Crowley W R, Ramoz G, Keefe K A, Torto R, Kalra S P, Hanson G R
Department of Pharmacology and Toxicology, University of Utah Health Sciences Center, College of Pharmacy, 30 South 2000 East, Room 201, Salt Lake City, UT 84112, USA.
Neuroscience. 2005;132(1):167-73. doi: 10.1016/j.neuroscience.2004.11.037.
Relatively little is known concerning the interaction of psychostimulants with hypothalamic neuropeptide systems or metabolic hormones implicated in regulation of energy balance. The present studies tested whether methamphetamine alters the expression of neuropeptide Y (NPY) and agouti-related peptide (AgRP), two important orexigenic neuropeptides, or proopiomelanocortin (POMC), the precursor for the anorexigenic peptide alpha-melanocyte-stimulating hormone, or the secretion of leptin, insulin and ghrelin, concomitant with inhibition of food intake. Female rats were either fed ad libitum (AL) or placed on a scheduled feeding (SF) regimen, with access to food limited to 4 h/day. Administration of (+/-)-methamphetamine (7.5 mg/kg, i.p.) 2 h prior to food presentation significantly inhibited food intake in SF animals, but did not affect intake in AL animals. In a separate study, AL and SF animals were killed just prior to expected food presentation, and expression of NPY, AgRP and POMC mRNAs in hypothalamus was determined using in situ hybridisation; concentrations of leptin, insulin and ghrelin in serum were determined with radioimmunoassays. In saline-treated, SF controls, NPY and AgRP mRNA expression in arcuate nucleus and serum ghrelin were significantly elevated, and serum leptin and insulin were significantly reduced. Methamphetamine reversed the up-regulation of NPY mRNA expression observed in the SF condition, without affecting AgRP mRNA or the serum concentrations of metabolic hormones. However, in AL animals, NPY mRNA expression in arcuate and dorsomedial nuclei was significantly increased by methamphetamine, which also reduced serum leptin and insulin and increased serum ghrelin concentrations. These findings suggest that the inhibition of NPY expression in SF animals may be a mechanism underlying the anorexigenic effect of methamphetamine seen in this condition. The increase in NPY expression produced by methamphetamine in AL animals may be mediated by the ability of this drug to decrease secretion of leptin and insulin and increase secretion of ghrelin.
关于精神兴奋剂与下丘脑神经肽系统或参与能量平衡调节的代谢激素之间的相互作用，人们了解得相对较少。本研究测试了甲基苯丙胺是否会改变神经肽Y（NPY）和刺鼠相关肽（AgRP）这两种重要的促食欲神经肽的表达，或者促食欲肽α-黑素细胞刺激激素的前体阿黑皮素原（POMC）的表达，以及瘦素、胰岛素和胃饥饿素的分泌，同时观察其对食物摄入的抑制作用。将雌性大鼠分为自由进食组（AL）或定时进食组（SF），定时进食组每天的进食时间限制为4小时。在喂食前2小时腹腔注射（±）-甲基苯丙胺（7.5mg/kg）可显著抑制定时进食组动物的食物摄入量，但对自由进食组动物的摄入量没有影响。在另一项研究中，在预期喂食前处死自由进食组和定时进食组动物，通过原位杂交测定下丘脑NPY、AgRP和POMC mRNA的表达；用放射免疫分析法测定血清中瘦素、胰岛素和胃饥饿素的浓度。在生理盐水处理的定时进食组对照中，弓状核中NPY和AgRP mRNA的表达以及血清胃饥饿素显著升高，血清瘦素和胰岛素显著降低。甲基苯丙胺逆转了定时进食组中观察到的NPY mRNA表达上调，而不影响AgRP mRNA或代谢激素的血清浓度。然而，在自由进食组动物中，甲基苯丙胺显著增加了弓状核和背内侧核中NPY mRNA的表达，同时也降低了血清瘦素和胰岛素水平，并增加了血清胃饥饿素浓度。这些发现表明，抑制定时进食组动物中NPY的表达可能是甲基苯丙胺在此条件下产生厌食作用的潜在机制。甲基苯丙胺在自由进食组动物中引起的NPY表达增加可能是由于该药物降低瘦素和胰岛素分泌以及增加胃饥饿素分泌的能力介导的。
