Impact of Cocaine History on Pharmacotherapy Effectiveness

项目总结 随着与可卡因有关的过量死亡人数每年都在增加，可卡因滥用是一个严重的公共卫生问题。 尽管几十年的基础研究，仍然没有食品和药物批准的可卡因药物疗法 使用障碍(CUD)。越来越多的证据表明，以前的可卡因使用史可能会改变 新的CUD药物疗法的开发和筛选。我们建议利用 临床前药物与非药物选择程序确定不同的可卡因自我给药史 影响M胆碱受体(MAChR)1正性变构调节剂作用的因素 VU0364572减轻可卡因对食物的选择和可卡因诱导的伏隔核(NAC)兴奋 多巴胺(DA)的释放使用纤维光度法(即dLight)。这个项目的科学前提是 在更广泛的实验范围内有效减少药物选择的候选药物 包括可卡因历史在内的条件在临床上会被假设为更有效。目标1将 确定行为史(即短期可卡因自我给药与长期可卡因自我给药)对 VU0364572减轻可卡因对食物选择行为的有效性。在2x4的实验设计中，每个 组将接受短期访问(SHA)或扩展访问(EA)可卡因自我给药条件。 在这两个进入条件下，4个处理(Vehicle、0.32、1.0和1.8 mg/kg VU0364572)的效果将 被评估。目的2将确定可卡因历史对VU0364572减毒效果的影响 可卡因-使用dLight技术增加NAC DA的释放。在3x2的实验设计中，每组将 暴露于三种可卡因接触条件之一(沙、EA或可卡因幼稚)，且车辆或 VU0364572治疗。使用dLight光纤光度法，将评估NAC DA对可卡因注射的反应。 这些神经化学终点将被跨组比较，并与可卡因和- 食物选择数据，允许在受试者内部比较神经化学和行为数据。完成 这些研究将测试有关可卡因影响的创新和翻译相关假说 MAChR1PAM降低可卡因自身给药和可卡因诱导增强作用的研究进展 中脑边缘DA信号。

PROJECT SUMMARY With cocaine-related overdose deaths increasing every year, cocaine abuse is a serious public health concern. Despite decades of basic research, there are still no Food and Drug-approved pharmacotherapies for cocaine use disorder (CUD). A growing body of evidence suggests that prior cocaine use history may alter the development and screening of new CUD pharmacotherapies. We propose to leverage the translational utility of preclinical drug-vs-nondrug choice procedures to determine how different cocaine self-administration histories impact the effectiveness of the muscarinic acetylcholine receptor (mAChR)1 positive allosteric modulator VU0364572 to attenuate cocaine-vs-food choice and cocaine-induced increases in nucleus accumbens (NAc) dopamine (DA) release using fiber photometry (i.e., dLight). The scientific premise of this project is that candidate medications that are effective in decreasing drug choice across a broader range of experimental conditions, including cocaine history, would be hypothesized to be more effective clinically. Aim 1 will determine the effects of behavioral history (i.e., short- vs extended-access cocaine self-administration) on VU0364572 effectiveness to attenuate cocaine-vs-food choice behavior. In a 2 x 4 experimental design, each group will undergo either short-access (ShA) or extended-access (EA) cocaine self-administration conditions. Under these two access conditions, effects of 4 treatments (vehicle, 0.32, 1.0, and 1.8 mg/kg VU0364572) will be assessed. Aim 2 will determine the effects of cocaine history on effectiveness of VU0364572 to attenuate cocaine-elevated NAc DA release using dLight technology. In a 3 x 2 experimental design, each group will be exposed to one of three cocaine access conditions (ShA, EA, or cocaine naïve) and either vehicle or VU0364572 treatment. Using dLight fiber photometry, NAc DA response to cocaine infusions will be assessed. These neurochemical endpoints will be compared across groups and collected in conjunction with cocaine-vs- food choice data, allowing for within-subjects comparison of neurochemical and behavioral data. Completion of these studies will test innovative and translationally relevant hypotheses regarding the effects of cocaine history on mAChR1 PAM efficacy to decrease cocaine self-administration and cocaine-induced enhancement of mesolimbic DA signaling.