Lecca Salvatore, Luchicchi Antonio, Scherma Maria, Fadda Paola, Muntoni Anna Lisa, Pistis Marco
Department of Biomedical Sciences, Division of Neuroscience and Clinical Pharmacology, University of Cagliari, Monserrato, Italy.
Section of Cagliari, Neuroscience Institute, National Research Council of Italy (CNR), Monserrato, Italy.
Front Behav Neurosci. 2019 Sep 6;13:202. doi: 10.3389/fnbeh.2019.00202. eCollection 2019.
The combination of prenatal, such as maternal infections, and postnatal environmental insults (e.g., adolescent drug abuse) increases risks for psychosis, as predicted by the two-hit hypothesis of schizophrenia. Cannabis abuse during adolescence is widespread and is associated with increased risk of psychoses later in life. Here, we hypothesized that adolescent Δ-tetrahydrocannabinol (THC) worsens the impact of prenatal maternal immune activation (MIA) on ventral tegmental area (VTA) dopamine cells in rat offspring. Additionally, since substance abuse disorder is particularly prevalent among schizophrenia patients, we also tested how VTA dopamine neurons in MIA offspring respond to acute nicotine and cocaine administration. We used a model of neurodevelopmental disruption based on prenatal administration of the polyriboinosinic-polyribocytidilic acid [poly (I:C)] in rats, which activates the maternal immune system by mimicking a viral infection and induces behavioral abnormalities and disruption of dopamine transmission relevant to psychiatric disorders in the offspring. Male offspring were administered THC (or vehicle) during adolescence (PND 45-55). Once adult (PND 70-90), we recorded the spontaneous activity of dopamine neurons in the VTA and their responses to nicotine and cocaine. MIA male offspring displayed reduced number, firing rate and altered activity pattern of VTA dopamine cells. Adolescent THC attenuated several MIA-induced effects. Both prenatal [poly (I:C)] and postnatal (THC) treatments affected the response to nicotine but not to cocaine. Contrary to our expectations, adolescent THC did not worsen MIA-induced deficits. Results indicate that the impact of cannabinoids in psychosis models is complex.
如母体感染等产前因素与产后环境损伤（如青少年药物滥用）相结合，会增加患精神病的风险，这正如精神分裂症的双打击假说所预测的那样。青少年时期滥用大麻的现象很普遍，且与日后患精神病的风险增加有关。在此，我们假设青少年δ-四氢大麻酚（THC）会加剧产前母体免疫激活（MIA）对大鼠后代腹侧被盖区（VTA）多巴胺能细胞的影响。此外，由于物质滥用障碍在精神分裂症患者中尤为普遍，我们还测试了MIA后代的VTA多巴胺神经元对急性给予尼古丁和可卡因的反应。我们使用了一种基于在大鼠产前给予聚肌苷酸-聚胞苷酸[poly（I:C）]的神经发育破坏模型，该模型通过模拟病毒感染激活母体免疫系统，并在后代中诱发与精神疾病相关的行为异常和多巴胺传递障碍。雄性后代在青少年期（出生后第45 - 55天）给予THC（或赋形剂）。成年后（出生后第70 - 90天），我们记录了VTA中多巴胺神经元的自发活动及其对尼古丁和可卡因的反应。MIA雄性后代的VTA多巴胺细胞数量减少、放电频率降低且活动模式改变。青少年期给予THC减轻了几种MIA诱导的效应。产前[poly（I:C）]和产后（THC）处理均影响对尼古丁的反应，但不影响对可卡因的反应。与我们的预期相反，青少年期给予THC并未加剧MIA诱导的缺陷。结果表明，大麻素在精神病模型中的影响是复杂的。
