Calcium Signaling in the Reward Circuit & Drug Addiction

奖赏回路中的钙信号传导

基本信息

批准号：
7070092
负责人：
HITOSHI MORIKAWA
金额：
$ 21.97万
依托单位：
UNIVERSITY OF TEXAS AT AUSTIN
依托单位国家：
美国
项目类别：
财政年份：
2003
资助国家：
美国
起止时间：
2003-09-01 至 2008-05-31
项目状态：
已结题

项目摘要

DESCRIPTION (provided by applicant): Dopaminergic neurons in the ventral midbrain, i.e., the ventral tegmental area and the substantia nigra pars compacta, are believed to be critically involved in the perception of reward and addiction to drugs of abuse, such as psychostimulants and opioids. The firing pattern of dopamine neurons, which is controlled by excitatory and inhibitory synaptic inputs, is significantly modulated by presentation of rewards and administration of drugs of abuse. Modulation of dopamine neuron firing affects dopamine release in target structures, and hence contributes to reward-driven motivated behaviors in vivo, including drug-seeking and drug-taking behaviors. It has been shown recently that repetitive stimulation of glutamatergic inputs to dopamine neurons evokes a slow inhibitory postsynaptic potential mediated by activation of metabotropic glutamate receptors (mGluRs). This hyperpolarization results from the opening of calcium-activated potassium channels following release of calcium from intracellular stores. The overall hypothesis of the proposal is that this calcium-mediated inhibition plays a key role in controlling the excitability of dopamine neurons and in psychostimulant-induced modulation of dopamine neuronal activity. The first aim is to determine the intracellular signaling pathway mediating the release of calcium following the activation of mGluRs. This will be accomplished by combined whole-cell patch clamp recording and confocal calcium imaging techniques using acutely prepared midbrain slices from rats. Furthermore, flash photolysis of caged compounds will be performed to examine the effects of second messengers applied directly into the cytosol on a millisecond time scale. These methods will enable detailed examination of the intracellular events that follow the activation of plasma membrane receptors. The second aim is to determine the impact of this glutamate-induced hyperpolarization on the firing pattern of dopamine neurons. An effort will be made to reproduce the firing pattern observed in vivo in an in vitro slice preparation. The third aim is to investigate how acute administration of psychostimulants interferes with the mGluR-induced inhibition to modulate the firing pattern of dopamine neurons. The information obtained will open a new avenue toward the understanding of the neural mechanism responsible for the development of drug addiction.

描述（由申请人提供）：腹脑中脑中的多巴胺能神经元，即腹侧对接区域和黑质Nigra pars compacta，被认为与对滥用药物的奖励和成瘾有关，例如心理临床和阿片类药物。由兴奋性和抑制性突触输入控制的多巴胺神经元的发射模式通过呈现奖励和滥用药物给药而受到显着调节。多巴胺神经元射击的调节会影响目标结构中的多巴胺释放，因此有助于体内奖励驱动的动机行为，包括寻求药物和吸毒行为。最近已经显示，对多巴胺神经元的谷氨酸能输入的重复刺激引起了抑制性的缓慢抑制性突触后电位，这是通过激活代谢性谷氨酸受体（MGLURS）介导的。这种超极化是由于钙从细胞内储存中释放出来后钙激活的钾通道的开放而产生的。该提案的总体假设是，该钙介导的抑制作用在控制多巴胺神经元的兴奋性以及心理刺激诱导的多巴胺神经元活性的调节中起着关键作用。第一个目的是确定介导mglurs激活后钙释放的细胞内信号通路。这将通过使用大鼠的敏锐准备的中脑切片组合在一起，将全细胞贴片夹记录和共共聚焦成像技术结合在一起。此外，将进行笼中化合物的闪光光解，以检查第二个使者直接以毫秒的时间尺度施加到细胞质中的效果。这些方法将对质膜受体激活后的细胞内事件进行详细检查。第二个目的是确定这种谷氨酸诱导的超极化对多巴胺神经元的发射模式的影响。将努力重现体外切片制剂中在体内观察到的射击模式。第三个目的是研究急性施用精神刺激剂如何干扰MGLUR诱导的抑制以调节多巴胺神经元的发射模式。获得的信息将为理解负责吸毒发展的神经机制开辟新的途径。