Research Service, Veterans Affairs Greater Los Angeles Healthcare System, Sepulveda, CA, USA.
Neuroscience. 2010 Apr 28;167(1):40-8. doi: 10.1016/j.neuroscience.2010.01.044. Epub 2010 Jan 28.
The perifornical-lateral hypothalamic area (PF-LHA) plays a central role in the regulation of behavioral arousal. The PF-LHA contains several neuronal types including wake-active hypocretin (HCRT) neurons that have been implicated in the promotion and/or maintenance of behavioral arousal. Adenosine is an endogenous sleep factor and recent evidence suggests that activation and blockade of adenosine A(1) receptors within the PF-LHA promote and suppress sleep, respectively. Although, an in vitro study indicates that adenosine inhibits HCRT neurons via A(1) receptor, the in vivo effects of A(1) receptor mediated adenosinergic transmission on PF-LHA neurons including HCRT neurons are not known. First, we determined the effects of N(6)-cyclopentyladenosine (CPA), an adenosine A(1) receptor agonist, on the sleep-wake discharge activity of the PF-LHA neurons recorded via microwires placed adjacent to the microdialysis probe used for its delivery. Second, we determined the effects of CPA and that of an A(1) receptor antagonist, 1,3-dipropyl-8-phenylxanthine (CPDX) into the PF-LHA on cFos-protein immunoreactivity (Fos-IR) in HCRT and non-HCRT neurons around the microdialysis probe used for their delivery. The effect of CPA on Fos-IR was studied in rats that were kept awake during lights-off phase, whereas the effect of CPDX was examined in undisturbed rats during lights-on phase. CPA significantly suppressed the sleep-wake discharge activity of PF-LHA neurons. Doses of CPA (50 muM) and CPDX (50 muM) that suppressed and induced arousal, respectively, in our earlier study [Alam MN, Kumar S, Rai S, Methippara M, Szymusiak R, McGinty D (2009) Brain Res 1304:96-104], significantly suppressed and increased Fos-IR in HCRT and non-HCRT neurons. These findings suggest that wake-promoting PF-LHA system is subject to increased endogenous adenosinergic inhibition and that adenosine acting via A(1) receptors, in part, inhibits HCRT neurons to promote sleep.
peri-fornical-lateral 下丘脑区域（PF-LHA）在调节行为觉醒中起着核心作用。PF-LHA 包含几种神经元类型，包括觉醒活性的食欲肽（HCRT）神经元，这些神经元被认为在促进和/或维持行为觉醒中发挥作用。腺苷是一种内源性睡眠因子，最近的证据表明，PF-LHA 内的腺苷 A1 受体的激活和阻断分别促进和抑制睡眠。尽管一项体外研究表明，腺苷通过 A1 受体抑制 HCRT 神经元，但 A1 受体介导的腺苷能传递对包括 HCRT 神经元在内的 PF-LHA 神经元的体内影响尚不清楚。首先，我们通过放置在与微透析探针相邻的微丝上记录的方法，确定了 N（6）-环戊基腺苷（CPA），一种腺苷 A1 受体激动剂，对 PF-LHA 神经元的睡眠-觉醒放电活动的影响。其次，我们确定了 CPA 和 A1 受体拮抗剂 1,3-二丙基-8-苯基黄嘌呤（CPDX）在 PF-LHA 中的作用对微透析探针周围 HCRT 和非 HCRT 神经元中 cFos 蛋白免疫反应性（Fos-IR）的影响。CPA 对 Fos-IR 的影响是在光照关闭阶段保持清醒的大鼠中进行研究的，而 CPDX 对光照开启阶段未受干扰的大鼠中的影响则是在光照开启阶段进行研究的。CPA 显著抑制了 PF-LHA 神经元的睡眠-觉醒放电活动。在我们之前的研究中，CPA（50 μM）和 CPDX（50 μM）的剂量分别抑制和诱导觉醒[Alam MN、Kumar S、Rai S、Methippara M、Szymusiak R、McGinty D（2009）Brain Res 1304：96-104]，显著抑制和增加了 HCRT 和非 HCRT 神经元中的 Fos-IR。这些发现表明，促觉醒的 PF-LHA 系统受到内源性腺苷能抑制的增强，并且通过 A1 受体作用的腺苷部分抑制 HCRT 神经元以促进睡眠。
