Dept. of Anatomy and Cell Biology & Dentistry, University of Western Ontario, London, Ontario, N6A 5C1, Canada.
Dept. of Psychiatry, Schulich School of Medicine & Dentistry, University of Western Ontario, London, Ontario, N6A 5C1, Canada.
Sci Rep. 2017 Sep 12;7(1):11420. doi: 10.1038/s41598-017-11645-8.
Chronic adolescent marijuana use has been linked to the later development of psychiatric diseases such as schizophrenia. GABAergic hypofunction in the prefrontal cortex (PFC) is a cardinal pathological feature of schizophrenia and may be a mechanism by which the PFC loses its ability to regulate sub-cortical dopamine (DA) resulting in schizophrenia-like neuropsychopathology. In the present study, we exposed adolescent rats to Δ-9-tetra-hydrocannabinol (THC), the psychoactive component in marijuana. At adulthood, we characterized the functionality of PFC GABAergic neurotransmission and its regulation of sub-cortical DA function using molecular, behavioral and in-vivo electrophysiological analyses. Our findings revealed a persistent attenuation of PFC GABAergic function combined with a hyperactive neuronal state in PFC neurons and associated disruptions in cortical gamma oscillatory activity. These PFC abnormalities were accompanied by hyperactive DAergic neuronal activity in the ventral tegmental area (VTA) and behavioral and cognitive abnormalities similar to those observed in psychiatric disorders. Remarkably, these neuronal and behavioral effects were reversed by pharmacological activation of GABA receptors in the PFC. Together, these results identify a mechanistic link between dysregulated frontal cortical GABAergic inhibition and sub-cortical DAergic dysregulation, characteristic of well-established neuropsychiatric endophenotypes.
慢性青少年吸食大麻与精神疾病（如精神分裂症）的后期发展有关。前额叶皮层（PFC）的 GABA 能功能低下是精神分裂症的主要病理特征，可能是 PFC 失去调节皮质下多巴胺（DA）的能力导致类似精神分裂症的神经精神病理学的机制。在本研究中，我们让青少年大鼠接触大麻中的精神活性成分 Δ-9-四氢大麻酚（THC）。成年后，我们使用分子、行为和体内电生理分析来描述 PFC GABA 能神经传递的功能及其对皮质下 DA 功能的调节。我们的研究结果显示，PFC GABA 能功能持续减弱，PFC 神经元呈过度活跃状态，皮质γ振荡活动出现相关紊乱。这些 PFC 异常伴随着腹侧被盖区（VTA）中 DA 能神经元活动的过度活跃以及类似精神疾病中观察到的行为和认知异常。值得注意的是，这些神经元和行为效应可通过 PFC 中 GABA 受体的药理学激活得到逆转。总之，这些结果确定了调节性前额皮质 GABA 能抑制与皮质下 DA 能失调之间的机制联系，这是既定的神经精神表型的特征。
