Molecular psychology: roles for the ERK MAP kinase cascade in memory. Annu Rev Pharmacol Toxicol 42:135–163
Agoglia AE, Sharko AC, Psilos KE, Holstein SE, Reid GT, Hodge CW (2015) Alcohol alters the activation of ERK1/2, a functional regulator of binge alcohol drinking in adult C57BL/6J mice. Alcohol Clin Exp Res 39:463–475
Arolfo MP, Overstreet DH, Yao L, Fan P, Lawrence AJ, Tao G, Keung WM, Vallee BL, Olive MF, Gass JT, Rubin E, Anni H, Hodge CW, Besheer J, Zablocki J, Leung K, Blackburn BK, Lange LG, Diamond I (2009) Suppression of heavy drinking and alcohol seeking by a selective ALDH-2 inhibitor. Alcohol Clin Exp Res 33:1935–1944
Bassareo V, Musio P, Di Chiara G (2011) Reciprocal responsiveness of nucleus accumbens shell and core dopamine to food- and drug-conditioned stimuli. Psychopharmacology (Berlin) 214:687–697
Berendse HW, Galis-de Graaf Y, Groenewegen HJ (1992) Topographical organization and relationship with ventral striatal compartments of prefrontal corticostriatal projections in the rat. J Comp Neurol 316:314–347
Besheer J, Fisher KR, Cannady R, Grondin JJ, Hodge CW (2012) Intra-amygdala inhibition of ERK (1/2) potentiates the discriminative stimulus effects of alcohol. Behav Brain Res 228:398–405
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
Besnard A, Laroche S, Caboche J (2014) Comparative dynamics of MAPK/ERK signalling components and immediate early genes in the hippocampus and amygdala following contextual fear conditioning and retrieval. Brain Struct Funct 219:415–430
Cabeza de Vaca S, Carr KD (1998) Food restriction enhances the central rewarding effect of abused drugs. J Neurosci 18:7502–7510
Cannady R, Fisher KR, Durant B, Besheer J, Hodge CW (2013) Enhanced AMPA receptor activity increases operant alcohol self-administration and cue-induced reinstatement. Addict Biol 18:54–65
Carelli RM, Ijames SG, Crumling AJ (2000) Evidence that separate neural circuits in the nucleus accumbens encode cocaine versus “natural” (water and food) reward. J Neurosci 20:4255–4266
Carelli RM, Wondolowski J (2006) Anatomic distribution of reinforcer selective cell firing in the core and shell of the nucleus accumbens. Synapse 59:69–73
Carnicella S, Kharazia V, Jeanblanc J, Janak PH, Ron D (2008) GDNF is a fast-acting potent inhibitor of alcohol consumption and relapse. Proc Natl Acad Sci U S A 105:8114–8119
Carr KD (2002) Augmentation of drug reward by chronic food restriction: behavioral evidence and underlying mechanisms. Physiol Behav 76:353–364
Carr KD, de Vaca SC, Sun Y, Chau LS, Pan Y, Dela Cruz J (2009) Effects of the MEK inhibitor, SL-327, on rewarding, motor- and cellular-activating effects of D-amphetamine and SKF-82958, and their augmentation by food restriction in rat. Psychopharmacology (Berlin) 201:495–506
Carr KD, Kim GY, Cabeza de Vaca S (2001) Rewarding and locomotor-activating effects of direct dopamine receptor agonists are augmented by chronic food restriction in rats. Psychopharmacology (Berlin) 154:420–428
Carroll ME, France CP, Meisch RA (1979) Food deprivation increases oral and intravenous drug intake in rats. Science 205:319–321
Chandler LJ, Sutton G (2005) Acute ethanol inhibits extracellular signal-regulated kinase, protein kinase B, and adenosine 3′:5′-cyclic monophosphate response element binding protein activity in an age- and brain region-specific manner. Alcohol Clin Exp Res 29:672–682
Clapp P (2012) Current progress in pharmacologic treatment strategies for alcohol dependence. Expert Rev Clin Pharmacol 5:427–435
Committee for the Update of the Guide for the Care and Use of Laboratory Animals IfLAR (2011) Guide for the care and use of laboratory animals (The National Academies Collection: reports funded by National Institutes of Health). National Academies Press, Washington (DC), p 220
Cui C, Noronha A, Morikawa H, Alvarez VA, Stuber GD, Szumlinski KK, Kash TL, Roberto M, Wilcox MV (2013) New insights on neurobiological mechanisms underlying alcohol addiction. Neuropharmacology 67:223–232
Cui SZ, Wang SJ, Li J, Xie GQ, Zhou R, Chen L, Yuan XR (2011) Alteration of synaptic plasticity in rat dorsal striatum induced by chronic ethanol intake and withdrawal via ERK pathway. Acta Pharmacol Sin 32:175–181
Davis S, Vanhoutte P, Pages C, Caboche J, Laroche S (2000) The MAPK/ERK cascade targets both Elk-1 and cAMP response element-binding protein to control long-term potentiation-dependent gene expression in the dentate gyrus in vivo. J Neurosci 20:4563–4572
Di Chiara G, Imperato A (1986) Preferential stimulation of dopamine release in the nucleus accumbens by opiates, alcohol, and barbiturates: studies with transcerebral dialysis in freely moving rats. Ann N Y Acad Sci 473:367–381
Ding ZM, Rodd ZA, Engleman EA, Bailey JA, Lahiri DK, McBride WJ (2013) Alcohol drinking and deprivation alter basal extracellular glutamate concentrations and clearance in the mesolimbic system of alcohol-preferring (P) rats. Addict Biol 18:297–306
Faccidomo S, Besheer J, Stanford PC, Hodge CW (2009) Increased operant responding for ethanol in male C57BL/6J mice: specific regulation by the ERK (1/2), but not JNK, MAP kinase pathway. Psychopharmacology (Berlin).
Franklin KBJ, Paxinos G (2001) The mouse brain in stereotaxic coordinates, 2nd edn. Academic Press, New York
Girault JA, Valjent E, Caboche J, Herve D (2007) ERK2: a logical AND gate critical for drug-induced plasticity? Curr Opin Pharmacol 7:77–85
Goulding SP, Obara I, Lominac KD, Gould AT, Miller BW, Klugmann M, Szumlinski KK (2011) Accumbens Homer2-mediated signaling: a factor contributing to mouse strain differences in alcohol drinking? Genes Brain Behav 10:111–26
Grant BF, Dawson DA, Stinson FS, Chou SP, Dufour MC, Pickering RP (2004) The 12-month prevalence and trends in DSM-IV alcohol abuse and dependence: United States, 1991–1992 and 2001–2002. Drug Alcohol Depend 74:223–234
Grant KA, Samson HH (1985) Oral self administration of ethanol in free feeding rats. Alcohol 2:317–321
Griffin WC, Haun HL, Hazelbaker CL, Ramachandra VS, Becker HC (2014) Increased extracellular glutamate in the nucleus accumbens promotes excessive ethanol drinking in ethanol dependent mice. Neuropsychopharmacology 39:707–717
Groblewski PA, Franken FH, Cunningham CL (2011) Inhibition of extracellular signal-regulated kinase (ERK) activity with SL327 does not prevent acquisition, expression, and extinction of ethanol-seeking behavior in mice. Behav Brain Res 217:399–407
Guo ML, Xue B, Jin DZ, Mao LM, Wang JQ (2012) Interactions and phosphorylation of postsynaptic density 93 (PSD-93) by extracellular signal-regulated kinase (ERK). Brain Res 1465:18–25
Haberny SL, Berman Y, Meller E, Carr KD (2004) Chronic food restriction increases D-1 dopamine receptor agonist-induced phosphorylation of extracellular signal-regulated kinase 1/2 and cyclic AMP response element-binding protein in caudate-putamen and nucleus accumbens. Neuroscience 125:289–298
Hasin DS, Stinson FS, Ogburn E, Grant BF (2007) Prevalence, correlates, disability, and comorbidity of DSM-IV alcohol abuse and dependence in the United States: results from the National Epidemiologic Survey on Alcohol and Related Conditions. Arch Gen Psychiatry 64:830–842
Hodge CW, Chappelle AM, Samson HH (1996) Dopamine receptors in the medial prefrontal cortex influence ethanol and sucrose-reinforced responding. Alcohol Clin Exp Res 20:1631–1638
Hodge CW, Samson HH, Lewis RS, Erickson HL (1993) Specific decreases in ethanol- but not water-reinforced responding produced by the 5-HT3 antagonist ICS 205-930. Alcohol 10:191–196
Ibba F, Vinci S, Spiga S, Peana AT, Assaretti AR, Spina L, Longoni R, Acquas E (2009) Ethanol-induced extracellular signal regulated kinase: role of dopamine D1 receptors. Alcohol Clin Exp Res 33:858–867
Jeanblanc J, Logrip ML, Janak PH, Ron D (2013) BDNF-mediated regulation of ethanol consumption requires the activation of the MAP kinase pathway and protein synthesis. Eur J Neurosci 37:607–612
Kalivas PW, Volkow N, Seamans J (2005) Unmanageable motivation in addiction: a pathology in prefrontal-accumbens glutamate transmission. Neuron 45:647–650
Kapasova Z, Szumlinski KK (2008) Strain differences in alcohol-induced neurochemical plasticity: a role for accumbens glutamate in alcohol intake. Alcohol Clin Exp Res 32:617–631
Liu S, Zheng D, Peng XX, Cabeza de Vaca S, Carr KD (2011) Enhanced cocaine-conditioned place preference and associated brain regional levels of BDNF, p-ERK1/2 and p-Ser845-GluA1 in food-restricted rats. Brain Res 1400:31–41
Lu L, Hope BT, Dempsey J, Liu SY, Bossert JM, Shaham Y (2005) Central amygdala ERK signaling pathway is critical to incubation of cocaine craving. Nat Neurosci 8:212–219
Mann K (2004) Pharmacotherapy of alcohol dependence: a review of the clinical data. CNS Drugs 18:485–504
Meisch RA, Thompson T (1973) Ethanol as a reinforcer: effects of fixed-ratio size and food deprivation. Psychopharmacologia 28:171–83
Nestler EJ (2001) Molecular basis of long-term plasticity underlying addiction. Nat Rev Neurosci 2:119–128
Olive MF, Mehmert KK, Messing RO, Hodge CW (2000) Reduced operant ethanol self-administration and in vivo mesolimbic dopamine responses to ethanol in PKCepsilon-deficient mice. Eur J Neurosci 12:4131–4140
Pandey SC, Zhang H, Roy A, Misra K (2006) Central and medial amygdaloid brain-derived neurotrophic factor signaling plays a critical role in alcohol-drinking and anxiety-like behaviors. J Neurosci 26:8320–8331
Pandey SC, Zhang H, Ugale R, Prakash A, Xu T, Misra K (2008) Effector immediate-early gene arc in the amygdala plays a critical role in alcoholism. J Neurosci 28:2589–2600
Qin Y, Zhu Y, Baumgart JP, Stornetta RL, Seidenman K, Mack V, van Aelst L, Zhu JJ (2005) State-dependent Ras signaling and AMPA receptor trafficking. Genes Dev 19:2000–2015
Radwanska K, Wrobel E, Korkosz A, Rogowski A, Kostowski W, Bienkowski P, Kaczmarek L (2007) Alcohol relapse induced by discrete cues activates components of ap-1 transcription factor and erk pathway in the rat basolateral and central amygdala. Neuropsychopharmacology.
Rimondini R, Arlinde C, Sommer W, Heilig M (2002) Long-lasting increase in voluntary ethanol consumption and transcriptional regulation in the rat brain after intermittent exposure to alcohol. FASEB J 16:27–35
Roberto M, Schweitzer P, Madamba SG, Stouffer DG, Parsons LH, Siggins GR (2004) Acute and chronic ethanol alter glutamatergic transmission in rat central amygdala: an in vitro and in vivo analysis. J Neurosci 24:1594–1603
Robinson DL, Carelli RM (2008) Distinct subsets of nucleus accumbens neurons encode operant responding for ethanol versus water. Eur J Neurosci 28:1887–1894
Roop RG, Hollander JA, Carelli RM (2002) Accumbens activity during a multiple schedule for water and sucrose reinforcement in rats. Synapse 43:223–226
Rosas M, Zaru A, Sabariego M, Giugliano V, Carboni E, Colombo G, Acquas E (2014) Differential sensitivity of ethanol-elicited ERK phosphorylation in nucleus accumbens of Sardinian alcohol-preferring and -non preferring rats. Alcohol 48:471–476
Samson HH, Pfeffer AO, Tolliver GA (1988) Oral ethanol self-administration in rats: models of alcohol-seeking behavior. Alcohol Clin Exp Res 12:591–598
Sanna PP, Simpson C, Lutjens R, Koob G (2002) ERK regulation in chronic ethanol exposure and withdrawal. Brain Res 948:186–191
Schier CJ, Dilly GA, Gonzales RA (2013) Intravenous ethanol increases extracellular dopamine in the medial prefrontal cortex of the Long-Evans rat. Alcohol Clin Exp Res 37:740–747
Schroeder JP, Olive F, Koenig H, Hodge CW (2003) Intra-amygdala infusion of the NPY Y1 receptor antagonist BIBP 3226 attenuates operant ethanol self-administration. Alcohol Clin Exp Res 27:1884–1891
Schroeder JP, Spanos M, Stevenson JR, Besheer J, Salling M, Hodge CW (2008) Cue-induced reinstatement of alcohol-seeking behavior is associated with increased ERK1/2 phosphorylation in specific limbic brain regions: blockade by the mGluR5 antagonist MPEP. Neuropharmacology 55:546–554
Self DW (2004) Regulation of drug-taking and -seeking behaviors by neuroadaptations in the mesolimbic dopamine system. Neuropharmacology 47(1):242–255
Shiflett MW, Balleine BW (2011) Contributions of ERK signaling in the striatum to instrumental learning and performance. Behav Brain Res 218:240–247
Spanos M, Besheer J, Hodge CW (2012) Increased sensitivity to alcohol induced changes in ERK Map kinase phosphorylation and memory disruption in adolescent as compared to adult C57BL/6J mice. Behav Brain Res 230:158–166
Szumlinski KK, Diab ME, Friedman R, Henze LM, Lominac KD, Bowers MS (2007) Accumbens neurochemical adaptations produced by binge-like alcohol consumption. Psychopharmacology (Berlin) 190:415–431
Thomas GM, Huganir RL (2004) MAPK cascade signalling and synaptic plasticity. Nat Rev Neurosci 5:173–183
Thorsell A, Tapocik JD, Liu K, Zook M, Bell L, Flanigan M, Patnaik S, Marugan J, Damadzic R, Dehdashti SJ, Schwandt ML, Southall N, Austin CP, Eskay R, Ciccocioppo R, Zheng W, Heilig M (2013) A novel brain penetrant NPS receptor antagonist, NCGC00185684, blocks alcohol-induced ERK-phosphorylation in the central amygdala and decreases operant alcohol self-administration in rats. J Neurosci 33:10132–10142
Valjent E, Caboche J, Vanhoutte P (2001) Mitogen-activated protein kinase/extracellular signal-regulated kinase induced gene regulation in brain: a molecular substrate for learning and memory? Mol Neurobiol 23:83–99
Valjent E, Corvol JC, Pages C, Besson MJ, Maldonado R, Caboche J (2000) Involvement of the extracellular signal-regulated kinase cascade for cocaine-rewarding properties. J Neurosci 20:8701–8709
Valjent E, Pages C, Herve D, Girault JA, Caboche J (2004) Addictive and non-addictive drugs induce distinct and specific patterns of ERK activation in mouse brain. Eur J Neurosci 19:1826–1836
Vanhoutte P, Barnier JV, Guibert B, Pages C, Besson MJ, Hipskind RA, Caboche J (1999) Glutamate induces phosphorylation of Elk-1 and CREB, along with c-fos activation, via an extracellular signal-regulated kinase-dependent pathway in brain slices. Mol Cell Biol 19:136–146
Wise RA, Koob GF (2014) The development and maintenance of drug addiction. Neuropsychopharmacology 39:254–262
Zamora-Martinez ER, Edwards S (2014) Neuronal extracellular signal-regulated kinase (ERK) activity as marker and mediator of alcohol and opioid dependence. Front Integr Neurosci 8:24
Zhai H, Li Y, Wang X, Lu L (2008) Drug-induced alterations in the extracellular signal-regulated kinase (ERK) signalling pathway: implications for reinforcement and reinstatement. Cell Mol Neurobiol 28:157–172
Zhu Y, Wang Y, Zhao B, Wei S, Xu M, Liu E, Lai J (2013) Differential phosphorylation of GluN1-MAPKs in rat brain reward circuits following long-term alcohol exposure. PLoS One 8:e54930
Acknowledgments
This research was supported by NIAAA grants R37AA014983 and P60AA011065 to CWH.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Faccidomo, S., Salling, M.C., Galunas, C. et al. Operant ethanol self-administration increases extracellular-signal regulated protein kinase (ERK) phosphorylation in reward-related brain regions: selective regulation of positive reinforcement in the prefrontal cortex of C57BL/6J mice. Psychopharmacology 232, 3417–3430 (2015). https://doi.org/10.1007/s00213-015-3993-z
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00213-015-3993-z