Li B H, Rowland N E
Psychology Department, University of Florida, Gainesville 32611-2250, USA.
Brain Res. 1996 Jul 29;728(2):188-92. doi: 10.1016/0006-8993(96)00397-6.
The acute appetite suppressant effect of dexfenfluramine (DF) in rats, which may depend upon its action to release serotonin (5-HT) in the brain, often declines with repeated dosing (tolerance). The mechanisms of this tolerance remain unclear. Previously, we used Fos-like immunoreactivity (Fos-IR) to map potential brain sites activated by single injections of DF in rats. A dose of 5 mg DF/kg activated the central amygdala (CeA), bed nucleus of the stria terminalis (BST), caudate-putamen (CPu), lateral parabrachial nucleus (LPB), nucleus tractus solitarius (NST), frontal cerebral cortex and the parvocellular paraventricular hypothalamic nucleus (PVN). We now report studies using Fos-IR in an attempt to understand which regions might underlie tolerance to the action of DF. Pretreatment of rats with an escalating dosage regimen of DF (0.5-4 mg/kg, i.p.) was associated with complete loss of Fos-IR to a probe dose (5 mg DF/kg) in the cortex, CPu, PVN and NTS, and partial loss of Fos-IR in the BST, CeA and LPB. Second, repeated treatment with DF (2 mg/kg), which has been shown to produce tolerance the anorexia caused by DF but not cholecystokinin (CCK), likewise reduced Fos-IR induced in the above brain regions, but had no effect on Fos-IR induced by either CCK or the 5-HT agonist, 5-carboxamidotryptamine. Third, repeated treatment with 5-HT (2 mg/kg, s.c.) had no effect on Fos-IR induced by a probe dose of DF. These data show that regionally heterogeneous hyporesponsiveness to the induction of Fos by DF develops after repeated low doses of DF; however, the Fos response to other putative anorectics or weight reducing agents is not affected. This may be related to behavioral tolerance.
右芬氟拉明（DF）对大鼠具有急性食欲抑制作用，这可能取决于其在大脑中释放5-羟色胺（5-HT）的作用，但该作用常随重复给药而减弱（耐受性）。这种耐受性的机制尚不清楚。此前，我们利用Fos样免疫反应性（Fos-IR）来定位大鼠单次注射DF后激活的潜在脑区。5mg DF/kg的剂量可激活中央杏仁核（CeA）、终纹床核（BST）、尾状核-壳核（CPu）、外侧臂旁核（LPB）、孤束核（NST）、额叶皮质以及下丘脑室旁核小细胞部（PVN）。我们现在报告利用Fos-IR进行的研究，以试图了解哪些区域可能是对DF作用产生耐受性的基础。用递增剂量方案（0.5 - 4mg/kg，腹腔注射）预处理大鼠后，对探针剂量（5mg DF/kg）的Fos-IR在皮质、CPu、PVN和NTS中完全丧失，在BST、CeA和LPB中部分丧失。其次，用DF（2mg/kg）重复治疗，已证明其可产生对DF而非胆囊收缩素（CCK）所致厌食的耐受性，同样降低了上述脑区诱导的Fos-IR，但对CCK或5-HT激动剂5-羧基色胺诱导的Fos-IR无影响。第三，用5-HT（2mg/kg，皮下注射）重复治疗对探针剂量DF诱导的Fos-IR无影响。这些数据表明，重复低剂量DF后，对DF诱导Fos的区域异质性低反应性会出现；然而，对其他假定的食欲抑制剂或减肥剂的Fos反应不受影响。这可能与行为耐受性有关。
