Caffeine-induced modulation of GABAergic transmission

描述（由申请人提供）：咖啡因是世界上最流行的精神药物，也是大脑兴奋性的强大调节剂。咖啡因的刺激特性取决于它与神经传递的相互作用，并通过控制神经递质的释放来增强神经元活动。然而，尽管咖啡因对兴奋性神经递质释放具有公认的刺激作用，但它对抑制性神经递质GABA释放的影响尚不完全清楚。我们实验室的研究结果表明，咖啡因抑制gaba能的传递。此外，当胞质钙（[Ca2+]i）升高时，咖啡因的作用可以被放大，这表明咖啡因可能通过调节[Ca2+]i的调节机制影响gaba能突触的传递。GABA能传递的代表性Ca2+依赖性调节是内源性大麻素（eCB）对GABA释放的逆行抑制。这个项目的工作假设是，咖啡因与大脑的eCB系统相互作用，通过启动合成和释放eCB所必需的Ca2+源来调节GABA的释放，从而负向控制GABA的释放。为了验证这一假设，我们提出了三个特定的目标：1)分离咖啡因诱导的Ca2+释放在eCB合成起始中的信号机制；2)确定咖啡因在诱导CRAC（钙释放激活钙进入）及其与eCB合成的功能偶联中的作用；3)确定咖啡因对eCB介导的海马突触可塑性和学习的影响。eCB是控制大脑奖励系统和边缘情感记忆和学习的新候选物。咖啡因对与大麻素共享神经化学特性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。完成本研究将增加我们对咖啡因与大脑内源性大麻素系统生理相互作用的离子和分子机制的理解，并填补目前关于gabatic传输调节的知识空白。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.