Maser Joya, Morrison Mary F, Khalid Helene Philogene, Cunningham Ronan, Yu Daohai, Walters M Ingre, Lu Xiaoning, Bolo Nicolas R
Department of Psychiatry, Lewis Katz School of Medicine, Temple University, Philadelphia, Pennsylvania.
Department of Psychiatry, Center for Substance Abuse Research, Lewis Katz School of Medicine, Temple University, Philadelphia, Pennsylvania.
Curr Ther Res Clin Exp. 2024 Jun 6;101:100751. doi: 10.1016/j.curtheres.2024.100751. eCollection 2024.
There is an urgent need for pharmacological treatment for cocaine (COC) use disorder (CUD). Glutamatergic transmission in the prefrontal cortex is affected by addictive behaviors. Clavulanic acid (CLAV), a glutamate transporter GLT-1 (excitatory amino acid transporter) activator, is a clinical-stage medication that has potential for treating CUD.
In a pilot study, nine participants with CUD received 500 mg CLAV with dose escalations to 750 mg and 1000 mg over 10 days. In 5 separate magnetic resonance imaging (MRI) sessions, brain anterior cingulate cortex (ACC) glutamate level and resting state network (RSN) functional connectivity (FC) were assessed using MR spectroscopy and functional MRI. Craving was assessed at the same time points, between baseline (before CLAV), 6 days, and 10 days of CLAV. Independent component analysis with dual regression was used to identify RSN FC changes from baseline to Days 6 and 10. Relationships among glutamate, craving, and resting state FC values were analyzed.
Participants who achieved high ACC glutamate levels after CLAV treatment had robust decreases in COC craving ( = -0.90, = 0.0009, = 9). The salience network (SN) and executive control network (ECN) demonstrated an association between increased FC after CLAV treatment and low baseline ACC Glu levels (SN CLAV 750 mg, = -0.82, = 0.007) (ECN CLAV 1000 mg, = -0.667, = 0.050; = 9).
Glutamate associated changes in craving and FC of the salience and executive control brain networks support CLAV as a potentially efficacious pharmacological treatment for CUD.
可卡因使用障碍（CUD）迫切需要药物治疗。前额叶皮质中的谷氨酸能传递受成瘾行为影响。克拉维酸（CLAV）是一种谷氨酸转运体GLT-1（兴奋性氨基酸转运体）激活剂，是一种处于临床阶段、有潜力治疗CUD的药物。
在一项试点研究中，9名CUD参与者接受500毫克CLAV治疗，在10天内剂量逐步增加至750毫克和1000毫克。在5次单独的磁共振成像（MRI）检查中，使用磁共振波谱和功能MRI评估脑前扣带回皮质（ACC）谷氨酸水平和静息态网络（RSN）功能连接性（FC）。在基线（CLAV治疗前）、CLAV治疗6天和10天的相同时间点评估渴望程度。采用独立成分分析和双重回归来确定从基线到第6天和第10天RSN FC的变化。分析谷氨酸、渴望程度和静息态FC值之间的关系。
CLAV治疗后ACC谷氨酸水平升高的参与者对可卡因的渴望显著降低（r = -0.90，p = 0.0009，n = 9）。突显网络（SN）和执行控制网络（ECN）显示，CLAV治疗后FC增加与基线ACC谷氨酸水平低之间存在关联（SN，CLAV 750毫克，r = -0.82，p = 0.007）（ECN，CLAV 1000毫克，r = -0.667，p = 0.050；n = 9）。
谷氨酸相关的渴望程度变化以及突显和执行控制脑网络的FC变化支持CLAV作为一种可能有效的CUD药物治疗方法。
