{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,27]],"date-time":"2026-02-27T16:23:18Z","timestamp":1772209398266,"version":"3.50.1"},"reference-count":48,"publisher":"MDPI AG","issue":"12","license":[{"start":{"date-parts":[[2021,12,11]],"date-time":"2021-12-11T00:00:00Z","timestamp":1639180800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Kubly Fund for Depression Research at the Medical College of Wisconsin","award":["N\/A"],"award-info":[{"award-number":["N\/A"]}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["GM080202"],"award-info":[{"award-number":["GM080202"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cells"],"abstract":"<jats:p>Both in utero exposure to maternal immune activation and cannabis use during adolescence have been associated with increased risk for the development of schizophrenia; however, whether these exposures exert synergistic effects on brain function is not known. In the present study, mild maternal immune activation (MIA) was elicited in mice with prenatal exposure to polyinosinic-polycytidylic acid (poly(I:C)), and \u22069-tetrahydrocannabinol (THC) was provided throughout adolescence in cereal (3 mg\/kg\/day for 5 days). Neither THC nor MIA pretreatments altered activity in assays used to characterize hyperdopaminergic states in adulthood: amphetamine hyperlocomotion and prepulse inhibition of the acoustic startle reflex. Adolescent THC treatment elicited deficits in spatial memory and enhanced spatial reversal learning in adult female mice in the Morris water maze, while exposure to MIA elicited female-specific deficits in fear extinction learning in adulthood. There were no effects in these assays in adult males, nor were there interactions between THC and MIA in adult females. While doses of poly(I:C) and THC were sufficient to elicit behavioral effects, particularly relating to cognitive performance in females, there was no evidence that adolescent THC exposure synergized with the risk imposed by MIA to worsen behavioral outcomes in adult mice of either sex.<\/jats:p>","DOI":"10.3390\/cells10123503","type":"journal-article","created":{"date-parts":[[2021,12,13]],"date-time":"2021-12-13T01:28:11Z","timestamp":1639358891000},"page":"3503","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":16,"title":["Adolescent THC Treatment Does Not Potentiate the Behavioral Effects in Adulthood of Maternal Immune Activation"],"prefix":"10.3390","volume":"10","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-8847-7406","authenticated-orcid":false,"given":"Todd M.","family":"Stollenwerk","sequence":"first","affiliation":[{"name":"Neuroscience Research Center, Department of Pharmacology and Toxicology, Medical College of Wisconsin, Wauwatosa, WI 53226, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9678-748X","authenticated-orcid":false,"given":"Cecilia J.","family":"Hillard","sequence":"additional","affiliation":[{"name":"Neuroscience Research Center, Department of Pharmacology and Toxicology, Medical College of Wisconsin, Wauwatosa, WI 53226, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2021,12,11]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"23","DOI":"10.1016\/j.pneurobio.2010.09.003","article-title":"The environment and susceptibility to schizophrenia","volume":"93","author":"Brown","year":"2011","journal-title":"Prog. Neurobiol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"189","DOI":"10.1001\/archpsyc.1988.01800260109013","article-title":"Adult Schizophrenia Following Prenatal Exposure to an Influenza Epidemic","volume":"45","author":"Mednick","year":"1988","journal-title":"Arch. Gen. Psychiatry"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"869","DOI":"10.1001\/archpsyc.1990.01810210077012","article-title":"Exposure to influenza epidemics during gestation and adult schizophrenia. A 40-year study","volume":"47","author":"Barr","year":"1990","journal-title":"Arch. Gen. Psychiatry"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"522","DOI":"10.1192\/bjp.163.4.522","article-title":"Epidemiological Evidence that Maternal Influenza Contributes to the Aetiology of Schizophrenia","volume":"163","author":"Adams","year":"1993","journal-title":"Br. J. Psychiatry"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"119","DOI":"10.1016\/S0006-3223(98)00359-X","article-title":"Schizophrenia and the influenza epidemics of 1957 in Japan","volume":"46","author":"Izumoto","year":"1999","journal-title":"Biol. Psychiatry"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"1100","DOI":"10.1176\/ajp.156.7.1100","article-title":"Association between prenatal exposure to poliovirus infection and adult schizophrenia","volume":"156","author":"Suvisaari","year":"1999","journal-title":"Am. J. Psychiatry"},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"1032","DOI":"10.1001\/archpsyc.58.11.1032","article-title":"Maternal Infections and Subsequent Psychosis Among Offspring","volume":"58","author":"Buka","year":"2001","journal-title":"Arch. Gen. Psychiatry"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"261","DOI":"10.1176\/appi.ajp.2009.09030361","article-title":"Prenatal Infection and Schizophrenia: A Review of Epidemiologic and Translational Studies","volume":"167","author":"Brown","year":"2010","journal-title":"Am. J. Psychiatry"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"1073","DOI":"10.1176\/appi.ajp.2018.17121311","article-title":"Maternal Immune Activation and Neuropsychiatric Illness: A Translational Research Perspective","volume":"175","author":"Brown","year":"2018","journal-title":"Am. J. Psychiatry"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"772","DOI":"10.1126\/science.aag3194","article-title":"Maternal immune activation: Implications for neuropsychiatric disorders","volume":"353","author":"Estes","year":"2016","journal-title":"Science"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"913","DOI":"10.1016\/j.neubiorev.2004.10.012","article-title":"Towards an immuno-precipitated neurodevelopmental animal model of schizophrenia","volume":"29","author":"Meyer","year":"2005","journal-title":"Neurosci. Biobehav. Rev."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"307","DOI":"10.1016\/j.biopsych.2013.07.011","article-title":"Prenatal Poly(I:C) Exposure and Other Developmental Immune Activation Models in Rodent Systems","volume":"75","author":"Meyer","year":"2014","journal-title":"Biol. Psychiatry"},{"key":"ref_13","doi-asserted-by":"crossref","unstructured":"Van Der Steur, S.J., Batalla, A., and Bossong, M.G. (2020). Factors Moderating the Association between Cannabis Use and Psychosis Risk: A Systematic Review. Brain Sci., 10.","DOI":"10.3390\/brainsci10020097"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"1262","DOI":"10.1093\/schbul\/sbw003","article-title":"Meta-analysis of the Association Between the Level of Cannabis Use and Risk of Psychosis","volume":"42","author":"Marconi","year":"2016","journal-title":"Schizophr. Bull."},{"key":"ref_15","first-page":"1297","article-title":"Adolescent Cannabinoid Exposure Induces a Persistent Sub-Cortical Hyper-Dopaminergic State and Associated Molecular Adaptations in the Prefrontal Cortex","volume":"27","author":"Renard","year":"2016","journal-title":"Cereb. Cortex"},{"key":"ref_16","unstructured":"McCutcheon, R.A., Reis Marques, T., and Howes, O.D. (2019). Schizophrenia\u2014An Overview. JAMA Psychiatry, 1\u201310."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"7503","DOI":"10.1523\/JNEUROSCI.0274-15.2015","article-title":"Increased Prefrontal Cortex Neurogranin Enhances Plasticity and Extinction Learning","volume":"35","author":"Zhong","year":"2015","journal-title":"J. Neurosci."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"181","DOI":"10.1001\/archpsyc.1990.01810140081011","article-title":"Sensorimotor gating and schizophrenia. Human and animal model studies","volume":"47","author":"Braff","year":"1990","journal-title":"Arch. Gen. Psychiatry"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"469","DOI":"10.1016\/j.bbi.2007.09.012","article-title":"Adult brain and behavioral pathological markers of prenatal immune challenge during early\/middle and late fetal development in mice","volume":"22","author":"Meyer","year":"2008","journal-title":"Brain Behav. Immun."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"404","DOI":"10.1038\/s41386-020-00855-w","article-title":"Transgenerational modification of dopaminergic dysfunctions induced by maternal immune activation","volume":"46","author":"Richetto","year":"2021","journal-title":"Neuropsychopharmacology"},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"5904","DOI":"10.7554\/eLife.18726","article-title":"Sexually dimorphic neuronal responses to social isolation","volume":"5","author":"Senst","year":"2016","journal-title":"eLife"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"1095","DOI":"10.1126\/science.1228261","article-title":"Stress in Puberty Unmasks Latent Neuropathological Consequences of Prenatal Immune Activation in Mice","volume":"339","author":"Giovanoli","year":"2013","journal-title":"Science"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"60","DOI":"10.1016\/j.bbi.2014.10.010","article-title":"Maternal immune activation differentially impacts mature and adult-born hippocampal neurons in male mice","volume":"45","author":"Zhang","year":"2015","journal-title":"Brain Behav. Immun."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"100156","DOI":"10.1016\/j.bbih.2020.100156","article-title":"Sensory filtering disruption caused by poly I:C\u2014Timing of exposure and other experimental considerations","volume":"9","author":"Haddad","year":"2020","journal-title":"Brain Behav. Immun. Health"},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"404","DOI":"10.1097\/FBP.0000000000000632","article-title":"TrkB agonist 7,8-dihydroxyflavone reverses an induced prepulse inhibition deficit selectively in maternal immune activation offspring: Implications for schizophrenia","volume":"32","author":"Jaehne","year":"2021","journal-title":"Behav. Pharmacol."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"416","DOI":"10.1002\/npr2.12178","article-title":"Inter-breeder differences in prepulse inhibition deficits of C57BL\/6J mice in a maternal immune activation model","volume":"41","author":"Kobayashi","year":"2021","journal-title":"Neuropsychopharmacol. Rep."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"643","DOI":"10.1016\/j.bbi.2018.07.014","article-title":"Mouse models of maternal immune activation: Mind your caging system!","volume":"73","author":"Mueller","year":"2018","journal-title":"Brain Behav. Immun."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"396","DOI":"10.1038\/s41380-020-00952-8","article-title":"Behavioral, neuroanatomical, and molecular correlates of resilience and susceptibility to maternal immune activation","volume":"26","author":"Mueller","year":"2021","journal-title":"Mol. Psychiatry"},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"175","DOI":"10.1016\/j.schres.2003.10.009","article-title":"Brief cognitive assessment in schizophrenia: Normative data for the Repeatable Battery for the Assessment of Neuropsychological Status","volume":"70","author":"Wilk","year":"2004","journal-title":"Schizophr. Res."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"912","DOI":"10.1093\/schbul\/sbm046","article-title":"How Should DSM-V Criteria for Schizophrenia Include Cognitive Impairment?","volume":"33","author":"Keefe","year":"2007","journal-title":"Schizophr. Bull."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"1080","DOI":"10.1176\/ajp.155.8.1080","article-title":"Symptoms, Cognitive Functioning, and Adaptive Skills in Geriatric Patients With Lifelong Schizophrenia: A Comparison Across Treatment Sites","volume":"155","author":"Harvey","year":"1998","journal-title":"Am. J. Psychiatry"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1186\/s13229-017-0125-0","article-title":"Vitamin D treatment during pregnancy prevents autism-related phenotypes in a mouse model of maternal immune activation","volume":"8","author":"Vuillermot","year":"2017","journal-title":"Mol. Autism"},{"key":"ref_33","first-page":"102","article-title":"Transgenerational transmission and modification of pathological traits induced by prenatal immune activation","volume":"22","author":"Richetto","year":"2016","journal-title":"Mol. Psychiatry"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"e637","DOI":"10.1038\/tp.2015.129","article-title":"Abnormal context\u2013reward associations in an immune-mediated neurodevelopmental mouse model with relevance to schizophrenia","volume":"5","author":"Labouesse","year":"2015","journal-title":"Transl. Psychiatry"},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"109","DOI":"10.1016\/j.neuroscience.2020.05.009","article-title":"Maternal Immune Activation in Mice Only Partially Recapitulates the Autism Spectrum Disorders Symptomatology","volume":"445","author":"Vigli","year":"2020","journal-title":"Neuroscience"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"168","DOI":"10.3389\/fnbeh.2014.00168","article-title":"Heightened fear in response to a safety cue and extinguished fear cue in a rat model of maternal immune activation","volume":"8","author":"Sangha","year":"2014","journal-title":"Front. Behav. Neurosci."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"1199","DOI":"10.1016\/j.jpsychires.2012.05.010","article-title":"Increased affective ultrasonic communication during fear learning in adult male rats exposed to maternal immune activation","volume":"46","author":"Yee","year":"2012","journal-title":"J. Psychiatr. Res."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"311","DOI":"10.1016\/j.jpsychires.2004.08.008","article-title":"Maternal immune activation leads to behavioral and pharmacological changes in the adult offspring","volume":"39","author":"Zuckerman","year":"2005","journal-title":"J. Psychiatr. Res."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"725","DOI":"10.1002\/syn.21561","article-title":"Prenatal immune challenge in rats: Altered responses to dopaminergic and glutamatergic agents, prepulse inhibition of acoustic startle, and reduced route-based learning as a function of maternal body weight gain after prenatal exposure to poly IC","volume":"66","author":"Vorhees","year":"2012","journal-title":"Synapse"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"1722","DOI":"10.1111\/bph.15394","article-title":"Detrimental effects of adolescent escalating low-dose \u0394(9) -tetrahydrocannabinol leads to a specific bio-behavioural profile in adult male rats","volume":"178","author":"Poulia","year":"2021","journal-title":"Br. J. Pharm."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"448","DOI":"10.1016\/j.pbb.2006.03.006","article-title":"Differential effects of delta9-THC on learning in adolescent and adult rats","volume":"83","author":"Cha","year":"2006","journal-title":"Pharmacol. Biochem. Behav."},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"563","DOI":"10.1097\/FBP.0b013e3282ee7b7e","article-title":"Sex differences in the effects of delta9-tetrahydrocannabinol on spatial learning in adolescent and adult rats","volume":"18","author":"Cha","year":"2007","journal-title":"Behav Pharm."},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"959","DOI":"10.1038\/s41386-020-00839-w","article-title":"Pharmacokinetic, behavioral, and brain activity effects of \u03949-tetrahydrocannabinol in adolescent male and female rats","volume":"46","author":"Ruiz","year":"2021","journal-title":"Neuropsychopharmacology"},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"151","DOI":"10.1124\/jpet.120.265892","article-title":"Comparative Pharmacokinetics of \u03949-Tetrahydrocannabinol in Adolescent and Adult Male Mice","volume":"374","author":"Torrens","year":"2020","journal-title":"J. Pharmacol. Exp. Ther."},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"691","DOI":"10.1037\/abn0000701","article-title":"Adolescent cannabis use and adult psychoticism: A longitudinal co-twin control analysis using data from two cohorts","volume":"130","author":"Schaefer","year":"2021","journal-title":"J. Abnorm. Psychol."},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"87","DOI":"10.1001\/jamapsychiatry.2018.2546","article-title":"Genetic Predisposition vs Individual-Specific Processes in the Association Between Psychotic-like Experiences and Cannabis Use","volume":"76","author":"Karcher","year":"2019","journal-title":"JAMA Psychiatry"},{"key":"ref_47","first-page":"644","article-title":"Genetic and Environmental Contributions to the Association Between Cannabis Use and Psychotic-Like Experiences in Young Adult Twins","volume":"43","author":"Gillespie","year":"2016","journal-title":"Schizophr. Bull."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"202","DOI":"10.3389\/fnbeh.2019.00202","article-title":"\u03949-Tetrahydrocannabinol During Adolescence Attenuates Disruption of Dopamine Function Induced in Rats by Maternal Immune Activation","volume":"13","author":"Lecca","year":"2019","journal-title":"Front. Behav. Neurosci."}],"container-title":["Cells"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2073-4409\/10\/12\/3503\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T07:45:28Z","timestamp":1760168728000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2073-4409\/10\/12\/3503"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2021,12,11]]},"references-count":48,"journal-issue":{"issue":"12","published-online":{"date-parts":[[2021,12]]}},"alternative-id":["cells10123503"],"URL":"https:\/\/doi.org\/10.3390\/cells10123503","relation":{},"ISSN":["2073-4409"],"issn-type":[{"value":"2073-4409","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,12,11]]}}}