Caffeine-induced modulation of GABAergic transmission

描述(申请人提供)：咖啡因是世界上最受欢迎的精神活性药物，也是大脑中强大的兴奋性调节剂。咖啡因的刺激性特性取决于它与神经传递相互作用的能力，并通过控制神经递质的释放来增强神经活动。然而，尽管咖啡因对兴奋性神经递质释放的刺激作用已经得到证实，但咖啡因对抑制性神经递质GABA的释放的影响并不完全清楚。我们实验室的研究结果表明，咖啡因可以抑制GABA能传递。此外，咖啡因的作用可在胞浆钙([Ca~(2+)]i)升高时被放大，提示咖啡因可能通过调节[Ca~(2+)]_i调节机制来影响GABA能突触传递。内源性大麻素(ECB)对GABA释放的逆行抑制是对GABA能传递的一种典型的钙依赖调节。该项目的工作假设是，咖啡因通过激活合成和释放ECB所需的钙源(S)，从而负向控制GABA的释放，从而与大脑的ECB系统相互作用，调节GABA的释放。为了验证这一假说，提出了三个具体的目标：1)分离咖啡因诱导的钙释放在启动ECB合成中的信号机制；2)确定咖啡因在诱导钙释放激活的钙进入(CRAC)中的作用及其与ECB合成的功能偶联；3)确定咖啡因对ECB介导的突触可塑性和学习的影响。欧洲央行是控制大脑奖励系统、边缘情绪记忆和学习的新兴候选者。咖啡因对与大麻素具有相同神经化学性质的奖赏回路有显著影响。这表明咖啡因有可能与大脑的内源性大麻素系统相互作用。这些目标的实现将增加我们对咖啡因和大脑内源性大麻素系统之间生理相互作用的离子和分子机制的理解，并填补目前关于GABA传递调控的知识空白。该项目致力于两种精神活性化合物(咖啡因和ECB)在健康和疾病(包括药物滥用、适应不良学习和成瘾)中对中枢神经元突触功能和可塑性的生理作用的新发现。

DESCRIPTION (provided by applicant): Caffeine is the world's most popular psychoactive drug and a powerful modulator of excitability in the brain. Caffeine's stimulant properties depend on its ability to interact with neurotransmission and enhance neuronal activities by controlling a release of neurotransmitters. Yet despite its well-established stimulatory effect on excitatory neurotransmitter release, caffeine's effect on the release of the inhibitory neurotransmitter, GABA, is not completely understood. Findings from our laboratory suggest caffeine inhibits GABAergic transmission. Moreover, caffeine's effect can be amplified when cytosolic calcium ([Ca2+]i) is elevated, suggesting that caffeine may affect GABAergic synaptic transmission by modulating [Ca2+]i regulatory mechanisms. A representative Ca2+-dependent modulation of GABAergic transmission is the retrograde suppression of GABA release by endogenous cannabinoid (eCB). The working hypothesis of this project is that caffeine interacts with the brains' eCB system in the regulation of GABA-release by priming the Ca2+ source(s) necessary for the synthesis and release of eCB, thus negatively controlling the release of GABA. In order to test this hypothesis, three Specific Aims are proposed: 1) To isolate the signaling mechanisms of caffeine-induced Ca2+ release in the initiation of eCB synthesis, 2) To determine the role of caffeine on the induction of CRAC (calcium release-activated calcium entry) and its functional coupling to the synthesis of eCB, 3) To identify the effect of caffeine on the eCB-mediated synaptic plasticity and learning in the hippocampus. eCB is an emerging new candidate for the control of the brain's reward system and limbic emotional memory and learning. Caffeine has a prominent effect on the reward circuits sharing neurochemical properties with cannabinoid. This suggests there is a potential that caffeine interacts with the brain's endogenous cannabinoid system. Accomplishing the proposed Aims will increase our understanding of the ionic and molecular mechanisms underlying the physiological interaction between caffeine and the brain's endogenous cannabinoid system, and fill the gaps in the current knowledge on the regulation of GABAertic transmission. This project is dedicated to new discoveries on the physiological roles of two psychoactive compounds (caffeine and eCB) in the synaptic function and plasticity of central neurons in health and diseases including substance abuse, maladaptive learning, and addiction.