Numan S, Lane-Ladd S B, Zhang L, Lundgren K H, Russell D S, Seroogy K B, Nestler E J
Laboratory of Molecular Psychiatry, Yale University School of Medicine and Connecticut Mental Health Center, New Haven, Connecticut 06508, USA.
J Neurosci. 1998 Dec 15;18(24):10700-8. doi: 10.1523/JNEUROSCI.18-24-10700.1998.
The neurotrophins brain-derived neurotrophic factor (BDNF) and neurotrophin-3 (NT-3) and their receptors trkB and trkC, respectively, are expressed in the locus coeruleus (LC) and ventral tegmental area (VTA), brain regions known to be involved in opiate addiction. Previously, administration of exogenous neurotrophins has been shown to oppose effects of chronic morphine treatment on LC and VTA neurons. However, the response of endogenous neurotrophins in LC and VTA to opiate treatment is unknown. In this study, BDNF, NT-3, trkB, and trkC mRNAs were analyzed in these regions after chronic morphine treatment and during antagonist precipitated withdrawal. Although chronic morphine exposure resulted in only modest increases in BDNF and NT-3 mRNA expression in LC, precipitated withdrawal led to a marked, rapid, and prolonged increase in BDNF mRNA and a delayed decrease in NT-3 mRNA. Levels of trkB and trkC mRNAs, which were unchanged by chronic morphine treatment, were elevated in LC at 2 and 6 hr of withdrawal. By 20 hr, trkB mRNA levels in LC had returned to control, whereas trkC mRNA levels fell below control values. In contrast to the substantial alterations observed in LC, there was no regulation of the neurotrophins or trk mRNAs within the VTA during chronic opiate treatment or withdrawal, with the exception of an increase in trkB mRNA at 6 hr of withdrawal. These results suggest that neurotrophins and their receptors per se may be involved in opiate-induced plasticity of the LC, whereas other mechanisms would appear to be involved in the VTA.
神经营养因子脑源性神经营养因子（BDNF）和神经营养因子-3（NT-3）及其各自的受体trkB和trkC，分别在蓝斑（LC）和腹侧被盖区（VTA）表达，这两个脑区已知与阿片类成瘾有关。此前，已表明给予外源性神经营养因子可对抗慢性吗啡治疗对LC和VTA神经元的影响。然而，LC和VTA中内源性神经营养因子对阿片类药物治疗的反应尚不清楚。在本研究中，分析了慢性吗啡治疗后以及拮抗剂诱发戒断期间这些区域中BDNF、NT-3、trkB和trkC的mRNA。尽管慢性吗啡暴露仅导致LC中BDNF和NT-3 mRNA表达适度增加，但诱发戒断导致BDNF mRNA显著、快速且持续增加，而NT-3 mRNA延迟下降。慢性吗啡治疗未改变的trkB和trkC mRNA水平，在戒断2小时和6小时时LC中升高。到20小时时，LC中trkB mRNA水平恢复到对照水平，而trkC mRNA水平降至对照值以下。与在LC中观察到的显著变化相反，在慢性阿片类药物治疗或戒断期间，VTA内的神经营养因子或trk mRNA没有调节，除了在戒断6小时时trkB mRNA增加。这些结果表明，神经营养因子及其受体本身可能参与阿片类药物诱导的LC可塑性，而其他机制似乎参与VTA。
