Clinical studies consistently report structural impairments (i.e.: ventricular enlargement, decreased volume of anterior cingulate cortex or hippocampus) and functional abnormalities including changes in regional cerebral blood flow in individuals suffering from schizophrenia, which can be evaluated by magnetic resonance imaging (MRI) techniques. The aim of this study was to assess cerebral blood perfusion in several schizophrenia-related brain regions using Arterial Spin Labelling MRI (ASL MRI, 9.4 T Bruker BioSpec 94/30USR scanner) in rats. In this study, prenatal exposure to methylazoxymethanol acetate (MAM, 22 mg/kg) at gestational day (GD) 17 and the perinatal treatment with Δ-9-tetrahydrocannabinol (THC, 5 mg/kg) from GD15 to postnatal day 9 elicited behavioral deficits consistent with schizophrenia-like phenotype, which is in agreement with the neurodevelopmental hypothesis of schizophrenia. In MAM exposed rats a significant enlargement of lateral ventricles and perfusion changes (i.e.: increased blood perfusion in the circle of Willis and sensorimotor cortex and decreased perfusion in hippocampus) were detected. On the other hand, the THC perinatally exposed rats did not show differences in the cerebral blood perfusion in any region of interest. These results suggest that although both pre/perinatal insults showed some of the schizophrenia-like deficits, these are not strictly related to distinct hemodynamic features.

Department of Biomedical and Biotechnological Sciences Section of Pharmacology School of Medicine University of Catania Catania Italy

Department of Biomedical Engineering Faculty of Electrical Engineering and Communication University of Technology Brno Czech Republic

Department of Pharmacology Faculty of Medicine Masaryk University Brno Czech Republic

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

Institute of Scientific Instruments of the Czech Academy of Sciences Brno Czech Republic

National Institute of Mental Health Klecany Czech Republic

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Radua J, et al. Multimodal meta-analysis of structural and functional brain changes in first episode psychosis and the effects of antipsychotic medication. Neurosci. Biobehav. Rev. 2012;36:2325–2333. doi: 10.1016/j.neubiorev.2012.07.012. PubMed DOI

Wright IC, et al. Meta-Analysis of Regional Brain Volumes in Schizophrenia. Am. J. Psychiatry. 2000;157:16–25. doi: 10.1176/ajp.157.1.16. PubMed DOI

Alsop DC, et al. Recommended implementation of arterial spin-labeled perfusion MRI for clinical applications: A consensus of the ISMRM perfusion study group and the European consortium for ASL in dementia. Magn. Reson. Med. 2015;73:102–116. doi: 10.1002/mrm.25197. PubMed DOI PMC

Belle V, et al. In vivo quantitative mapping of cardiac perfusion in rats using a noninvasive MR spin-labeling method. J. Magn. Reson. Imaging JMRI. 1998;8:1240–1245. doi: 10.1002/jmri.1880080610. PubMed DOI

Zhu J, et al. Altered resting-state cerebral blood flow and its connectivity in schizophrenia. J. Psychiatr. Res. 2015;63:28–35. doi: 10.1016/j.jpsychires.2015.03.002. PubMed DOI

Horn H, et al. Structural and metabolic changes in language areas linked to formal thought disorder. Br. J. Psychiatry. 2009;194:130–138. doi: 10.1192/bjp.bp.107.045633. PubMed DOI

Pinkham A, et al. Resting quantitative cerebral blood flow in schizophrenia measured by pulsed arterial spin labeling perfusion MRI. Psychiatry Res. 2011;194:64–72. doi: 10.1016/j.pscychresns.2011.06.013. PubMed DOI PMC

Owen MJ, O’Donovan MC, 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

Van den Bergh, B. R. H. et al. Prenatal developmental origins of behavior and mental health: The influence of maternal stress in pregnancy. Neurosci. Biobehav. Rev (2017). PubMed

Young JW, Zhou X, Geyer MA. Animal models of schizophrenia. Curr Top Behav Neurosci. 2010;4:391–433. doi: 10.1007/7854_2010_62. PubMed DOI

Micale V, Di Marzo V, Sulcova A, Wotjak CT, Drago F. Endocannabinoid system and mood disorders: Priming a target for new therapies. Pharmacol. Ther. 2013;138:18–37. doi: 10.1016/j.pharmthera.2012.12.002. PubMed DOI

Calvigioni D, Hurd YL, Harkany T, Keimpema E. Neuronal substrates and functional consequences of prenatal cannabis exposure. Eur. Child Adolesc. Psychiatry. 2014;23:931–941. doi: 10.1007/s00787-014-0550-y. PubMed DOI PMC

Jaques SC, et al. Cannabis, the pregnant woman and her child: weeding out the myths. J. Perinatol. 2014;34:417. doi: 10.1038/jp.2013.180. PubMed DOI

Sundram S. Cannabis and neurodevelopment: implications for psychiatric disorders. Hum. Psychopharmacol. Clin. Exp. 2006;21:245–254. doi: 10.1002/hup.762. 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

Bolhuis K, Kushner SA, Hillegers MHJ, Tiemeier H, El Marroun H. F33. Matenal and paternal canabbis use during pregnancy and risk of psychotic symptoms in the offspring. Schizophr. Bull. 2018;44:S231–S232. doi: 10.1093/schbul/sby017.564. PubMed DOI

Grant KS, Petroff R, Isoherranen N, Stella N, Burbacher TM. Cannabis use during pregnancy: Pharmacokinetics and effects on child development. Pharmacol. Ther. 2018;182:133–151. doi: 10.1016/j.pharmthera.2017.08.014. PubMed DOI PMC

Drazanova E, et al. Poly(I:C) model of schizophrenia in rats induces sex-dependent functional brain changes detected by MRI that are not reversed by aripiprazole treatment. Brain Res. Bull. 2017;137:146–155. doi: 10.1016/j.brainresbull.2017.11.008. PubMed DOI

Ozdemir YG, Bolay H, Erdem E, Dalkara T. Occlusion of the MCA by an intraluminal filament may cause disturbances in the hippocampal blood flow due to anomalies of circle of Willis and filament thickness. Brain Res. 1999;822:260–264. doi: 10.1016/S0006-8993(99)01175-0. PubMed DOI

Uylings HBM, Groenewegen HJ, Kolb B. Do rats have a prefrontal cortex? Behav. Brain Res. 2003;146:3–17. doi: 10.1016/j.bbr.2003.09.028. PubMed DOI

Zhou Y, Fan L, Qiu C, Jiang T. Prefrontal cortex and the dysconnectivity hypothesis of schizophrenia. Neurosci. Bull. 2015;31:207–219. doi: 10.1007/s12264-014-1502-8. PubMed DOI PMC

Hokama H, et al. Caudate, putamen, and globus pallidus volume in schizophrenia: a quantitative MRI study. Psychiatry Res. 1995;61:209–229. doi: 10.1016/0925-4927(95)02729-H. PubMed DOI

Mikell CB, et al. The hippocampus and nucleus accumbens as potential therapeutic targets for neurosurgical intervention in schizophrenia. Stereotact. Funct. Neurosurg. 2009;87:256–265. doi: 10.1159/000225979. PubMed DOI PMC

Uttl, L. 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. 12 (2018). PubMed PMC

Webster, G. R., Sarna, L. & Mechoulam, R. Conversion of cbd to delta8-thc and delta9-thc (2004).

Molina-Holgado F, Amaro A, Gonzalez MI, Alvarez FJ, Leret ML. Effect of maternal delta 9-tetrahydrocannabinol on developing serotonergic system. Eur J Pharmacol. 1996;316:39–42. doi: 10.1016/S0014-2999(96)00753-4. PubMed DOI

D’Addario C, 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

Moore H, Jentsch JD, Ghajarnia M, Geyer MA, Grace AA. A neurobehavioral systems analysis of adult rats exposed to methylazoxymethanol acetate on E17: implications for the neuropathology of schizophrenia. Biol. Psychiatry. 2006;60:253–264. doi: 10.1016/j.biopsych.2006.01.003. PubMed DOI PMC

Ruda-Kucerova J, et al. 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

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, 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

Stark T, 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

Campolongo P, et al. Perinatal exposure to delta-9-tetrahydrocannabinol causes enduring cognitive deficits associated with alteration of cortical gene expression and neurotransmission in rats. Addict. Biol. 2007;12:485–495. doi: 10.1111/j.1369-1600.2007.00074.x. PubMed DOI

Trezza V, et al. Effects of perinatal exposure to delta-9-tetrahydrocannabinol on the emotional reactivity of the offspring: a longitudinal behavioral study in Wistar rats. Psychopharmacology (Berl.) 2008;198:529–537. doi: 10.1007/s00213-008-1162-3. PubMed DOI

Zamberletti E, Vigano D, Guidali C, Rubino T, Parolaro D. Long-lasting recovery of psychotic-like symptoms in isolation-reared rats after chronic but not acute treatment with the cannabinoid antagonist AM251. Int J Neuropsychopharmacol. 2012;15:267–80. doi: 10.1017/S1461145710001185. PubMed DOI

Uylings, H. B. M. & van Eden, C. G. Chapter 3 Qualitative and quantitative comparison of the prefrontal cortex in rat and in primates, including humans. In Progress in Brain Research (eds Uylings, H. B. M., Van Eden, C. G., De Bruin, J. P. C., Corner, M. A. & Feenstra, M. G. P.) 85, 31–62 (Elsevier, 1991). PubMed

Ellison-Wright I, Glahn DC, Laird AR, Thelen SM, Bullmore E. The Anatomy of First-Episode and Chronic Schizophrenia: An Anatomical Likelihood Estimation Meta-Analysis. Am. J. Psychiatry. 2008;165:1015–1023. doi: 10.1176/appi.ajp.2008.07101562. PubMed DOI PMC

Paxinos, G. & Watson, C. The rat brain in stereotaxic coordinates. (Elsevier, 2007). PubMed

Hildebrandt IJ, Su H, Weber WA. Anesthesia and other considerations for in vivo imaging of small animals. ILAR J. 2008;49:17–26. doi: 10.1093/ilar.49.1.17. PubMed DOI

Leithner C, et al. Determination of the brain-blood partition coefficient for water in mice using MRI. J. Cereb. Blood Flow Metab. Off. J. Int. Soc. Cereb. Blood Flow Metab. 2010;30:1821–1824. doi: 10.1038/jcbfm.2010.160. PubMed DOI PMC

Chin C-L, et al. Structural abnormalities revealed by magnetic resonance imaging in rats prenatally exposed to methylazoxymethanol acetate parallel cerebral pathology in schizophrenia. Synapse. 2011;65:393–403. doi: 10.1002/syn.20857. PubMed DOI

Young, J. W., Zhou, X. & Geyer, M. A. Animal Models of Schizophrenia. in Behavioral Neurobiology of Schizophrenia and Its Treatment 391–433 (Springer, Berlin, Heidelberg, 2010). PubMed

Lodge DJ, Grace AA. Gestational methylazoxymethanol acetate administration: a developmental disruption model of schizophrenia. Behav Brain Res. 2009;204:306–12. doi: 10.1016/j.bbr.2009.01.031. PubMed DOI PMC

Risterucci C, et al. Functional magnetic resonance imaging reveals similar brain activity changes in two different animal models of schizophrenia. Psychopharmacology (Berl.) 2005;180:724–734. doi: 10.1007/s00213-005-2204-8. PubMed DOI

Bassanini S, et al. Early cerebrovascular and parenchymal events following prenatal exposure to the putative neurotoxin methylazoxymethanol. Neurobiol. Dis. 2007;26:481–495. doi: 10.1016/j.nbd.2007.02.008. PubMed DOI PMC

Lombard C, Hegde VL, Nagarkatti M, Nagarkatti PS. Perinatal exposure to Δ9-tetrahydrocannabinol triggers profound defects in T cell differentiation and function in fetal and postnatal stages of life, including decreased responsiveness to HIV antigens. J. Pharmacol. Exp. Ther. 2011;339:607–617. doi: 10.1124/jpet.111.181206. PubMed DOI PMC

Hudson R, Rushlow W, Laviolette SR. Phytocannabinoids modulate emotional memory processing through interactions with the ventral hippocampus and mesolimbic dopamine system: implications for neuropsychiatric pathology. Psychopharmacology (Berl.) 2018;235:447–458. doi: 10.1007/s00213-017-4766-7. PubMed DOI

Bloom AS, Tershner S, Fuller SA, Stein EA. Cannabinoid-Induced Alterations in Regional Cerebral Blood Flow in the Rat. Pharmacol. Biochem. Behav. 1997;57:625–631. doi: 10.1016/S0091-3057(96)00475-3. PubMed DOI

Linszen D, van Amelsvoort T. Cannabis and psychosis: an update on course and biological plausible mechanisms. Curr. Opin. Psychiatry. 2007;20:116–120. doi: 10.1097/YCO.0b013e32803577fb. PubMed DOI

Sultan, S. R., Millar, S. A., O’Sullivan, S. E. & England, T. J. A Systematic Review and Meta-Analysis of the In Vivo Haemodynamic Effects of Δ8-Tetrahydrocannabinol. Pharm. Basel Switz. 11 (2018). PubMed PMC

Mathew RJ, et al. Time course of tetrahydrocannabinol-induced changes in regional cerebral blood flow measured with positron emission tomography. Psychiatry Res. Neuroimaging. 2002;116:173–185. doi: 10.1016/S0925-4927(02)00069-0. PubMed DOI

Filbey FM, Aslan S, Lu H, Peng S-L. Residual Effects of THC via Novel Measures of Brain Perfusion and Metabolism in a Large Group of Chronic Cannabis Users. Neuropsychopharmacol. Off. Publ. Am. Coll. Neuropsychopharmacol. 2018;43:700–707. doi: 10.1038/npp.2017.44. PubMed DOI PMC

Scheef L, et al. Resting-State Perfusion in Nonmedicated Schizophrenic Patients: A Continuous Arterial Spin-labeling 3.0-T MR Study. Radiology. 2010;256:253–260. doi: 10.1148/radiol.10091224. PubMed DOI

Sabri O, et al. Regional Cerebral Blood Flow and Negative/Positive Symptoms in 24 Drug-Naive Schizophrenics. J. Nucl. Med. 1997;38:181–188. PubMed

Wake R, et al. Characteristic brain hypoperfusion by 99mTc-ECD single photon emission computed tomography (SPECT) in patients with the first-episode schizophrenia. Eur. Psychiatry. 2010;25:361–365. doi: 10.1016/j.eurpsy.2009.12.005. PubMed DOI

Lahti AC, Weiler MA, Medoff DR, Tamminga CA, Holcomb HH. Functional effects of single dose first- and second-generation antipsychotic administration in subjects with schizophrenia. Psychiatry Res. Neuroimaging. 2005;139:19–30. doi: 10.1016/j.pscychresns.2005.02.006. PubMed DOI

Navari S, Dazzan P. Do antipsychotic drugs affect brain structure? A systematic and critical review of MRI findings. Psychol. Med. 2009;39:1763–1777. doi: 10.1017/S0033291709005315. PubMed DOI

Kempton MJ, Stahl D, Williams SCR, DeLisi LE. Progressive lateral ventricular enlargement in schizophrenia: A meta-analysis of longitudinal MRI studies. Schizophr. Res. 2010;120:54–62. doi: 10.1016/j.schres.2010.03.036. PubMed DOI

Bertrand J-B, et al. Longitudinal MRI monitoring of brain damage in the neonatal ventral hippocampal lesion rat model of schizophrenia. Hippocampus. 2010;20:264–278. PubMed

Jaaro-Peled H, Ayhan Y, Pletnikov MV, Sawa A. Review of pathological hallmarks of schizophrenia: comparison of genetic models with patients and nongenetic models. Schizophr. Bull. 2010;36:301–313. doi: 10.1093/schbul/sbp133. PubMed DOI PMC

Brugger SP, Howes OD. Heterogeneity and Homogeneity of Regional Brain Structure in Schizophrenia: A Meta-analysis. JAMA Psychiatry. 2017;74:1104–1111. doi: 10.1001/jamapsychiatry.2017.2663. PubMed DOI PMC

Zhang T, Koutsouleris N, Meisenzahl E, Davatzikos C. Heterogeneity of Structural Brain Changes in Subtypes of Schizophrenia Revealed Using Magnetic Resonance Imaging Pattern Analysis. Schizophr. Bull. 2015;41:74–84. doi: 10.1093/schbul/sbu136. PubMed DOI PMC

Iadecola C. Neurogenic control of the cerebral microcirculation: is dopamine minding the store? Nat. Neurosci. 1998;1:263–265. doi: 10.1038/1074. PubMed DOI

Krimer LS, Muly EC, Williams GV, Goldman-Rakic PS. Dopaminergic regulation of cerebral cortical microcirculation. Nat. Neurosci. 1998;1:286–289. doi: 10.1038/1099. 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

CBD enhances the cognitive score of adolescent rats prenatally exposed to THC and fine-tunes relevant effectors of hippocampal plasticity

Prenatal Exposure to Δ9-Tetrahydrocannabinol Affects Hippocampus-Related Cognitive Functions in the Adolescent Rat Offspring: Focus on Specific Markers of Neuroplasticity

The Effects of Peripubertal THC Exposure in Neurodevelopmental Rat Models of Psychopathology

Early Blockade of CB1 Receptors Ameliorates Schizophrenia-like Alterations in the Neurodevelopmental MAM Model of Schizophrenia