Adolescent exposure to cannabinoids as a postnatal environmental insult may increase the risk of psychosis in subjects exposed to perinatal insult, as suggested by the two-hit hypothesis of schizophrenia. Here, we hypothesized that peripubertal Δ9-tetrahydrocannabinol (aTHC) may affect the impact of prenatal methylazoxymethanol acetate (MAM) or perinatal THC (pTHC) exposure in adult rats. We found that MAM and pTHC-exposed rats, when compared to the control group (CNT), were characterized by adult phenotype relevant to schizophrenia, including social withdrawal and cognitive impairment, as revealed by social interaction test and novel object recognition test, respectively. At the molecular level, we observed an increase in cannabinoid CB1 receptor (Cnr1) and/or dopamine D2/D3 receptor (Drd2, Drd3) gene expression in the prefrontal cortex of adult MAM or pTHC-exposed rats, which we attributed to changes in DNA methylation at key regulatory gene regions. Interestingly, aTHC treatment significantly impaired social behavior, but not cognitive performance in CNT groups. In pTHC rats, aTHC did not exacerbate the altered phenotype nor dopaminergic signaling, while it reversed cognitive deficit in MAM rats by modulating Drd2 and Drd3 gene expression. In conclusion, our results suggest that the effects of peripubertal THC exposure may depend on individual differences related to dopaminergic neurotransmission.

Canada Excellence Research Chair on the Microbiome Endocannabinoidome Axis in Metabolic Health Faculty of Medicine Agricultural and Food Sciences CRIUCPQ INAF and Centre NUTRISS Université Laval Quebec City QC G1V 4G5 Canada

Central Nervous System Diseases Research Boehringer Ingelheim Pharma GmbH and Co KG 88397 Biberach an der Riss Germany

Department of Biomedical and Biotechnological Sciences University of Catania 95123 Catania Italy

Department of Bioscience and Technology for Food Agriculture and Environment University of Teramo 64100 Teramo Italy

Department of Pharmacology Faculty of Medicine Masaryk University 62500 Brno Czech Republic

Endocannabinoid Research Group Institute of Biomolecular Chemistry Consiglio Nazionale delle Ricerche 80078 Pozzuoli Italy

Forensic Laboratory of Biologically Active Substances Department of Chemistry of Natural Compounds University of Chemistry and Technology Prague 16628 Prague Czech Republic

Psychedelic Research Centre National Institute of Mental Health Topolová 748 25067 Klecany Czech Republic

Scientific Core Unit Neuroimaging Max Planck Institute of Psychiatry 80804 Munich Germany

Zobrazit více v PubMed

Owen M.J., O’ Donovan M.C., Thapar A., Craddock N. Neurodevelopmental hypothesis of schizophrenia. Br. J. Psychiatry. 2011;198:173–175. doi: 10.1192/bjp.bp.110.084384. PubMed DOI PMC

Nadeem A., Ahmad S.F., Al-Harbi N.O., Attia S.M., Bakheet S.A., Ibrahim K.E., Alqahtani F., Alqinyah M. Nrf2 activator, sulforaphane ameliorates autism-like symptoms through suppression of Th17 related signaling and rectification of oxidant-antioxidant imbalance in periphery and brain of BTBR T+tf/J mice. Behav. Brain Res. 2019;364:213–224. doi: 10.1016/j.bbr.2019.02.031. PubMed DOI

Ahmad S.F., Ansari M.A., Nadeem A., Bakheet S.A., Alshammari M.A., Attia S.M. Protection by tyrosine kinase inhibitor, tyrphostin AG126, through the suppression of IL-17A, RORγt, and T-bet signaling, in the BTBR mouse model of autism. Brain Res. Bull. 2018;142:328–337. doi: 10.1016/j.brainresbull.2018.08.020. PubMed DOI

Ahmad S.F., Ansari M.A., Nadeem A., Bakheet S.A., Alqahtani F., Alhoshani A.R., Alasmari F., Alsaleh N.B., Attia S.M. 5-aminoisoquinolinone attenuates social behavior deficits and immune abnormalities in the BTBR T+ Itpr3tf/J mouse model for autism. Pharmacol. Biochem. Behav. 2020;189:172859. doi: 10.1016/j.pbb.2020.172859. PubMed DOI

Al-Mazroua H.A., Nadeem A., Ansari M.A., Attia S.M., Albekairi T.H., Bakheet S.A., Alobaidi A.F., Alhosaini K., Alqarni S.A., Ibrahim K.E., et al. Methylmercury chloride exposure exacerbates existing neurobehavioral and immune dysfunctions in the BTBR T+ Itpr3tf/J mouse model of autism. Immunol. Lett. 2022;244:19–27. doi: 10.1016/j.imlet.2022.03.001. PubMed DOI

Higuera-Matas A., Ucha M., Ambrosio E. Long-term consequences of perinatal and adolescent cannabinoid exposure on neural and psychological processes. Neurosci. Biobehav. Rev. 2015;55:119–146. doi: 10.1016/j.neubiorev.2015.04.020. PubMed DOI

Stiles J., Jernigan T.L. The Basics of Brain Development. Neuropsychol. Rev. 2010;20:327–348. doi: 10.1007/s11065-010-9148-4. PubMed DOI PMC

Giedd J.N., Blumenthal J., Jeffries N.O., Castellanos F.X., Liu H., Zijdenbos A., Paus T., Evans A.C., Rapoport J.L. Brain development during childhood and adolescence: A longitudinal MRI study. Nat. Neurosci. 1999;2:861–863. doi: 10.1038/13158. PubMed DOI

Spear L.P. The adolescent brain and age-related behavioral manifestations. Neurosci. Biobehav. Rev. 2020;24:417–463. doi: 10.1016/S0149-7634(00)00014-2. PubMed DOI

Andersen S.L. Trajectories of brain development: Point of vulnerability or window of opportunity? Neurosci. Biobehav. Rev. 2003;27:3–18. doi: 10.1016/S0149-7634(03)00005-8. PubMed DOI

Micale V., Kucerova J., Sulcova A. Leading compounds for the validation of animal models of psychopathology. Cell Tissue Res. 2013;354:309–330. doi: 10.1007/s00441-013-1692-9. PubMed DOI

Alpár A., Di Marzo V., Harkany T. At the Tip of an Iceberg: Prenatal Marijuana and Its Possible Relation to Neuropsychiatric Outcome in the Offspring. Biol. Psychiatry. 2016;79:e33–e45. doi: 10.1016/j.biopsych.2015.09.009. PubMed DOI

Di Bartolomeo M., Stark T., Maurel O.M., Iannotti F.A., Kuchar M., Ruda-Kucerova J., Piscitelli F., Laudani S., Pekarik V., Salomone S., et al. Crosstalk between the transcriptional regulation of dopamine D2 and cannabinoid CB1 receptors in schizophrenia: Analyses in patients and in perinatal Δ9-tetrahydrocannabinol-exposed rats. Pharmacol. Res. 2021;164:105357. doi: 10.1016/j.phrs.2020.105357. PubMed DOI

Stark T., Di Martino S., Drago F., Wotjak C.T., Micale V. Phytocannabinoids and schizophrenia: Focus on adolescence as a critical window of enhanced vulnerability and opportunity for treatment. Pharmacol. Res. 2021;174:105938. doi: 10.1016/j.phrs.2021.105938. PubMed DOI

Hermann H., Marsicano G., Lutz B. Coexpression of the cannabinoid receptor type 1 with dopamine and serotonin receptors in distinct neuronal subpopulations of the adult mouse forebrain. Neuroscience. 2002;109:451–460. doi: 10.1016/S0306-4522(01)00509-7. PubMed DOI

Meschler J.P., Howlett A.C. Signal transduction interactions between CB1 cannabinoid and dopamine receptors in the rat and monkey striatum. Neuropharmacology. 2001;40:918–926. doi: 10.1016/S0028-3908(01)00012-0. PubMed DOI

Stark T., Iannotti F.A., Di Martino S., Di Bartolomeo M., Ruda-Kucerova J., Piscitelli F., Wotjak C.T., D’Addario C., Drago F., Di Marzo V., et al. Early Blockade of CB1 Receptors Ameliorates Schizophrenia-like Alterations in the Neurodevelopmental MAM Model of Schizophrenia. Biomolecules. 2022;12:108. doi: 10.3390/biom12010108. PubMed DOI PMC

Ruda-Kucerova J., Babinska Z., Amchova P., Stark T., Drago F., Sulcova A., Micale V. Reactivity to addictive drugs in the methylazoxymethanol (MAM) model of schizophrenia in male and female rats. World J. Biol. Psychiatry. 2017;18:129–142. doi: 10.1080/15622975.2016.1190032. PubMed DOI

D’Addario C., Micale V., Di Bartolomeo M., Stark T., Pucci M., Sulcova A., Palazzo M., Babinska Z., Cremaschi L., Drago F., et al. A preliminary study of endocannabinoid system regulation in psychosis: Distinct alterations of CNR1 promoter DNA methylation in patients with schizophrenia. Schizophr. Res. 2017;188:132–140. doi: 10.1016/j.schres.2017.01.022. PubMed DOI

Stark T., Ruda-Kucerova J., Iannotti F.A., D’Addario C., Di Marco R., Pekarik V., Drazanova E., Piscitelli F., Bari M., Babinska Z., et al. Peripubertal cannabidiol treatment rescues behavioral and neurochemical abnormalities in the MAM model of schizophrenia. Neuropharmacology. 2019;146:212–221. doi: 10.1016/j.neuropharm.2018.11.035. PubMed DOI

Stark T., Di Bartolomeo M., Di Marco R., Drazanova E., Platania C.B.M., Iannotti F.A., Ruda-Kucerova J., D’Addario C., Kratka L., Pekarik V., et al. Altered dopamine D3 receptor gene expression in MAM model of schizophrenia is reversed by peripubertal cannabidiol treatment. Biochem. Pharmacol. 2020;177:114004. doi: 10.1016/j.bcp.2020.114004. PubMed DOI

Drazanova E., Ruda-Kucerova J., Kratka L., Stark T., Kuchar M., Maryska M., Drago F., Starcuk Z., Micale V. Different effects of prenatal MAM vs. perinatal THC exposure on regional cerebral blood perfusion detected by Arterial Spin Labelling MRI in rats. Sci. Rep. 2019;9:6062. doi: 10.1038/s41598-019-42532-z. PubMed DOI PMC

Kucerova J., Tabiova K., Drago F., Micale V. Therapeutic Potential of Cannabinoids in Schizophrenia. Recent Pat. CNS Drug Discov. 2014;9:13–25. doi: 10.2174/1574889809666140307115532. PubMed DOI

Peters K.Z., Naneix F. The role of dopamine and endocannabinoid systems in prefrontal cortex development: Adolescence as a critical period. Front. Neural Circuits. 2022;16:939235. doi: 10.3389/fncir.2022.939235. PubMed DOI PMC

Micale V., Di Bartolomeo M., Di Martino S., Stark T., Dell’Osso B., Drago F., D’Addario C. Are the epigenetic changes predictive of therapeutic efficacy for psychiatric disorders? A translational approach towards novel drug targets. Pharmacol. Ther. 2023;241:108279. doi: 10.1016/j.pharmthera.2022.108279. PubMed DOI

Howes O.D., Kapur S. The Dopamine Hypothesis of Schizophrenia: Version III--The Final Common Pathway. Schizophr. Bull. 2009;35:549–562. doi: 10.1093/schbul/sbp006. PubMed DOI PMC

Shing N., Walker M.C., Chang P. The role of aberrant neural oscillations in the hippocampal-medial prefrontal cortex circuit in neurodevelopmental and neurological disorders. Neurobiol. Learn. Mem. 2022;195:107683. doi: 10.1016/j.nlm.2022.107683. PubMed DOI

Eggan S.M., Hashimoto T., Lewis D.A. Reduced Cortical Cannabinoid 1 Receptor Messenger RNA and Protein Expression in Schizophrenia. Arch. Gen. Psychiatry. 2008;65:772. doi: 10.1001/archpsyc.65.7.772. PubMed DOI PMC

DiNieri J.A., Wang X., Szutorisz H., Spano S.M., Kaur J., Casaccia P., Dow-Edwards D., Hurd Y.L. Maternal Cannabis Use Alters Ventral Striatal Dopamine D2 Gene Regulation in the Offspring. Biol. Psychiatry. 2011;70:763–769. doi: 10.1016/j.biopsych.2011.06.027. PubMed DOI PMC

Wang X., Dow-Edwards D., Anderson V., Minkoff H., Hurd Y.L. In utero marijuana exposure associated with abnormal amygdala dopamine D2 gene expression in the human fetus. Biol. Psychiatry. 2004;56:909–915. doi: 10.1016/j.biopsych.2004.10.015. PubMed DOI

Saito A., Ballinger M.D.L., Pletnikov M.V., Wong D.F., Kamiya A. Endocannabinoid system: Potential novel targets for treatment of schizophrenia. Neurobiol. Dis. 2013;53:10–17. doi: 10.1016/j.nbd.2012.11.020. PubMed DOI PMC

Ruggiero R.N., Rossignoli M.T., De Ross J.B., Hallak J.E.C., Leite J.P., Bueno-Junior L.S. Cannabinoids and Vanilloids in Schizophrenia: Neurophysiological Evidence and Directions for Basic Research. Front. Pharmacol. 2017;8:399. doi: 10.3389/fphar.2017.00399. PubMed DOI PMC

Schneider M. Adolescence as a vulnerable period to alter rodent behavior. Cell Tissue Res. 2013;354:99–106. doi: 10.1007/s00441-013-1581-2. PubMed DOI

Feigenson K.A., Kusnecov A.W., Silverstein S.M. Inflammation and the two-hit hypothesis of schizophrenia. Neurosci. Biobehav. Rev. 2014;38:72–93. doi: 10.1016/j.neubiorev.2013.11.006. PubMed DOI PMC

Gomes F.V., Guimarães F.S., Grace A.A. Effects of Pubertal Cannabinoid Administration on Attentional Set-Shifting and Dopaminergic Hyper-Responsivity in a Developmental Disruption Model of Schizophrenia. Int. J. Neuropsychopharmacol. 2015;18:pyu018. doi: 10.1093/ijnp/pyu018. PubMed DOI PMC

Aguilar D.D., Giuffrida A., Lodge D.J. Adolescent Synthetic Cannabinoid Exposure Produces Enduring Changes in Dopamine Neuron Activity in a Rodent Model of Schizophrenia Susceptibility. Int. J. Neuropsychopharmacol. 2018;21:393–403. doi: 10.1093/ijnp/pyy003. PubMed DOI PMC

Lecca S., Luchicchi A., Scherma M., Fadda P., Muntoni A.L., Pistis M. Δ9-Tetrahydrocannabinol During Adolescence Attenuates Disruption of Dopamine Function Induced in Rats by Maternal Immune Activation. Front. Behav. Neurosci. 2019;13:202. doi: 10.3389/fnbeh.2019.00202. PubMed DOI PMC

Ruda-Kucerova J., Babinska Z., Stark T., Micale V. Suppression of Methamphetamine Self-Administration by Ketamine Pre-treatment Is Absent in the Methylazoxymethanol (MAM) Rat Model of Schizophrenia. Neurotox. Res. 2017;32:121–133. doi: 10.1007/s12640-017-9718-9. PubMed DOI

Večeřa J., Bártová E., Krejčí J., Legartová S., Komůrková D., Rudá-Kučerová J., Štark T., Dražanová E., Kašpárek T., Šulcová A., et al. HDAC1 and HDAC3 underlie dynamic H3K9 acetylation during embryonic neurogenesis and in schizophrenia-like animals. J. Cell. Physiol. 2018;233:530–548. doi: 10.1002/jcp.25914. PubMed DOI PMC

Horska K., Kotolova H., Karpisek M., Babinska Z., Hammer T., Prochazka J., Stark T., Micale V., Ruda-Kucerova J. Metabolic profile of methylazoxymethanol model of schizophrenia in rats and effects of three antipsychotics in long-acting formulation. Toxicol. Appl. Pharmacol. 2020;406:115214. doi: 10.1016/j.taap.2020.115214. PubMed DOI

Kucera J., Horska K., Hruska P., Kuruczova D., Micale V., Ruda-Kucerova J., Bienertova-Vasku J. Interacting effects of the MAM model of schizophrenia and antipsychotic treatment: Untargeted proteomics approach in adipose tissue. Progr. Neuro-Psychopharmacol. Biol. Psychiatry. 2021;108:110165. doi: 10.1016/j.pnpbp.2020.110165. PubMed DOI

Uttl L., Szczurowska E., Hájková K., Horsley R.R., Štefková K., Hložek T., Šíchová K., Balíková M., Kuchař M., Micale v., et al. Behavioral and Pharmacokinetic Profile of Indole-Derived Synthetic Cannabinoids JWH-073 and JWH-210 as Compared to the Phytocannabinoid Δ9-THC in Rats. Front. Neurosci. 2018;12:703. doi: 10.3389/fnins.2018.00703. PubMed DOI PMC

Brancato A., Castelli V., Lavanco G., Tringali G., Micale V., Kuchar M., D’Amico C., Pizzolanti G., Feo S., Cannizzaro C. Binge-like Alcohol Exposure in Adolescence: Behavioural, Neuroendocrine and Molecular Evidence of Abnormal Neuroplasticity… and Return. Biomedicines. 2021;9:1161. doi: 10.3390/biomedicines9091161. PubMed DOI PMC

Molina-Holgado F., Amaro A., González M.I., Alvarez F.J., Leret M.L. Effect of maternal Δ9-tetrahydrocannabinol on developing serotonergic system. Eur. J. Pharmacol. 1996;316:39–42. doi: 10.1016/S0014-2999(96)00753-4. PubMed DOI

Scherma M., Dessì C., Muntoni A.L., Lecca S., Satta V., Luchicchi A., Pistis M., Panlilio L.V., Fattore L., Goldberg S.R., et al. Adolescent Δ9-Tetrahydrocannabinol Exposure Alters WIN55,212-2 Self-Administration in Adult Rats. Neuropsychopharmacology. 2016;41:1416–1426. doi: 10.1038/npp.2015.295. PubMed DOI PMC

Terzian A.L., Drago F., Wotjak C.T., Micale V. The Dopamine and Cannabinoid Interaction in the Modulation of Emotions and Cognition: Assessing the Role of Cannabinoid CB1 Receptor in Neurons Expressing Dopamine D1 Receptors. Front. Behav. Neurosci. 2011;5:49. doi: 10.3389/fnbeh.2011.00049. PubMed DOI PMC

Terzian A.L.B., Micale V., Wotjak C.T. Cannabinoid receptor type 1 receptors on GABAergic vs. glutamatergic neurons differentially gate sex-dependent social interest in mice. Eur. J. Neurosci. 2014;40:2293–2298. doi: 10.1111/ejn.12561. PubMed DOI

Chiodi V., Domenici M.R., Biagini T., de Simone R., Tartaglione A.M., Di Rosa M., lo Re O., Mazza T., Micale V., Vinciguerra M. Systemic depletion of histone macroH2A1.1 boosts hippocampal synaptic plasticity and social behavior in mice. FASEB J. 2021;35:e21793. doi: 10.1096/fj.202100569R. PubMed DOI

Raffaele M., Kovacovicova K., Biagini T., Lo Re O., Frohlich J., Giallongo S., Nhan J.D., Giannone A.G., Cabibi D., Ivanov M., et al. Nociceptin/orphanin FQ opioid receptor (NOP) selective ligand MCOPPB links anxiolytic and senolytic effects. Geroscience. 2022;44:463–483. doi: 10.1007/s11357-021-00487-y. PubMed DOI PMC

Paxinos G., Watson C. The Rat Brain in Stereotaxic Coordinates. 4th ed. Academic Press; San Diego, CA, USA: 1998.

Drago F., Nicolosi A., Micale V., Lo Menzo G. Placebo affects the performance of rats in models of depression: Is it a good control for behavioral experiments? Eur. Neuropsychopharmacol. 2001;11:209–213. doi: 10.1016/S0924-977X(01)00084-0. PubMed DOI

Tamburella A., Micale V., Navarria A., Drago F. Antidepressant properties of the 5-HT4 receptor partial agonist, SL65.0155: Behavioral and neurochemical studies in rats. Progr. Neuro-Psychopharmacol. Biol. Psychiatry. 2009;33:1205–1210. doi: 10.1016/j.pnpbp.2009.07.001. PubMed DOI

Tamburella A., Micale V., Mazzola C., Salomone S., Drago F. The selective norepinephrine reuptake inhibitor atomoxetine counteracts behavioral impairments in trimethyltin-intoxicated rats. Eur. J. Pharmacol. 2012;683:148–154. doi: 10.1016/j.ejphar.2012.02.045. PubMed DOI

Pamplona F.A., Henes K., Micale V., Mauch C.P., Takahashi R.N., Wotjak C.T. Prolonged fear incubation leads to generalized avoidance behavior in mice. J. Psychiatr. Res. 2011;45:354–360. doi: 10.1016/j.jpsychires.2010.06.015. PubMed DOI

Ruda-Kucerova J., Amchova P., Babinska Z., Dusek L., Micale V., Sulcova A. Sex Differences in the Reinstatement of Methamphetamine Seeking after Forced Abstinence in Sprague-Dawley Rats. Front. Psychiatry. 2015;6:91. doi: 10.3389/fpsyt.2015.00091. PubMed DOI PMC

Lyon E. Mutation detection using fluorescent hybridization probes and melting curve analysis. Expert Rev. Mol. Diagn. 2011;1:92–101. doi: 10.1586/14737159.1.1.92. PubMed DOI

Livak K.J., Schmittgen T.D. Analysis of Relative Gene Expression Data Using Real-Time Quantitative PCR and the 2−ΔΔCT Method. Methods. 2001;25:402–408. doi: 10.1006/meth.2001.1262. PubMed DOI

Prenatal MAM exposure raises kynurenic acid levels in the prefrontal cortex of adult rats

Olanzapine, but not haloperidol, exerts pronounced acute metabolic effects in the methylazoxymethanol rat model