Sex and Adolescent Ethanol Exposure Influence Pavlovian Conditioned Approach
Open accessAbstract
Background: Alcohol use among adolescents is widespread and a growing concern due to long‐term behavioral deficits, including altered Pavlovian behavior, that potentially contribute to addiction vulnerability. We tested the hypothesis that adolescent intermittent ethanol ( AIE ) exposure alters Pavlovian behavior in males and females as measured by a shift from goal‐tracking to sign‐tracking. Additionally, we investigated GLT ‐1, an astrocytic glutamate transporter, as a potential contributor to a sign‐tracking phenotype. Methods: Male and female Sprague‐Dawley rats were exposed to AIE (5 g/kg, intragastric) or water intermittently 2 days on and 2 days off from postnatal day (P) 25 to 54. Around P70, animals began 20 daily sessions of Pavlovian conditioned approach (PCA), where they learned that a cue predicted noncontingent reward delivery. Lever pressing indicated interaction with the cue, or sign‐tracking, and receptacle entries indicated approach to the reward delivery location, or goal‐tracking. To test for effects of AIE on nucleus accumbens (NAcc) excitatory signaling, we isolated membrane subfractions and measured protein levels of the glutamate transporter GLT ‐1 after animals completed behavior as a measure of glutamate homeostasis. Results: Females exhibited elevated sign‐tracking compared to males with significantly more lever presses, faster latency to first lever press, and greater probability to lever press in a trial. AIE significantly increased lever pressing while blunting goal‐tracking, as indicated by fewer cue‐evoked receptacle entries, slower latency to receptacle entry, and lower probability to enter the receptacle in a trial. No significant sex‐by‐exposure interactions were observed in sign‐ or goal‐tracking metrics. Moreover, we found no significant effects of sex or exposure on membrane GLT ‐1 expression in the NAcc. Conclusions: Females exhibited enhanced sign‐tracking compared to males, while AIE decreased goal‐tracking compared to control exposure. Our findings support the hypothesis that adolescent binge ethanol can shift conditioned behavior from goal‐ to cue‐directed in PCA, especially in females.
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
Adolescent alcohol exposure amplifies the incentive value and attraction of reward-predictive cues through potentiation of dopamine signaling.
“In particular, adolescent alcohol exposure amplifies the incentive value and attraction of reward-predictive cues (Hellberg, Levit, & Robinson, 2018; Madayag, Stringfield, Reissner, Boettiger, & Robinson, 2017), and does so through potentiation of dopamine signaling (Spoelder, Tsutsui, Lesscher, Vanderschuren, & Clark, 2015).”
From Cued for Risk: Evidence for an Incentive Sensitization Framework to Explain the Interplay between Stress and Anxiety, Substance Abuse, and Reward Uncertainty in Disordered Gambling Behavior (2019) · cites this paper as Madayag, Stringfield, Reissner, Boettiger, & Robinson, 2017
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Cites
Danbolt, N. C. (2001) · Progress in Neurobiology · doi:10.1016/s0301-0082(00)00067-8 · Cited by 4,068 · see citing works
Berridge, K. C., & Robinson, T. E. (2003) · Trends in Neurosciences · doi:10.1016/s0166-2236(03)00233-9 · Cited by 1,869 · see citing works
The glutamate homeostasis hypothesis of addiction
Kalivas, P. W. (2009) · Nature Reviews Neuroscience · doi:10.1038/nrn2515 · Cited by 1,350 · see citing works
Female mice liberated for inclusion in neuroscience and biomedical research
Prendergast, B. J., Onishi, K. G., & Zucker, I. (2014) · Neuroscience & Biobehavioral Reviews · doi:10.1016/j.neubiorev.2014.01.001 · Cited by 788 · see citing works
Sex Differences in Animal Models: Focus on Addiction
Becker, J. B., & Koob, G. F. (2016) · Pharmacological Reviews · doi:10.1124/pr.115.011163 · Cited by 725 · see citing works
The Origin and Neuronal Function ofIn VivoNonsynaptic Glutamate
Baker, D. L., Xi, Z., Shen, H., Swanson, C. J., & Kalivas, P. W. (2002) · Journal of Neuroscience · doi:10.1523/jneurosci.22-20-09134.2002 · Cited by 584 · see citing works
Neurocognitive Functioning of Adolescents: Effects of Protracted Alcohol Use
Brown, S. A., Tapert, S. F., Granholm, E. L., & Delis, D. C. (2000) · Alcoholism Clinical and Experimental Research · doi:10.1111/j.1530-0277.2000.tb04586.x · Cited by 575 · see citing works
Stahre, M. A., Roeber, J., Kanny, D., Brewer, R. D., & Zhang, X. (2014) · Preventing Chronic Disease · doi:10.5888/pcd11.130293 · Cited by 561 · see citing works
Glutamate transporters: confining runaway excitation by shaping synaptic transmission
Tzingounis, A. V., & Wadiche, J. I. (2007) · Nature reviews. Neuroscience · doi:10.1038/nrn2274 · Cited by 496 · see citing works
Neuropsychosocial profiles of current and future adolescent alcohol misusers
Whelan, R., Watts, R., Orr, C., Althoff, R., Artiges, E., Banaschewski, T., Barker, G., Bokde, A., Büchel, C., Carvalho, F. M., et al. (2014) · Nature · doi:10.1038/nature13402 · Cited by 438 · see citing works
Zou, J., & Crews, F. T. (2005) · Brain Research · doi:10.1016/j.brainres.2004.11.014 · Cited by 410 · see citing works
Ceftriaxone Restores Glutamate Homeostasis and Prevents Relapse to Cocaine Seeking
Knackstedt, L. A., Meléndez, R. I., & Kalivas, P. W. (2009) · Biological Psychiatry · doi:10.1016/j.biopsych.2009.07.018 · Cited by 396 · see citing works
Adolescent Alcohol Exposure Persistently Impacts Adult Neurobiology and Behavior
Crews, F. T., Vetreno, R. P., Broadwater, M., & Robinson, D. L. (2016) · Pharmacological Reviews · doi:10.1124/pr.115.012138 · Cited by 332 · see citing works
Self-citationPascual, M., Boix, J., Felipo, V., & Guerri, C. (2008) · Journal of Neurochemistry · doi:10.1111/j.1471-4159.2008.05835.x · Cited by 318 · see citing works
The role of dopamine in the accumbens core in the expression of Pavlovian‐conditioned responses
Saunders, B. T., & Robinson, T. E. (2012) · European Journal of Neuroscience · doi:10.1111/j.1460-9568.2012.08217.x · Cited by 293 · see citing works
Flagel, S. B., Watson, S. J., Robinson, T. E., & Akil, H. (2006) · Psychopharmacology · doi:10.1007/s00213-006-0535-8 · Cited by 290 · see citing works
Extreme Binge Drinking Among 12th-Grade Students in the United States
Patrick, M. E., Schulenberg, J. E., Martz, M. E., Maggs, J. L., O’Malley, P. M., & Johnston, L. D. (2013) · Archives of Pediatrics and Adolescent Medicine · doi:10.1001/jamapediatrics.2013.2392 · Cited by 241 · see citing works
Gass, J. T., Glen, W. B., McGonigal, J. T., Trantham-Davidson, H., Lopez, M. F., Randall, P. K., Yaxley, R., Floresco, S. B., & Chandler, L. J. (2014) · Neuropsychopharmacology · doi:10.1038/npp.2014.109 · Cited by 197 · see citing works
Glutamate transporter GLT ‐1 mediates N ‐acetylcysteine inhibition of cocaine reinstatement
Reissner, K. J., Gipson, C. D., Tran, P. K., Knackstedt, L. A., Scofield, M. D., & Kalivas, P. W. (2014) · Addiction Biology · doi:10.1111/adb.12127 · Cited by 179 · see citing works
Self-citationColeman, L. G., Liu, W., Oguz, I., Styner, M., & Crews, F. T. (2014) · Pharmacology Biochemistry and Behavior · doi:10.1016/j.pbb.2013.11.021 · Cited by 170 · see citing works
The attribution of incentive salience to a stimulus that signals an intravenous injection of cocaine
Uslaner, J. M., Acerbo, M. J., Jones, S., & Robinson, T. E. (2006) · Behavioural Brain Research · doi:10.1016/j.bbr.2006.02.001 · Cited by 167 · see citing works
Synaptic Glutamate Spillover Due to Impaired Glutamate Uptake Mediates Heroin Relapse
Shen, H., Scofield, M. D., Boger, H. A., Hensley-Simon, M. E., & Kalivas, P. W. (2014) · Journal of Neuroscience · doi:10.1523/jneurosci.4564-13.2014 · Cited by 164 · see citing works
Adolescent brain development in normality and psychopathology
Luciana, M. M. (2013) · Development and Psychopathology · doi:10.1017/s0954579413000643 · Cited by 157 · see citing works
Pascual, M., Couto, B. R. D., Alfonso‐Loeches, S., Aguilar, M. A., Rodríguez‐Arias, M., & Guerri, C. (2012) · Neuropharmacology · doi:10.1016/j.neuropharm.2012.01.011 · Cited by 131 · see citing works
Das, S. C., Yamamoto, B. K., Hristov, A. M., & Sari, Y. (2015) · Neuropharmacology · doi:10.1016/j.neuropharm.2015.05.009 · Cited by 125 · see citing works
SPEAR, L. P., & Varlinskaya, E. I. (2010) · Developmental Psychobiology · doi:10.1002/dev.20457 · Cited by 120 · see citing works
Adolescents and alcohol: Acute sensitivities, enhanced intake, and later consequences
SPEAR, L. P. (2013) · Neurotoxicology and Teratology · doi:10.1016/j.ntt.2013.11.006 · Cited by 116 · see citing works
Vetreno, R. P., Broadwater, M., Liu, W., SPEAR, L. P., & Crews, F. T. (2014) · PLoS ONE · doi:10.1371/journal.pone.0113421 · Cited by 101 · see citing works
Robinson, D. L., Howard, E. C., McConnell, S., Gonzales, R. A., & Wightman, R. M. (2009) · Alcoholism Clinical and Experimental Research · doi:10.1111/j.1530-0277.2009.00942.x · Cited by 97 · see citing works
Self-citationSari, Y., Sreemantula, S. N., Lee, M. R., & Choi, D. (2013) · Journal of Molecular Neuroscience · doi:10.1007/s12031-013-0064-y · Cited by 96 · see citing works
Pitchers, K. K., Flagel, S. B., O'Donnell, E. G., Woods, L. C. S., Sarter, M. F., & Robinson, T. E. (2014) · Behavioural Brain Research · doi:10.1016/j.bbr.2014.10.036 · Cited by 95 · see citing works
Degenhardt, L. J., O'Loughlin, C., Swift, W., Romaniuk, H., Carlin, J. B., Coffey, C., Hall, W., & Patton, G. C. (2013) · BMJ Open · doi:10.1136/bmjopen-2013-003015 · Cited by 95 · see citing works
Sondheimer, I., & Knackstedt, L. A. (2011) · Behavioural Brain Research · doi:10.1016/j.bbr.2011.07.041 · Cited by 85 · see citing works
Besheer, J., Palmatier, M. I., Metschke, D. M., & Bevins, R. A. (2004) · Psychopharmacology · doi:10.1007/s00213-003-1621-9 · Cited by 85 · see citing works
Effects of adolescent ethanol exposure on ethanol consumption in adult rats
Slawecki, C. J., & Betancourt, M. (2002) · Alcohol · doi:10.1016/s0741-8329(01)00192-6 · Cited by 74 · see citing works
Vetreno, R. P., Yaxley, R. H., Paniagua, B., & Crews, F. T. (2015) · Addiction Biology · doi:10.1111/adb.12232 · Cited by 69 · see citing works
Risher, M., Sexton, H. G., Risher, W. C., Wilson, W. A., Fleming, R. L., Madison, R. D., Moore, S. D., Eroğlu, Ç., & Swartzwelder, H. S. (2015) · Alcoholism Clinical and Experimental Research · doi:10.1111/acer.12913 · Cited by 69 · see citing works
Alajaji, M., Bowers, M. S., Knackstedt, L. A., & Damaj, M. I. (2013) · Psychopharmacology · doi:10.1007/s00213-013-3047-3 · Cited by 66 · see citing works
The Role of Alcohol in Adolescent Relapse and Outcome
Brown, S. A., Tapert, S. F., Tate, S. R., & Abrantes, A. M. (2000) · Journal of Psychoactive Drugs · doi:10.1080/02791072.2000.10400216 · Cited by 55 · see citing works
Griffin, W. C., Ramachandra, V. S., Knackstedt, L. A., & Becker, H. C. (2015) · Frontiers in Pharmacology · doi:10.3389/fphar.2015.00027 · Cited by 52 · see citing works
Koss, W. A., Sadowski, R. N., Sherrill, L. K., Gulley, J. M., & Juraska, J. M. (2012) · Brain Research · doi:10.1016/j.brainres.2012.05.023 · Cited by 50 · see citing works
Palmatier, M. I., Marks, K. R., Jones, S. A., Freeman, K. S., Wissman, K. M., & Sheppard, A. B. (2012) · Psychopharmacology · doi:10.1007/s00213-012-2892-9 · Cited by 50 · see citing works
Pati, D., Kelly, K. B., Stennett, B., Frazier, C. J., & Knackstedt, L. A. (2016) · European Journal of Neuroscience · doi:10.1111/ejn.13284 · Cited by 50 · see citing works
Spoelder, M., Tsutsui, K. T., Lesscher, H. M. B., Vanderschuren, L. J. M. J., & Clark, J. J. (2015) · Neuropsychopharmacology · doi:10.1038/npp.2015.139 · Cited by 48 · see citing works
Developmental Differences in the Accumbal Dopaminergic Response to Repeated Ethanol Exposure
PHILPOT, R., & Kirstein, C. L. (2004) · Annals of the New York Academy of Sciences · doi:10.1196/annals.1308.056 · Cited by 45 · see citing works
The temporal “pulse” of drinking: Tracking 5 years of binge drinking in emerging adults.
Reich, R. R., Cummings, J. R., Greenbaum, P. E., Moltisanti, A. J., & Goldman, M. S. (2015) · Journal of Abnormal Psychology · doi:10.1037/abn0000061 · Cited by 45 · see citing works
Day, A. M., Celio, M. A., Lisman, S. A., Johansen, G. E., & SPEAR, L. P. (2013) · Journal of Studies on Alcohol and Drugs · doi:10.15288/jsad.2013.74.635 · Cited by 40 · see citing works
Carrara‐Nascimento, P. F., Griffin, W. C., Pastrello, D. M., Olive, M. F., & Camarini, R. (2011) · Alcohol · doi:10.1016/j.alcohol.2011.01.002 · Cited by 40 · see citing works
Anderson, R. I., & SPEAR, L. P. (2011) · Pharmacology Biochemistry and Behavior · doi:10.1016/j.pbb.2011.01.004 · Cited by 38 · see citing works
Toward isolating the role of dopamine in the acquisition of incentive salience attribution
Chow, J. J., Nickell, J. R., Darna, M., & Beckmann, J. S. (2016) · Neuropharmacology · doi:10.1016/j.neuropharm.2016.06.028 · Cited by 36 · see citing works
Yager, L. M., & Robinson, T. E. (2015) · Psychopharmacology · doi:10.1007/s00213-015-3962-6 · Cited by 34 · see citing works
McClory, A. J., & SPEAR, L. P. (2014) · Alcohol · doi:10.1016/j.alcohol.2014.05.006 · Cited by 33 · see citing works
Toalston, J. E., Deehan, G. A., Hauser, S. R., Engleman, E. A., Bell, R. L., Murphy, J. M., McBride, W. J., & Rodd, Z. A. (2015) · Alcohol · doi:10.1016/j.alcohol.2015.04.007 · Cited by 23 · see citing works
Palmatier, M. I., Kellicut, M. R., Brianna Sheppard, A., Brown, R. W., & Robinson, D. L. (2014) · Pharmacology Biochemistry and Behavior · doi:10.1016/j.pbb.2014.08.012 · Cited by 21 · see citing works
Self-citationSchuckit, M. A., Smith, T. L., Danko, G. P., Bucholz, K. K., Arpana Agrawal, A., Dick, D. M., Nürnberger, J. I., Kramer, J. R., Hesselbrock, M. N., Saunders, G., et al. (2014) · Journal of Studies on Alcohol and Drugs · doi:10.15288/jsad.2014.75.24 · Cited by 21 · see citing works
Peters, J., & Vries, T. J. D. (2013) · Psychopharmacology · doi:10.1007/s00213-013-3258-7 · Cited by 19 · see citing works
Flagged first, then by citations
Cited by
Sorted by citations
Adolescent neurodevelopment and substance use: receptor expression and behavioral consequences
Thorpe, H. H. A., Hamidullah, S., Jenkins, B. W., & Khokhar, J. Y. (2020) · Pharmacology & Therapeutics · doi:10.1016/j.pharmthera.2019.107431 · Cited by 97 · see citing works
Hellberg, S. N., Levit, J. D., & Robinson, M. J. F. (2018) · Behavioural Brain Research · doi:10.1016/j.bbr.2017.09.036 · Cited by 70 · see citing works
Hellberg, S. N., Russell, T. I., & Robinson, M. J. F. (2019) · Cognitive, Affective, & Behavioral Neuroscience · doi:10.3758/s13415-018-00662-3 · Cited by 65 · see citing works
- Authors
- Madayag, A. C., Stringfield, S. J., Reissner, K. J., Boettiger, C. A., & Robinson, D. L.
- Affiliations
- University of North Carolina at Chapel Hill (US)
- Corresponding author
- Robinson, Donita L.
- ORCID
- Venue
- Alcoholism: Clinical and Experimental Research
- Publisher
- Wiley
- Published
- 2017-03-13
- Volume
- 41
- Issue
- 4
- Pages
- 846-856
- ISSN
- 0145-6008 (ISSN-L)
- 1530-0277
- PMC
- PMC5419304
- OpenAlex
- W2588840624
- Cited by
- 50
- References
- 56
- Citations by year
- 2026: 3 · 2025: 3 · 2024: 7 · 2023: 8 · 2022: 4 · 2021: 6 · 2020: 5 · 2019: 7 · 2018: 4 · 2017: 3
- FWCI
- 2.54
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Alcoholism Clinical and Experimental Research (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Carolina Digital Repository (University of North Carolina at Chapel Hill) (submittedVersion)
- UNC Libraries
- Funders
- National Institute on Alcohol Abuse and Alcoholism (P60 AA011605, U24 AA020024, U01 AA019972, R00 DA031790)
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neurotransmitter Receptor Influence on Behavior
- Health Sciences › Medicine › Epidemiology › Substance Abuse Treatment and Outcomes
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Keywords
- Pavlovian conditioned approach, sign-tracking, goal tracking, sex differences, binge drinking, GLT-1, glutamate transporters, nucleus accumbens, glutamate homeostasis
- MeSH terms
- Age Factors, Ethanol, Animals, Conditioning, Classical, Female, Male, Reaction Time, Sex Factors, Rats, Sprague-Dawley, Rats, Binge Drinking
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
