Leite-Morris K A, Kaplan G B, Smith J G, Sears M T
Department of Psychiatry and Human Behavior, Veterans Affairs Medical Center, 830 Chalkstone Avenue, Providence, RI 02912, USA.
Brain Res. 1998 Aug 31;804(1):52-62. doi: 10.1016/s0006-8993(98)00582-4.
Regulation of post-receptor signaling provides a mechanism of adaptation to chronic psychotropic drug treatment. In this study, the regulation of guanine nucleotide binding proteins (G proteins) and G protein-stimulated adenylyl cyclase activity was examined in brain regions of caffeine-tolerant and -dependent mice. Chronic caffeine doses were administered via mini-osmotic pumps over 7 days at 0, 42, 85 and 125 mg kg-1 day-1. These chronic caffeine doses were linearly correlated with plasma caffeine concentrations. In behavioral studies, the stimulant effects of acute caffeine on motor activity were significantly diminished in a dose-dependent manner after chronic caffeine, suggesting the development of tolerance. Abrupt discontinuation of chronic caffeine treatment (at 85 and 125 mg kg-1 day-1) produced a dose-dependent and reversible reduction in motor activity 24 h later, suggestive of a caffeine withdrawal syndrome. Utilizing quantitative immunoblotting methods, we found that hippocampal Gialpha1,2 and Gialpha3 subunits were significantly reduced by 20.2% and 11.1%, respectively, in caffeine tolerant/dependent mice (caffeine 125 mg kg-1 day-1 vs. vehicle controls). Decreases in inhibitory G protein subunit concentrations in hippocampus were accompanied by a significant increase (by 21%) in hippocampal G protein function, as measured by guanine nucleotide-stimulated adenylyl cyclase activity, in caffeine-treated mice. This same caffeine treatment also produced significant decreases in cortical Gsalpha subunits of 14.0%. Since short-term caffeine treatment has been shown to reduce adenylyl cyclase activity, chronic caffeine treatment could produce adaptive increases in G protein-stimulated adenylyl cyclase to oppose this effect via G protein regulation.
受体后信号传导的调节提供了一种适应慢性精神药物治疗的机制。在本研究中，我们检测了咖啡因耐受和依赖小鼠脑区中鸟嘌呤核苷酸结合蛋白（G蛋白）的调节以及G蛋白刺激的腺苷酸环化酶活性。通过微型渗透泵在7天内以0、42、85和125mg kg-1天-1的剂量给予慢性咖啡因。这些慢性咖啡因剂量与血浆咖啡因浓度呈线性相关。在行为学研究中，慢性咖啡因处理后，急性咖啡因对运动活动的兴奋作用以剂量依赖性方式显著减弱，提示耐受性的产生。慢性咖啡因处理（85和125mg kg-1天-1）突然停药24小时后，运动活动出现剂量依赖性和可逆性降低，提示咖啡因戒断综合征。利用定量免疫印迹法，我们发现咖啡因耐受/依赖小鼠（咖啡因125mg kg-1天-1与载体对照）海马中的Gialpha1,2和Gialpha3亚基分别显著降低了20.2%和11.1%。海马中抑制性G蛋白亚基浓度的降低伴随着咖啡因处理小鼠中海马G蛋白功能的显著增加（增加21%），这通过鸟嘌呤核苷酸刺激的腺苷酸环化酶活性来衡量。相同的咖啡因处理还使皮质Gsalpha亚基显著降低了14.0%。由于短期咖啡因处理已被证明会降低腺苷酸环化酶活性，慢性咖啡因处理可能会通过G蛋白调节使G蛋白刺激的腺苷酸环化酶产生适应性增加，以对抗这种作用。
