Synergistic Effect between Maternal Infection and Adolescent Cannabinoid Exposure on Serotonin Receptor Binding in the Hippocampus: Testing the \lquotelcurlybrcurlybTwo Hit\rquotelcurlybrcurlyb Hypothesis for the Development of Schizophrenia
Infections during pregnancy and adolescent cannabis use have both been identified as environmental risk factors for schizophrenia. We combined these factors in an animal model and looked at their effects, alone and in combination, on serotonin 5 H T 1 A receptor binding ( 5 H T 1 A R ) binding longitudinally from late adolescence to adulthood. Pregnant rats were exposed to the viral mimic poly I:C on embryonic day 15. Adolescent offspring received daily injections of the cannabinoid HU210 for 14 days starting on postnatal day (PND) 35. Hippocampal and cortical 5 H T 1 A R binding was quantified autoradiographically using [3H]8-OH-DPAT, in late adolescent (PND 55), young adult (PND 65) and adult (PND 90) rats. Descendants of poly I:C treated rats showed significant increases of 15–18% in 5 H T 1 A R in the hippocampus (CA1) compared to controls at all developmental ages. Offspring of poly I:C treated rats exposed to HU210 during adolescence exhibited even greater elevations in 5 H T 1 A R (with increases of 44, 29, and 39% at PNDs 55, 65, and 90). No effect of HU210 alone was observed. Our results suggest a synergistic effect of prenatal infection and adolescent cannabinoid exposure on the integrity of the serotoninergic system in the hippocampus that may provide the neurochemical substrate for abnormal hippocampal-related functions relevant to schizophrenia. 1. Introduction Schizophrenia is a chronic, severe and disabling brain disease, affecting approximately one percent of the population worldwide [1]. The overt signs and symptoms of schizophrenia do not usually manifest until late adolescence but it is believed that the disorder arises from genetic and/or environmental factors encountered prior to disease onset. Amongst the early insults that increase the risk for schizophrenia, prenatal exposure to viral or bacterial infection has been implicated as a strong risk factor by epidemiological studies [2]. The mechanisms by which brain development is altered in offspring following maternal infection remain unknown but it appears that maternal immune activation and in particular proinflammatory cytokines produced in order to fight the infection, rather the infection per se, is responsible [3–5]. Although late risk factors have been difficult to identify, various lines of evidence suggest an association between cannabis use in adolescence and the onset of schizophrenia symptoms. Cannabis increases the risk for psychotic outcomes in a dose-response manner [6]. However, only a minority of cannabis users develop psychosis suggesting that cannabis may interact
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