GABA Deficits and Vulnerability to Cannabinoid-Induced Psychosis

描述(由申请人提供)：GABA缺陷和对大麻素诱导的精神病(CBS)的脆弱性会在健康人中引起一过性精神病症状和认知功能障碍，并加剧精神分裂症患者的症状。然而，后者更容易受到大麻素的影响。精神分裂症患者对大麻类药物敏感性的增强可能是由精神分裂症患者中伽马氨基丁酸(GABA)受体缺陷所致。临床前证据表明CB和GABA系统之间存在重要的相互作用。CB1受体(CB1-Rs)存在于胆囊收缩素(CCK)的轴突终末，含有以锥体细胞为靶细胞的GABA神经元。这些GABA神经元协调神经活动的同步，被认为在感知、记忆和注意过程中发挥重要作用。激活含有GABA的CCK神经元轴突终末上的CB1-Rs可减少GABA的释放，从而解除对锥体细胞活动的抑制。如果在GABA缺乏的情况下发生这种情况，就像精神分裂症的情况一样，这可能会导致锥体细胞活动的进一步去抑制和去同步，导致门控和联想功能的扰动，最终导致精神病症状。假设：如果GABA缺陷增加了精神分裂症患者对大麻类药物作用的易感性，那么在健康受试者中诱导GABA缺陷将加强由？9-THC产生的精神分裂、健忘和神经同步缺陷。我们已经证明，在健康人中，1)9-THC诱导一过性精神病和记忆障碍，2)急性和长期暴露于大麻类药物与神经同步性改变有关，以及3)由异马西尼产生的GABA缺陷，增强了5-羟色胺能药的拟精神效应。方法：健康受试者将完成4个试验日，在此期间，他们将接受静脉注射异马西尼或安慰剂，随后接受静脉注射？9-THC或安慰剂，采用双盲、随机、平衡设计。将评估知觉改变、精神病样症状和记忆力。神经同步性指数将通过测量20、30和40赫兹的听觉咔哒声序列诱发的脑电频谱功率来评估。公共卫生相关性：该项目的目的是评估大脑中主要抑制性化学信使系统--GABA受体系统的减少是否会增加大麻的主要活性成分THC对精神分裂效应的易感性。

DESCRIPTION (provided by applicant): GABA Deficits and Vulnerability to Cannabinoid-Induced Psychosis Cannabinoids (CBs) induce transient psychotic symptoms and cognitive dysfunction in healthy individuals and exacerbate symptoms in schizophrenia patients. However, the latter are more vulnerable to the effects of cannabinoids. The enhanced cannabinoid sensitivity in schizophrenia might be driven by the well documented gamma-amino butyric acid (GABA) receptor deficits in schizophrenia. Converging preclinical evidence suggests important interactions between CB and GABA systems. CB1 receptors (CB1-Rs) are present on the axon terminals of cholecystokinin (CCK) containing GABA neurons that target pyramidal cells. These GABA neurons orchestrate the synchronization of neural activity which is believed to play an important rolein perceptual, memory and attentional processes. Activation of CB1-Rs on the axon terminals of CCK containing GABA neurons reduces GABA release, resulting in disinhibition of pyramidal cell activity. If this were to occur in the presence of a GABA deficit, as might be the case in schizophrenia, this could lead to further disinhibition and desynchronization of pyramidal cell activity, leading to perturbation of gating and associative functions, culminating in psychotic symptoms. Hypothesis: If GABA deficits increase the vulnerability of schizophrenic patients to the effects of cannabinoids, then inducing a GABA deficit in healthy subjects will potentiate the psychotomimetic, amnestic and neural synchrony deficits produced by ?9-THC. We have shown that in healthy individuals 1) ?9-THC induces transient psychosis and memory impairments, 2) both acute and chronic exposure to cannabinoids is associated with alterations in neural synchrony, and 3) GABA deficits produced by iomazenil, enhanced the psychotomimetic effects of a serotonergic agent. Methods: Healthy subjects will complete 4 test days during which they will receive intravenous iomazenil or placebo pretreatment, followed by intravenous ?9-THC or placebo, in a double-blind, randomized, counterbalanced design. Perceptual alterations, psychotic-like symptoms and memory will be assessed. Indices of neural synchrony will be assessed by measurement of EEG spectral power evoked by presentation of auditory click trains at 20, 30 and 40 Hz. PUBLIC HEALTH RELEVANCE: The aim of this project is to evaluate whether a reduction in the principal inhibitory chemical messenger system in the brain, the GABA receptor system, enhances the vulnerability to the psychotomimetic effects of THC, the main active component of cannabis.