Retinoic acid signaling: a novel factor for addiction-related behavior

视黄酸信号传导:成瘾相关行为的新因素

基本信息

项目摘要

ABSTRACT The development of pharmacotherapeutics for cocaine use disorder has lagged behind treatments for other neuropsychiatric conditions, emphasizing the need for new targets. Preliminary data suggest that rats with a protective phenotype for cocaine taking/seeking produced by environmental enrichment have less retinoic acid signaling in the nucleus accumbens, a brain region highly implicated in addiction. Additional preliminary data show that increasing retinoic acid signaling increases neuronal firing and EPSCs in the nucleus accumbens (NAc) shell and increases cocaine taking/seeking in rats. Inversely, decreasing one aspect of retinoic acid signaling in the NAc in vivo decreases neuronal firing and cocaine taking. The current proposal will generate specific mechanistic evidence regarding how retinoic acid signaling confers susceptibility to cocaine self- administration. Accordingly, the overall hypothesis of this proposal is that specific components of the retinoic acid signaling pathway in the NAc shell control susceptibility/resilience to cocaine self-administration and will represent valuable novel targets for the future treatment of cocaine dependence. Thus, the successful completion of this project will prioritize high-quality “druggable” targets in the retinoic acid pathway for subsequent pharmacotherapeutic development that can be developed and translated into clinical practice. The first aim will determine if decreasing retinoic acid synthesis in the NAc shell alone confers a protective phenotype for cocaine self-administration. Expression of the retinoic acid synthesis enzyme Aldh1a1 will be knocked down in vivo using a novel adeno-associated viral vector (AAV) prior to behavioral phenotyping and electrophysiological analysis. Next, the acute effects of Aldh1a1 inhibition on behavior, firing, and synaptic transmission will be tested using a small-molecule inhibitor. The second aim will determine the relative influence of retinoic acid receptor (RAR) vs. peroxisome proliferative receptor (PPARbeta/delta) signaling mechanisms. AAV vectors will be used to either knock down PPARbeta/delta or overexpress RARbeta to create a protective behavioral and electrophysiological phenotype in susceptible rats. The results will determine which of the competing mechanisms contains the most promising therapeutic target. The third aim will determine the relative genomic vs. non-genomic influence of retinoic acid signaling in rat NAc. Chromatin immunoprecipitation will be employed with DNA sequencing to assess the genomic aspect. The non-genomic side of the equation will focus on rapid RA-dependent homeostatic synaptic plasticity from neuronal RNA granules. The final result of this project will be a much-needed novel candidate target for therapeutic development for cocaine addiction.
摘要

项目成果

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Thomas Arthur Green其他文献

Thomas Arthur Green的其他文献

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{{ truncateString('Thomas Arthur Green', 18)}}的其他基金

Neurotoxicology of deltamethrin in the developing brain
发育中大脑中溴氰菊酯的神经毒理学
  • 批准号:
    10430263
  • 财政年份:
    2020
  • 资助金额:
    $ 44.08万
  • 项目类别:
Neurotoxicology of deltamethrin in the developing brain
发育中大脑中溴氰菊酯的神经毒理学
  • 批准号:
    10663801
  • 财政年份:
    2020
  • 资助金额:
    $ 44.08万
  • 项目类别:
Neurotoxicology of deltamethrin in the developing brain
发育中大脑中溴氰菊酯的神经毒理学
  • 批准号:
    10271267
  • 财政年份:
    2020
  • 资助金额:
    $ 44.08万
  • 项目类别:
Gpr12: a novel factor for addiction and mental health
Gpr12:成瘾和心理健康的新因素
  • 批准号:
    9813292
  • 财政年份:
    2019
  • 资助金额:
    $ 44.08万
  • 项目类别:
Retinoic acid signaling: a novel factor for addiction-related behavior
视黄酸信号传导:成瘾相关行为的新因素
  • 批准号:
    10425348
  • 财政年份:
    2018
  • 资助金额:
    $ 44.08万
  • 项目类别:
Amygdala Serotonin Neurotransmission and Neuropathic Pain
杏仁核血清素神经传递和神经性疼痛
  • 批准号:
    8576928
  • 财政年份:
    2013
  • 资助金额:
    $ 44.08万
  • 项目类别:
Amygdala Serotonin Neurotransmission and Neuropathic Pain
杏仁核血清素神经传递和神经性疼痛
  • 批准号:
    8917636
  • 财政年份:
    2013
  • 资助金额:
    $ 44.08万
  • 项目类别:
Amygdala Serotonin Neurotransmission and Neuropathic Pain
杏仁核血清素神经传递和神经性疼痛
  • 批准号:
    9250231
  • 财政年份:
    2013
  • 资助金额:
    $ 44.08万
  • 项目类别:
Amygdala Serotonin Neurotransmission and Neuropathic Pain
杏仁核血清素神经传递和神经性疼痛
  • 批准号:
    8843055
  • 财政年份:
    2013
  • 资助金额:
    $ 44.08万
  • 项目类别:
Amygdala Serotonin Neurotransmission and Neuropathic Pain
杏仁核血清素神经传递和神经性疼痛
  • 批准号:
    9039670
  • 财政年份:
    2013
  • 资助金额:
    $ 44.08万
  • 项目类别:

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Do short term changes in atmospheric pressure affect the calling behavior of male crickets
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