Chronic Δ9-Tetrahydrocannabinol During Adolescence Provokes Sex-Dependent Changes in the Emotional Profile in Adult Rats: Behavioral and Biochemical Correlates
Abstract
Few and often contradictory reports exist on the long-term neurobiological consequences of cannabinoid consumption in adolescents. The endocannabinoid system plays an important role during the different stages of brain development as cannabinoids influence the release and action of different neurotransmitters and promote neurogenesis. This study tested whether long-lasting interference by cannabinoids with the developing endogenous cannabinoid system during adolescence caused persistent behavioral alterations in adult rats. Adolescent female and male rats were treated with increasing doses of Delta(9)-tetrahydrocannabinol (THC) for 11 days (postnatal day (PND) 35-45) and left undisturbed until adulthood (PND 75) when behavioral and biochemical assays were carried out. CB1 receptor level and CB1/G-protein coupling were significantly reduced by THC exposure in the amygdala (Amyg), ventral tegmental area (VTA) and nucleus accumbens (NAc) of female rats, whereas male rats had significant alterations only in the amygdala and hippocampal formation. Neither female nor male rats showed any changes in anxiety responses (elevated plus maze and open-field tests) but female rats presented significant 'behavioral despair' (forced swim test) paralleled by anhedonia (sucrose preference). In contrast, male rats showed no behavioral despair but did present anhedonia. This different behavioral picture was supported by biochemical parameters of depression, namely CREB alteration. Only female rats had low CREB activity in the hippocampal formation and prefrontal cortex and high activity in the NAc paralleled by increases in dynorphin expression. These results suggest that heavy cannabis consumption in adolescence may induce subtle alterations in the emotional circuit in female rats, ending in depressive-like behavior, whereas male rats show altered sensitivity to rewarding stimuli.
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In animals, CB1 receptor levels are higher in males than females.
“Animal data showing higher CB1 receptor levels in male relative to female animals18, 56, 57”
From Elevated brain cannabinoid CB1 receptor availability in post-traumatic stress disorder: A positron emission tomography study (2013) · cites this paper as [57]
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- Authors
- Rubino, T., Vigano', D., Realini, N., Guidali, C., Braida, D., Capurro, V., Castiglioni, C., Cherubino, F., Romualdi, P., Candeletti, S., Sala, M., & Parolaro, D.
- Affiliations
- University of Insubria (IT)
- University of Milan (IT)
- University of Bologna (IT)
- Corresponding author
- Parolaro, Daniela
- ORCID
- Venue
- Neuropsychopharmacology
- Published
- 2008-01-02
- Volume
- 33
- Issue
- 11
- Pages
- 2760-2771
- ISSN
- 0893-133X (ISSN-L)
- 1740-634X
- OpenAlex
- W2005270780
- Cited by
- 345
- References
- 48
- Citations by year
- 2026: 10 · 2025: 18 · 2024: 9 · 2023: 15 · 2022: 22 · 2021: 32 · 2020: 29 · 2019: 20 · 2018: 22 · 2017: 18 · 2016: 19 · 2015: 30 · 2014: 14 · 2013: 21 · 2012: 20
- FWCI
- 10.53
- Type
- journal article
- Language
- en
- Open access
- closed
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Neuropsychopharmacology (publishedVersion)
- PubMed (publishedVersion)
- Archivio istituzionale della ricerca (Alma Mater Studiorum Università di Bologna) (submittedVersion)
- IrInSubria (University of Insubria) (submittedVersion)
- Funders
- Università degli Studi dell'Insubria
- Topics
- Health Sciences › Medicine › Pharmacology › Cannabis and Cannabinoid Research
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neurotransmitter Receptor Influence on Behavior
- Life Sciences › Neuroscience › Behavioral Neuroscience › Stress Responses and Cortisol
- Keywords
- adolescent cannabis exposure, delta-9-tetrahydrocannabinol, endocannabinoid system, sex differences, CB1 receptor, amygdala, ventral tegmental area, nucleus accumbens, hippocampus, anhedonia, behavioral despair, depression-like behavior, CREB, dynorphin, reward sensitivity, anxiety
- MeSH terms
- Age Factors, Animals, Conditioning, Operant, Drug Administration Schedule, Emotions, Female, Male, Motor Activity, Sex Characteristics, Dronabinol, Rats, Sprague-Dawley, Maze Learning, Rats
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