Abstract
The prefrontal cortex (PFC) is a brain region that is critically involved in cognitive function and inhibitory control of behavior, and adolescence represents an important period of continued PFC development that parallels the maturation of these functions. Evidence suggests that this period of continued development of the PFC may render it especially vulnerable to environmental insults that impact PFC function in adulthood. Experimentation with alcohol typically begins during adolescence when binge-like consumption of large quantities is common. In the present study, we investigated the effects of repeated cycles of adolescent intermittent ethanol (AIE) exposure (postnatal days 28–42) by vapor inhalation on different aspects of executive functioning in the adult rat. In an operant set-shifting task, AIE-exposed rats exhibited deficits in their ability to shift their response strategy when the rules of the task changed, indicating reduced behavioral flexibility. There were no differences in progressive ratio response for the reinforcer suggesting that AIE did not alter reinforcer motivation. Examination of performance on the elevated plus maze under conditions designed to minimize stress revealed that AIE exposure enhanced the number of entries into the open arms, which may reflect either reduced anxiety and/or disinhibition of exploratory-like behavior. In rats that trained to self-administer ethanol in an operant paradigm, AIE increased resistance to extinction of ethanol-seeking behavior. This resistance to extinction was reversed by positive allosteric modulation of mGluR5 during extinction training, an effect that is thought to reflect promotion of extinction learning mechanisms within the medial PFC. Consistent with this, CDPPB was also observed to reverse the deficits in behavioral flexibility. Finally, diffusion tensor imaging with multivariate analysis of 32 brain areas revealed that while there were no differences in the total brain volume, the volume of a subgroup of regions (hippocampus, thalamus, dorsal striatum, neocortex, and hypothalamus) were significantly different in AIE-exposed adults compared with litter-matched Control rats. Taken together, these findings demonstrate that binge-like exposure to alcohol during early to middle adolescence results in deficits in PFC-mediated behavioral control in adulthood.
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References
Abernathy K, Chandler LJ, Woodward JJ (2010). Alcohol and the prefrontal cortex. Int Rev Neurobiol 91: 289–320.
Alaux-Cantin S, Warnault V, Legastelois R, Botia B, Pierrefiche O, Vilpoux C et al (2013). Alcohol intoxications during adolescence increase motivation for alcohol in adult rats and induce neuroadaptations in the nucleus accumbens. Neuropharmacology 67: 521–531.
Ayala JE, Chen Y, Banko JL, Sheffler DJ, Williams R, Telk AN et al (2009). mGluR5 positive allosteric modulators facilitate both hippocampal LTP and LTD and enhance spatial learning. Neuropsychopharmacology 34: 2057–2071.
Birrell JM, Brown VJ (2000). Medial frontal cortex mediates perceptual attentional set shifting in the rat. J Neurosci 20: 4320–4324.
Blakemore SJ, Robbins TW (2012). Decision-making in the adolescent brain. Nat Neurosci 15: 1184–1191.
Block AE, Dhanji H, Thompson-Tardif SF, Floresco SB (2007). Thalamic-prefrontal cortical-ventral striatal circuitry mediates dissociable components of strategy set shifting. Cereb Cortex 17: 1625–1636.
Boulougouris V, Dalley JW, Robbins TW (2007). Effects of orbitofrontal, infralimbic and prelimbic cortical lesions on serial spatial reversal learning in the rat. Behav Brain Res 179: 219–228.
Casey BJ, Jones RM (2010). Neurobiology of the adolescent brain and behavior: implications for substance use disorders. J Am Acad Child Adolesc Psychiatry 49: 1189–1201 quiz 1285.
Chambers RA, Taylor JR, Potenza MN (2003). Developmental neurocircuitry of motivation in adolescence: a critical period of addiction vulnerability. Am J Psychiatry 160: 1041–1052.
Clark JJ, Nasrallah NA, Hart AS, Collins AL, Bernstein IL, Phillips PE (2012). Altered risk-based decision making following adolescent alcohol use results from an imbalance in reinforcement learning in rats. PLoS One 7: e37357.
Cleva RM, Hicks MP, Gass JT, Wischerath KC, Plasters ET, Widholm JJ et al (2011). mGluR5 positive allosteric modulation enhances extinction learning following cocaine self-administration. Behav Neurosci 125: 10–19.
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. Alcohol Clin Exp Res 36: 1623–1633.
Crews FT, Nixon K, Wilkie ME (2004). Exercise reverses ethanol inhibition of neural stem cell proliferation. Alcohol 33: 63–71.
Cruz AP, Frei F, Graeff FG (1994). Ethopharmacological analysis of rat behavior on the elevated plus-maze. Pharmacol Biochem Behav 49: 171–176.
Darrah JM, Stefani MR, Moghaddam B (2008). Interaction of N-methyl-D-aspartate and group 5 metabotropic glutamate receptors on behavioral flexibility using a novel operant set-shift paradigm. Behav Pharmacol 19: 225–234.
Ehlers CL, Liu W, Wills DN, Crews FT (2013a). Periadolescent ethanol vapor exposure persistently reduces measures of hippocampal neurogenesis that are associated with behavioral outcomes in adulthood. Neuroscience 244: 1–15.
Ehlers CL, Oguz I, Budin F, Wills DN, Crews FT (2013b). Peri-adolescent ethanol vapor exposure produces reductions in hippocampal volume that are correlated with deficits in prepulse inhibition of the startle. Alcohol Clin Exp Res 37: 1466–1475.
Enomoto T, Tse MT, Floresco SB (2011). Reducing prefrontal gamma-aminobutyric acid activity induces cognitive, behavioral, and dopaminergic abnormalities that resemble schizophrenia. Biol Psychiatry 69: 432–441.
Fabio MC, Nizhnikov ME, Spear NE, Pautassi RM (2013). Binge ethanol intoxication heightens subsequent ethanol intake in adolescent, but not adult, rats. Dev Psychobiol 56: 574–583.
Fernandes C, File SE (1996). The influence of open arm ledges and maze experience in the elevated plus-maze. Pharmacol Biochem Behav 54: 31–40.
Flagel SB, Waselus M, Clinton SM, Watson SJ, Akil H (2013). Antecedents and consequences of drug abuse in rats selectively bred for high and low response to novelty. Neuropharmacology 76 Pt B: 425–436.
Floresco SB, Block AE, Tse MT (2008). Inactivation of the medial prefrontal cortex of the rat impairs strategy set-shifting, but not reversal learning, using a novel, automated procedure. Behav Brain Res 190: 85–96.
Floresco SB, Ghods-Sharifi S, Vexelman C, Magyar O (2006). Dissociable roles for the nucleus accumbens core and shell in regulating set shifting. J Neurosci 26: 2449–2457.
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.
Gass JT, Chandler LJ (2013). The plasticity of extinction: contribution of the prefrontal cortex in treating addiction through inhibitory learning. Front Psychiatry 4: 46.
Gass JT, Olive MF (2009). Positive allosteric modulation of mGluR5 receptors facilitates extinction of a cocaine contextual memory. Biol Psychiatry 65: 717–720.
Gilpin NW, Karanikas CA, Richardson HN (2012). Adolescent binge drinking leads to changes in alcohol drinking, anxiety, and amygdalar corticotropin releasing factor cells in adulthood in male rats. PLoS One 7: e31466.
Grant BF, Stinson FS, Harford TC (2001). Age at onset of alcohol use and DSM-IV alcohol abuse and dependence: a 12-year follow-up. J Subst Abuse 13: 493–504.
Haluk DM, Floresco SB (2009). Ventral striatal dopamine modulation of different forms of behavioral flexibility. Neuropsychopharmacology 34: 2041–2052.
Hasin DS, Glick H (1992). Severity of DSM-III-R alcohol dependence: United States, 1988. Br J Addict 87: 1725–1730.
Horio M, Fujita Y, Hashimoto K (2013). Therapeutic effects of metabotropic glutamate receptor 5 positive allosteric modulator CDPPB on phencyclidine-induced cognitive deficits in mice. Fundam Clin Pharmacol 27: 483–488.
Hulvershorn LA, Finn P, Hummer TA, Leibenluft E, Ball B, Gichina V et al (2013). Cortical activation deficits during facial emotion processing in youth at high risk for the development of substance use disorders. Drug Alcohol Depend 131: 230–237.
Kroker KS, Rast G, Rosenbrock H (2011). Differential effect of the mGlu5 receptor positive allosteric modulator ADX-47273 on early and late hippocampal LTP. Neuropharmacology 61: 707–714.
Kufahl PR, Hood LE, Nemirovsky NE, Barabas P, Halstengard C, Villa A et al (2012). Positive allosteric modulation of mGluR5 accelerates extinction learning but not relearning following methamphetamine self-administration. Front Pharmacol 3: 194.
Kupila J, Karkkainen O, Laukkanen V, Tupala E, Tiihonen J, Storvik M (2013). mGluR1/5 receptor densities in the brains of alcoholic subjects: a whole-hemisphere autoradiography study. Psychiatry Res 212: 245–250.
Maldonado-Devincci AM, Alipour KK, Michael LA, Kirstein CL (2010). Repeated binge ethanol administration during adolescence enhances voluntary sweetened ethanol intake in young adulthood in male and female rats. Pharmacol Biochem Behav 96: 476–487.
McQueeny T, Schweinsburg BC, Schweinsburg AD, Jacobus J, Bava S, Frank LR et al (2009). Altered white matter integrity in adolescent binge drinkers. Alcohol Clin Exp Res 33: 1278–1285.
Nasrallah NA, Clark JJ, Collins AL, Akers CA, Phillips PE, Bernstein IL (2011). Risk preference following adolescent alcohol use is associated with corrupted encoding of costs but not rewards by mesolimbic dopamine. Proc Natl Acad Sci USA 108: 5466–5471.
Nasrallah NA, Yang TW, Bernstein IL (2009). Long-term risk preference and suboptimal decision making following adolescent alcohol use. Proc Natl Acad Sci USA 106: 17600–17604.
Nixon K, Crews FT (2002). Binge ethanol exposure decreases neurogenesis in adult rat hippocampus. J Neurochem 83: 1087–1093.
Paxinos G, Watson C (2005) The Rat Brain in Stereotaxic Coordinates 5th edn. Academic Press: San Diego.
Pellow S, Chopin P, File SE, Briley M (1985). Validation of open:closed arm entries in an elevated plus-maze as a measure of anxiety in the rat. J Neurosci Methods 14: 149–167.
Petanjek Z, Judas M, Simic G, Rasin MR, Uylings HB, Rakic P et al (2011). Extraordinary neoteny of synaptic spines in the human prefrontal cortex. Proc Natl Acad Sci USA 108: 13281–13286.
Peters J, Kalivas PW, Quirk GJ (2009). Extinction circuits for fear and addiction overlap in prefrontal cortex. Learn Mem 16: 279–288.
Ragozzino ME, Detrick S, Kesner RP (1999). Involvement of the prelimbic-infralimbic areas of the rodent prefrontal cortex in behavioral flexibility for place and response learning. J Neurosci 19: 4585–4594.
Ragozzino ME, Ragozzino KE, Mizumori SJ, Kesner RP (2002). Role of the dorsomedial striatum in behavioral flexibility for response and visual cue discrimination learning. Behav Neurosci 116: 105–115.
Rakic P, Bourgeois JP, Goldman-Rakic PS (1994). Synaptic development of the cerebral cortex: implications for learning, memory, and mental illness. Prog Brain Res 102: 227–243.
Ranaldi R, Roberts DC (1996). Initiation, maintenance and extinction of cocaine self-administration with and without conditioned reward. Psychopharmacology (Berl) 128: 89–96.
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.
Richardson NR, Roberts DC (1996). Progressive ratio schedules in drug self-administration studies in rats: a method to evaluate reinforcing efficacy. J Neurosci Methods 66: 1–11.
Rumple A, McMurray M, Johns J, Lauder J, Makam P, Radcliffe M et al (2013). 3-dimensional diffusion tensor imaging (DTI) atlas of the rat brain. PLoS One 8: e67334.
Russell VA (2011). Overview of animal models of attention deficit hyperactivity disorder (ADHD). Curr Protoc Neurosci Chapter 9: Unit 9 35.
Shah AA, Sjovold T, Treit D (2004). Inactivation of the medial prefrontal cortex with the GABAA receptor agonist muscimol increases open-arm activity in the elevated plus-maze and attenuates shock-probe burying in rats. Brain Res 1028: 112–115.
Simms JA, Bito-Onon JJ, Chatterjee S, Bartlett SE (2010). Long-Evans rats acquire operant self-administration of 20% ethanol without sucrose fading. Neuropsychopharmacology 35: 1453–1463.
Simms JA, Richards JK, Mill D, Kanholm I, Holgate JY, Bartlett SE (2011). Induction of multiple reinstatements of ethanol- and sucrose-seeking behavior in Long-Evans rats by the alpha-2 adrenoreceptor antagonist yohimbine. Psychopharmacology (Berl) 218: 101–110.
Slawecki CJ, Betancourt M (2002). Effects of adolescent ethanol exposure on ethanol consumption in adult rats. Alcohol 26: 23–30.
Spear LP (2000). The adolescent brain and age-related behavioral manifestations. Neurosci Biobehav Rev 24: 417–463.
Stefani MR, Groth K, Moghaddam B (2003). Glutamate receptors in the rat medial prefrontal cortex regulate set-shifting ability. Behav Neurosci 117: 728–737.
Stefani MR, Moghaddam B (2005). Systemic and prefrontal cortical NMDA receptor blockade differentially affect discrimination learning and set-shift ability in rats. Behav Neurosci 119: 420–428.
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.
Uslaner JM, Parmentier-Batteur S, Flick RB, Surles NO, Lam JS, McNaughton CH et al (2009). Dose-dependent effect of CDPPB, the mGluR5 positive allosteric modulator, on recognition memory is associated with GluR1 and CREB phosphorylation in the prefrontal cortex and hippocampus. Neuropharmacology 57: 531–538.
Vetter CS, Doremus-Fitzwater TL, Spear LP (2007). Time course of elevated ethanol intake in adolescent relative to adult rats under continuous, voluntary-access conditions. Alcohol Clin Exp Res 31: 1159–1168.
Witt ED (2010). Research on alcohol and adolescent brain development: opportunities and future directions. Alcohol 44: 119–124.
Xu J, Zhu Y, Kraniotis S, He Q, Marshall JJ, Nomura T et al (2013). Potentiating mGluR5 function with a positive allosteric modulator enhances adaptive learning. Learn Mem 20: 438–445.
Acknowledgements
This work is funded by grants U01AA019967, U24AA020023, U24AA020024, P50AA010761, R01AA010983, K99AA020537, F32AA021642, CIHR MOP102478, P30CA016086-35-37, and U54CA151652-01-04.
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Gass, J., Glen, W., McGonigal, J. et al. Adolescent Alcohol Exposure Reduces Behavioral Flexibility, Promotes Disinhibition, and Increases Resistance to Extinction of Ethanol Self-Administration in Adulthood. Neuropsychopharmacol 39, 2570–2583 (2014). https://doi.org/10.1038/npp.2014.109
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DOI: https://doi.org/10.1038/npp.2014.109
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