Changes in hippocampal morphology and neuroplasticity induced by adolescent THC treatment are associated with cognitive impairment in adulthood
Abstract
Marijuana and hashish are the illicit drugs most frequently used by human adolescents. Given the continued neurodevelopment throughout adolescence, adolescents may be more vulnerable than adults to certain neural consequences of heavy marijuana use. This study aimed to assess whether an experimental model of adolescent chronic exposure to Delta9-tetrahydrocannabinol (THC), may induce lasting effects on learning and memory. Adolescent rats have been treated with THC or its vehicle from 35 to 45 postnatal days (PND) and left undisturbed until their adulthood (75 PND) when aversive and spatial memory was assessed using the passive avoidance and radial maze tasks. No alteration was found in aversive memory, but in the radial maze THC pretreated animals exhibited a worse performance than vehicles, suggesting a deficit in spatial working memory. To correlate memory impairment to altered neuroplasticity, level of marker proteins was investigated in the hippocampus, the most relevant area mediating spatial memory. A significant decrease in the astroglial marker glial fibrillar acid protein was found as well as in pre- and postsynaptic protein expression (VAMP2, PSD95) and NMDA receptor levels in pretreated rats. To parallel these changes to alteration in dendritic morphology, Golgi-Cox staining was performed in the hippocampal dentate gyrus. Pretreated rats had a significantly lower total dendritic length and number than vehicles, as well as reduced spine density. Our data suggest that THC pretreated rats may establish less synaptic contacts and/or less efficient synaptic connections throughout the hippocampus and this could represent the molecular underpinning of the cognitive deficit induced by adolescent THC treatment.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
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?
The potency of cannabis has generally increased since 1980 and varies across geographic location.
“Furthermore, the potency of cannabis has generally increased since 1980, 76 and potency varies across geographic location.8”
From Association of Cannabis Use in Adolescence and Risk of Depression, Anxiety, and Suicidality in Young Adulthood (2019) · cites this paper as [76]
Cites
Anatomical MRI of the developing human brain: what have we learned?
DURSTON, S., HULSHOFF POL, H. E., CASEY, B. J., GIEDD, J. N., BUITELAAR, J. K., & VAN ENGELAND, H. (2001) · Journal of the American Academy of Child & Adolescent Psychiatry · doi:10.1097/00004583-200109000-00009 · Cited by 410 · cited 2× · see citing works
“Although development of overall brain size is largely complete by age 5 (Durston et al., 2001), specific structural and functional changes continue into adolescence, leading to greater cognitive efficiency.”
BackgroundImpact of Cannabis Use on Brain Function in Adolescents
JACOBSEN, L. K., MENCL, W. E., WESTERVELD, M., & PUGH, K. R. (2004) · Annals of the New York Academy of Sciences · doi:10.1196/annals.1308.053 · Cited by 128 · see citing works
Flagged first, then by citations
Cited by
Sorted by citations
Persistent cannabis users show neuropsychological decline from childhood to midlife
Meier, M. H., Caspi, A., Ambler, A., Harrington, H., Houts, R., Keefe, R. S. E., McDonald, K., Ward, A., Poulton, R., & Moffitt, T. E. (2012) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1206820109 · Cited by 1,523 · see citing works
The endocannabinoid system and the brain.
Mechoulam, R., & Parker, L. A. (2013) · Annual Review of Psychology · doi:10.1146/annurev-psych-113011-143739 · Cited by 1,090 · see citing works
Gobbi, G., Atkin, T., Zytynski, T., Wang, S., Askari, S., Boruff, J., Ware, M., Marmorstein, N., Cipriani, A., Dendukuri, N., et al. (2019) · JAMA Psychiatry · doi:10.1001/jamapsychiatry.2018.4500 · Cited by 914 · see citing works
Dendritic spine pathology in schizophrenia
Glausier, J. R., & Lewis, D. A. (2013) · Neuroscience · doi:10.1016/j.neuroscience.2012.04.044 · Cited by 581 · see citing works
Lisdahl, K. M., Gilbart, E. R., Wright, N. E., & Shollenbarger, S. (2013) · Frontiers in Psychiatry · doi:10.3389/fpsyt.2013.00053 · Cited by 284 · see citing works
Adolescent cannabis use and psychosis: epidemiology and neurodevelopmental models
Malone, D. T., Hill, M. N., & Rubino, T. (2010) · British Journal of Pharmacology · doi:10.1111/j.1476-5381.2010.00721.x · Cited by 237 · see citing works
Self-citationEffects of endocannabinoid system modulation on cognitive and emotional behavior
Zanettini, C. (2011) · Frontiers in Behavioral Neuroscience · doi:10.3389/fnbeh.2011.00057 · Cited by 214 · see citing works
The Impact of Exposure to Cannabinoids in Adolescence: Insights From Animal Models
Rubino, T., & Parolaro, D. (2016) · Biological Psychiatry · doi:10.1016/j.biopsych.2015.07.024 · Cited by 183 · see citing works
Self-citationImpact of adolescent marijuana use on intelligence: Results from two longitudinal twin studies
Jackson, N. J., Isen, J. D., Khoddam, R., Irons, D., Tuvblad, C., Iacono, W. G., McGue, M., Raine, A., & Baker, L. A. (2016) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1516648113 · Cited by 178 · see citing works
Lisdahl, K. M., Wright, N. E., Medina-Kirchner, C., Maple, K. E., & Shollenbarger, S. (2014) · Current Addiction Reports · doi:10.1007/s40429-014-0019-6 · Cited by 160 · see citing works
Mechanisms of Action and Persistent Neuroplasticity by Drugs of Abuse
Korpi, E. R., den Hollander, B., Farooq, U., Vashchinkina, E., Rajkumar, R., Nutt, D. J., Hyytiä, P., & Dawe, G. S. (2015) · Pharmacological Reviews · doi:10.1124/pr.115.010967 · Cited by 148 · see citing works
The long-term cognitive consequences of adolescent exposure to recreational drugs of abuse
Mooney-Leber, S. M., & Gould, T. J. (2018) · Learning & Memory · doi:10.1101/lm.046672.117 · Cited by 140 · see citing works
“Moreover, reductions in HC dendritic length and number of proximal and distal dendrites in adults previously exposed to THC as adolescents has been reported (Rubino et al. 2009b).”
BackgroundInfluentialDelgado y Palacios, R., Campo, A., Henningsen, K., Verhoye, M., Poot, D., Dijkstra, J., Van Audekerke, J., Benveniste, H., Sijbers, J., Wiborg, O., et al. (2011) · Biological Psychiatry · doi:10.1016/j.biopsych.2011.05.014 · Cited by 113 · see citing works
Mateos, B., Borcel, E., Loriga, R., Luesu, W., Bini, V, Llorente, R., Castelli, M., & Viveros, M.-P. (2011) · Journal of Psychopharmacology · doi:10.1177/0269881110370503 · Cited by 108 · see citing works
Renard, J., Rushlow, W. J., & Laviolette, S. R. (2018) · Frontiers in Psychiatry · doi:10.3389/fpsyt.2018.00281 · Cited by 62 · see citing works
Preliminary in vivo evidence of lower hippocampal synaptic density in cannabis use disorder
D’Souza, D. C., Radhakrishnan, R., Naganawa, M., Ganesh, S., Nabulsi, N., Najafzadeh, S., Ropchan, J., Ranganathan, M., Cortes-Briones, J., Huang, Y., et al. (2021) · Molecular Psychiatry · doi:10.1038/s41380-020-00891-4 · Cited by 55 · see citing works
Lee, H.-L., Jung, K.-M., Fotio, Y., Squire, E., Palese, F., Lin, L., Torrens, A., Ahmed, F., Mabou Tagne, A., Ramirez, J., et al. (2022) · Biological Psychiatry · doi:10.1016/j.biopsych.2022.04.017 · Cited by 38 · see citing works
Disentangling the lasting effects of adolescent cannabinoid exposure
Stringfield, S. J., & Torregrossa, M. M. (2021) · Progress in Neuro-Psychopharmacology and Biological Psychiatry · doi:10.1016/j.pnpbp.2020.110067 · Cited by 32 · see citing works
Le, A. A., Quintanilla, J., Amani, M., Piomelli, D., Lynch, G., & Gall, C. M. (2022) · Neurobiology of Disease · doi:10.1016/j.nbd.2021.105565 · Cited by 22 · see citing works
- Authors
- Rubino, T., Realini, N., Braida, D., Guidi, S., Capurro, V., Viganò, D., Guidali, C., Pinter, M., Sala, M., Bartesaghi, R., & Parolaro, D.
- Affiliations
- University of Insubria (IT)
- University of Milan (IT)
- University of Bologna (IT)
- Corresponding author
- Rubino, Tiziana
- ORCID
- Venue
- Hippocampus
- Publisher
- Wiley
- Published
- 2009-01-20
- Volume
- 19
- Issue
- 8
- Pages
- 763-772
- ISSN
- 1050-9631 (ISSN-L)
- 1098-1063
- OpenAlex
- W2022974589
- Cited by
- 282
- References
- 2
- Citations by year
- 2026: 4 · 2025: 11 · 2024: 12 · 2023: 10 · 2022: 17 · 2021: 24 · 2020: 32 · 2019: 15 · 2018: 24 · 2017: 13 · 2016: 16 · 2015: 23 · 2014: 16 · 2013: 12 · 2012: 18
- FWCI
- 12.68
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Hippocampus (publishedVersion)
- PubMed (publishedVersion)
- Archivio istituzionale della ricerca (Alma Mater Studiorum Università di Bologna) (submittedVersion)
- IrInSubria (University of Insubria) (submittedVersion)
- Topics
- Health Sciences › Medicine › Pharmacology › Cannabis and Cannabinoid Research
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Life Sciences › Neuroscience › Cognitive Neuroscience › Memory and Neural Mechanisms
- Keywords
- delta-9-tetrahydrocannabinol, spatial working memory, cognitive impairment, neuroplasticity, glial fibrillary acidic protein, VAMP2, PSD-95, NMDA receptor, dendritic spines, dentate gyrus, passive avoidance memory, radial maze, cannabis use, adolescent drug exposure
- MeSH terms
- Disks Large Homolog 4 Protein, Aging, Animals, Avoidance Learning, Cognition Disorders, Dendrites, Glial Fibrillary Acidic Protein, Hippocampus, Male, Membrane Proteins, Memory, Neuronal Plasticity, Psychotropic Drugs, Dronabinol, Tubulin, Receptors, N-Methyl-D-Aspartate, Synaptophysin, Rats, Sprague-Dawley, Maze Learning, Intracellular Signaling Peptides and Proteins, Vesicle-Associated Membrane Protein 2, Rats
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
