Curet O, Dennis T, Scatton B
J Pharmacol Exp Ther. 1987 Jan;240(1):327-36.
In an attempt to evaluate the possible functional role of alpha-2 adrenoceptors located on noradrenergic nerve endings in the regulation of cerebral norepinephrine metabolism, we have measured the effects of clonidine and idazoxan on cerebral free 3,4-dihydroxyphenylethyleneglycol (DOPEG) levels (an index of norepinephrine turnover) in the rat after surgical and experimental manipulations that allow an exclusive interaction of the alpha-2 adrenergic agents with presynaptic alpha-2 autoreceptors. The possible contribution of distant (to cell bodies) transsynaptic feedback mechanisms triggered by stimulation of postsynaptic alpha-2 adrenoceptors and of somatodendritic alpha-2 autoreceptor-mediated regulatory mechanisms was eliminated by a local infusion of tetrodotoxin (50 ng) into the ascending noradrenergic bundle followed by electrical stimulation (at a frequency of 8 Hz) of this pathway distally to the neurotoxin injection site in chloral hydrate-anesthetized rats. Under these conditions, systemic injection of idazoxan (20 mg/kg i.p.) and clonidine (0.3 mg/kg i.p.) provoked an increase and a decrease, respectively, in free DOPEG levels in the hypothalamus, cerebral cortex and medial septum which were similar to those measured in naive rats. Moreover, in these animals the effect of idazoxan (1 mg/kg i.p.) was surmounted by a large dose of clonidine (0.3 mg/kg i.p.). The possible contribution of feedback mechanisms triggered by activation of postsynaptic alpha-2 adrenoceptors and mediated via local (to terminals) circuits (or a putative humoral agent released postsynaptically) was eliminated subsequently by a local injection of ibotenic acid in noradrenergic projection areas. Systemic administration of idazoxan (20 mg/kg i.p.) to ibotenate-lesioned rats elicited an increase in septal- and hypothalamic-free DOPEG levels comparable to that found in sham-operated rats. The effectiveness of the lesion was attested by a massive neuronal depopulation in the lesioned areas. Finally, ibotenic acid-induced destruction of noradrenergic target cells and local infusion of tetrodotoxin into followed by electrical stimulation of the ascending noradrenergic pathways were combined. Under these conditions, idazoxan still increased hypothalamic- and septal-free DOPEG levels, the extent of this alteration being similar to that found in normal rats. Altogether, these results suggest that irrespective of their low density, presynaptic alpha-2 autoreceptors play a cardinal role in the regulation of central nervous system norepinephrine metabolism.
为了评估去甲肾上腺素能神经末梢上的α₂肾上腺素受体在调节脑内去甲肾上腺素代谢中可能的功能作用，我们在进行了手术和实验操作后，测量了可乐定和咪唑克生对大鼠脑内游离3,4 - 二羟基苯乙二醇（DOPEG）水平（去甲肾上腺素周转的一个指标）的影响，这些操作使得α₂肾上腺素能药物仅与突触前α₂自身受体相互作用。通过向去甲肾上腺素能上行束局部注入河豚毒素（50 ng），随后在水合氯醛麻醉的大鼠中，在神经毒素注射部位远端对该通路进行电刺激（频率为8 Hz），消除了由突触后α₂肾上腺素受体刺激触发的远距离（至细胞体）跨突触反馈机制以及树突 - 胞体α₂自身受体介导的调节机制的可能贡献。在这些条件下，腹腔注射咪唑克生（20 mg/kg）和可乐定（0.3 mg/kg）分别引起下丘脑、大脑皮层和内侧隔区游离DOPEG水平的升高和降低，这与在未处理大鼠中测得的结果相似。此外，在这些动物中，大剂量可乐定（0.3 mg/kg腹腔注射）可克服咪唑克生（1 mg/kg腹腔注射）的作用。随后，通过在去甲肾上腺素能投射区域局部注射鹅膏蕈氨酸，消除了由突触后α₂肾上腺素受体激活触发并通过局部（至终末）回路（或突触后释放的一种假定体液因子）介导的反馈机制的可能贡献。向经鹅膏蕈氨酸损伤的大鼠腹腔注射咪唑克生（20 mg/kg），引起隔区和下丘脑游离DOPEG水平升高，与假手术大鼠中的情况相当。损伤区域大量神经元缺失证明了损伤的有效性。最后，将鹅膏蕈氨酸诱导的去甲肾上腺素能靶细胞破坏与向去甲肾上腺素能上行通路局部注入河豚毒素并随后进行电刺激相结合。在这些条件下，咪唑克生仍可增加下丘脑和隔区游离DOPEG水平，这种变化程度与正常大鼠中的情况相似。总之，这些结果表明，无论其低密度如何，突触前α₂自身受体在调节中枢神经系统去甲肾上腺素代谢中起主要作用。
