Owesson Catarina A, Hopwood Sarah E, Callado Luis F, Seif Isabelle, McLaughlin Daniel P, Stamford Jonathan A
Neurotransmission Laboratory, Academic Department of Anaesthesia and Intensive Care, Barts and The London School of Medicine and Dentistry, Alexandra Wing, Royal London Hospital, Whitechapel, London E1 1BB, UK.
Eur J Neurosci. 2002 May;15(9):1516-22. doi: 10.1046/j.1460-9568.2002.01986.x.
Monoamine oxidase-A knockout (MAO-A KO) mice have elevated brain serotonin (5-HT) and noradrenaline (NA) levels, and one would therefore anticipate increased monoamine release and compensatory changes in other aspects of presynaptic monoamine function. In this study we used voltammetry in brain slices from the locus coeruleus (LC), dorsal raphe (DRN) and striatum (CPu) in 7-week-old MAO-A KO and C3H control mice to measure stimulated monoamine efflux and its control by amine transporters and autoreceptors. In LC, peak NA efflux on stimulation (99 pulses, 100 Hz) was higher in MAO-A KO than C3H mice (938 +/- 58 nm cf. 511 +/- 42 nm; P < 0.001). The NA uptake half time (t(1/2)) was longer in MAO-A KO than in C3H mice (6.0 +/- 0.9 s cf. 1.9 +/- 0.3 s; P < 0.001) and the selective NA reuptake inhibitor desipramine (50 nm) had a smaller effect in MAO-A KO mice. NA transporter binding was significantly lower in the LC of MAO-A KO mice compared to C3H controls (P < 0.01) but not in the DRN. The alpha 2 agonist dexmedetomidine (10 nm) decreased stimulated NA efflux more in C3H than in MAO-A KO mice (73.3% cf. 29.6% inhibition, P < 0.001). In DRN, peak 5-HT efflux on stimulation (99 pulses, 100 Hz) was greater (P < 0.01) in MAO-A KO (262 +/- 44 nm) than C3H mice (157 +/- 16 nm). Moreover, 5-HT uptake t(1/2) was longer (P < 0.05) in MAO-A KO than in C3H mice (8.8 +/- 1.1 s cf. 4.9 +/- 0.6 s, P < 0.05) and the effect of citalopram (75 nm) was attenuated in MAO-A KOs. Serotonin transporter binding was also lower in both the DRN and LC of MAO-A KO mice. The 5-HT(1A) agonist 8-OH-DPAT (1 microm) decreased 5-HT efflux more in C3H than in MAO-A KO mice (38.3% inhibition cf. 21.6%, P < 0.001). In contrast, there were no significant differences between MAO-A KO and C3H mice in CPu dopamine efflux and uptake and the effect of the D(2/3) agonist quinpirole was similar in the two strains. In summary, MAO-A KO mice show major dysregulation of monoaminergic presynaptic mechanisms such as autoreceptor control and transporter kinetics.
单胺氧化酶A基因敲除（MAO - A KO）小鼠的脑内血清素（5 - HT）和去甲肾上腺素（NA）水平升高，因此人们预期单胺释放会增加，并且突触前单胺功能的其他方面会发生代偿性变化。在本研究中，我们使用伏安法，对7周龄的MAO - A KO小鼠和C3H对照小鼠的蓝斑（LC）、中缝背核（DRN）和纹状体（CPu）脑片进行检测，以测量刺激后的单胺流出及其受胺转运体和自身受体的调控情况。在LC中，刺激时（99个脉冲，100Hz）MAO - A KO小鼠的NA流出峰值高于C3H小鼠（938±58nm对比511±42nm；P < 0.001）。MAO - A KO小鼠的NA摄取半衰期（t(1/2)）比C3H小鼠长（6.0±0.9s对比1.9±0.3s；P < 0.001），且选择性NA再摄取抑制剂地昔帕明（50nm）对MAO - A KO小鼠的作用较小。与C3H对照相比，MAO - A KO小鼠LC中的NA转运体结合显著降低（P < 0.01），但在DRN中没有这种情况。α2激动剂右美托咪定（10nm）对C3H小鼠刺激后NA流出的减少作用比对MAO - A KO小鼠更明显（抑制率73.3%对比29.6%，P < 0.001）。在DRN中，刺激时（99个脉冲，100Hz）MAO - A KO小鼠（262±44nm）的5 - HT流出峰值高于C3H小鼠（157±16nm）（P < 0.01）。此外，MAO - A KO小鼠的5 - HT摄取t(1/2)比C3H小鼠长（P < 0.05）（8.8±1.1s对比4.9±0.6s，P < 0.05），且西酞普兰（75nm）对MAO - A KO小鼠的作用减弱。MAO - A KO小鼠DRN和LC中的5 - HT转运体结合也较低。5 - HT(1A)激动剂8 - OH - DPAT（1μm）对C3H小鼠5 - HT流出的减少作用比对MAO - A KO小鼠更明显（抑制率38.3%对比21.6%，P < 0.001）。相比之下，MAO - A KO小鼠和C3H小鼠在CPu多巴胺流出、摄取以及D(2/3)激动剂喹吡罗的作用方面没有显著差异。总之，MAO - A KO小鼠显示出单胺能突触前机制的主要失调，如自身受体调控和转运体动力学。
