Abstract
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 5HT1A receptor binding (5HT1AR) 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 5HT1AR 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 5HT1AR 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 5HT1AR (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.
Highlights
Schizophrenia is a chronic, severe and disabling brain disease, affecting approximately one percent of the population worldwide [1]
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 [3,4,5]
We examined the impact of prenatal immune challenge by the viral mimic polyriboinosinicpolyribocytidilic acid (poly I):C alone and in combination with adolescent HU210 exposure (“two hit” model) on 5HT1A receptor binding (5HT1AR) binding in the cortex and hippocampus of late adolescent, young adult and adult rats
Summary
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. 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 [3,4,5]. 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 doseresponse manner [6]. Only a minority of cannabis users develop psychosis suggesting that cannabis may interact with other genetic and/or environmental susceptibilities in order to precipitate the disorder (“two hit” hypothesis)
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