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Differential regulation of calcium ion signals in dopamine neurons: A potential mechanism for neuroadaptive changes underlying drug addiction .

机译：多巴胺神经元中钙离子信号的差异调节：潜在的药物成瘾神经适应性变化的潜在机制。

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摘要

A key adaptive change in the brain reward circuitry during the development of drug addiction is augmented dopamine (DA) release in response to addictive drugs. Potentiated glutamatergic synaptic transmission onto midbrain DA neurons has been suggested to be one of the cellular mechanisms mediating this change. Intracellular Ca2+ ([Ca2+]i) rise associated with postsynaptic bursts of action potentials (APs) and metabotropic glutamate receptor (mGluR) activation has been implicated in the induction of long-term potentiation (LTP) and long-term depression (LTD), respectively, of glutamate transmission in DA neurons. In this dissertation, we found a unique mechanism that differentially regulates these two opposing Ca 2+ signals. We performed patch-clamp recordings from DA neurons in acutely cut brain slices, and showed that tonic activation of metabotropic neurotransmitter receptors (such as mGluRs, alpha1 adrenergic receptors, and muscarinic acetylcholine receptors), attained by weak, sustained (∼1 sec) synaptic stimulation or bath application of selective agonists, augmented AP-induced Ca2+ transients while inhibiting Ca2+ signals elicited by strong, transient activation of mGluRs. This differential regulation is mediated by increased intracellular inositol 1,4,5-triphosphate (IP3) levels, since it was blocked by IP3 receptor antagonist heparin and reproduced by photolytic application of IP3. We further showed that AP-induced Ca2+ transients were regulated by the firing context of dopamine neurons. Evoking APs repetitively at low frequency (2 Hz) mimicking the basal firing of DA neurons caused inactivation of IP 3 receptors and inhibited AP-induced Ca2+ transients. IP3 facilitation of single AP-induced Ca2+ signals was completely abolished during the AP train, while facilitation of Ca 2+ signals triggered by bursts of APs (5 spikes at 20 Hz) was attenuated by less than half, indicating that increased IP3 level selectively amplifies Ca2+ signals associated with bursts but not single APs in a tonicly firing neuron. Finally, we obtained evidence suggesting that psychostimulant amphetamine may augment burst-induced Ca2+ signals via both depression of basal firing and production of IP3. We propose that the differential Ca2+ regulation mechanisms described in this dissertation may induce a shift in the balance of plasticity toward burst-dependent LTP in DA neurons and may contribute to the development of drug addiction.
机译：在药物成瘾过程中，大脑奖赏电路的关键自适应变化是对成瘾药物的反应中多巴胺（DA）释放增加。增强的谷氨酸能突触传递到中脑DA神经元已被认为是介导这种变化的细胞机制之一。突触后突触动作电位（APs）和代谢型谷氨酸受体（mGluR）激活相关的细胞内Ca2 +（[Ca2 +] i）升高与长期增强（LTP）和长期抑郁（LTD）的诱导有关，分别在DA神经元中传递谷氨酸。在本文中，我们发现了一种独特的机制来差异调节这两个相反的Ca 2+信号。我们在急性切开的脑切片中进行了DA神经元的膜片钳记录，并显示了代谢性神经递质受体（例如mGluR，α1肾上腺素能受体和毒蕈碱乙酰胆碱受体）的强音激活是通过弱的，持续的（约1秒）突触来实现的。选择性激动剂的刺激或沐浴应用，可增强AP诱导的Ca2 +瞬变，同时抑制mGluRs的强而短暂的激活引起的Ca2 +信号。这种差异调节是由细胞内肌醇1,4,5-三磷酸（IP3）水平升高介导的，因为它被IP3受体拮抗剂肝素阻断并通过光解IP3产生。我们进一步表明，AP诱导的Ca2 +瞬变受多巴胺神经元的放电环境的调节。在低频（2 Hz）下反复模仿AP，模仿DA神经元的基础放电，导致IP 3受体失活并抑制AP诱导的Ca2 +瞬变。在AP训练期间，完全消除了单个AP诱导的Ca2 +信号的IP3促进作用，而由AP爆发（20 Hz处的5个尖峰）触发的Ca 2+信号的促进作用衰减了不到一半，表明增加的IP3水平选择性地放大了Ca2 +信号与爆发性神经元中的爆发相关，但与单个AP无关。最后，我们获得的证据表明，精神兴奋剂苯丙胺可能通过抑制基础放电和产生IP3来增强猝发诱导的Ca2 +信号。我们提出，本文描述的不同的Ca2 +调节机制可能会诱导可塑性平衡向DA神经元中的依赖于突释的LTP转移，并可能有助于药物成瘾的发展。

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  • 作者

    Cui, Guohong.;

  • 作者单位

    The University of Texas at Austin.$bInstitute for Neuroscience.;

  • 授予单位 The University of Texas at Austin.$bInstitute for Neuroscience.;
  • 学科 Biology Neuroscience.
  • 学位 Ph.D.
  • 年度 2007
  • 页码 150 p.
  • 总页数 150
  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类 神经科学;
  • 关键词

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