Clavulanic Acid-Mediated Increases in Anterior Cingulate Glutamate Levels are Associated With Decreased Cocaine Craving and Brain Network Functional Connectivity Changes
Background: 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 cl...
Saved in:
| Main Authors: | , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Elsevier
2024-01-01
|
| Series: | Current Therapeutic Research |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S0011393X24000213 |
| Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
| _version_ | 1850119486351343616 |
|---|---|
| author | Joya Maser, MS Mary F. Morrison, MD Helene Philogene Khalid, PhD Ronan Cunningham Daohai Yu, PhD M. Ingre Walters, MD Xiaoning Lu Nicolas R. Bolo, PhD |
| author_facet | Joya Maser, MS Mary F. Morrison, MD Helene Philogene Khalid, PhD Ronan Cunningham Daohai Yu, PhD M. Ingre Walters, MD Xiaoning Lu Nicolas R. Bolo, PhD |
| author_sort | Joya Maser, MS |
| collection | DOAJ |
| description | Background: 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. Methods: 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. Results: Participants who achieved high ACC glutamate levels after CLAV treatment had robust decreases in COC craving (r = −0.90, P = 0.0009, n = 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, r = −0.82, P = 0.007) (ECN CLAV 1000 mg, r = −0.667, P = 0.050; n = 9). Conclusions: 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. |
| format | Article |
| id | doaj-art-88aa577ebef74cccb86bfd770902f3da |
| institution | OA Journals |
| issn | 0011-393X |
| language | English |
| publishDate | 2024-01-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Current Therapeutic Research |
| spelling | doaj-art-88aa577ebef74cccb86bfd770902f3da2025-08-20T02:35:37ZengElsevierCurrent Therapeutic Research0011-393X2024-01-0110110075110.1016/j.curtheres.2024.100751Clavulanic Acid-Mediated Increases in Anterior Cingulate Glutamate Levels are Associated With Decreased Cocaine Craving and Brain Network Functional Connectivity ChangesJoya Maser, MS0Mary F. Morrison, MD1Helene Philogene Khalid, PhD2Ronan Cunningham3Daohai Yu, PhD4M. Ingre Walters, MD5Xiaoning Lu6Nicolas R. Bolo, PhD7Department of Psychiatry, Lewis Katz School of Medicine, Temple University, Philadelphia, Pennsylvania; Address correspondence to: Joya Maser, MS, Temple University Hospital Episcopal Campus, 100 E Lehigh Avenue, Medical Arts Building, Suite 305A, Philadelphia, PA 19125.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, PennsylvaniaDepartment of Psychiatry, Center for Substance Abuse Research, Lewis Katz School of Medicine, Temple University, Philadelphia, PennsylvaniaDepartment of Psychiatry, Lewis Katz School of Medicine, Temple University, Philadelphia, PennsylvaniaDepartment of Biomedical Education and Data Science, Center for Biostatistics & Epidemiology, Philadelphia, Pennsylvania; Lewis Katz School of Medicine, Temple University, Philadelphia, PennsylvaniaDepartment of Psychiatry, Lewis Katz School of Medicine, Temple University, Philadelphia, PennsylvaniaDepartment of Biomedical Education and Data Science, Center for Biostatistics & Epidemiology, Philadelphia, Pennsylvania; Lewis Katz School of Medicine, Temple University, Philadelphia, PennsylvaniaDepartment of Psychiatry, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MassachusettsBackground: 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. Methods: 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. Results: Participants who achieved high ACC glutamate levels after CLAV treatment had robust decreases in COC craving (r = −0.90, P = 0.0009, n = 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, r = −0.82, P = 0.007) (ECN CLAV 1000 mg, r = −0.667, P = 0.050; n = 9). Conclusions: 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.http://www.sciencedirect.com/science/article/pii/S0011393X24000213anterior cingulate cortexclavulanic acidcocaine cravingcocaine use disorderglutamateresting state magnetic functional resonance imaging |
| spellingShingle | Joya Maser, MS Mary F. Morrison, MD Helene Philogene Khalid, PhD Ronan Cunningham Daohai Yu, PhD M. Ingre Walters, MD Xiaoning Lu Nicolas R. Bolo, PhD Clavulanic Acid-Mediated Increases in Anterior Cingulate Glutamate Levels are Associated With Decreased Cocaine Craving and Brain Network Functional Connectivity Changes Current Therapeutic Research anterior cingulate cortex clavulanic acid cocaine craving cocaine use disorder glutamate resting state magnetic functional resonance imaging |
| title | Clavulanic Acid-Mediated Increases in Anterior Cingulate Glutamate Levels are Associated With Decreased Cocaine Craving and Brain Network Functional Connectivity Changes |
| title_full | Clavulanic Acid-Mediated Increases in Anterior Cingulate Glutamate Levels are Associated With Decreased Cocaine Craving and Brain Network Functional Connectivity Changes |
| title_fullStr | Clavulanic Acid-Mediated Increases in Anterior Cingulate Glutamate Levels are Associated With Decreased Cocaine Craving and Brain Network Functional Connectivity Changes |
| title_full_unstemmed | Clavulanic Acid-Mediated Increases in Anterior Cingulate Glutamate Levels are Associated With Decreased Cocaine Craving and Brain Network Functional Connectivity Changes |
| title_short | Clavulanic Acid-Mediated Increases in Anterior Cingulate Glutamate Levels are Associated With Decreased Cocaine Craving and Brain Network Functional Connectivity Changes |
| title_sort | clavulanic acid mediated increases in anterior cingulate glutamate levels are associated with decreased cocaine craving and brain network functional connectivity changes |
| topic | anterior cingulate cortex clavulanic acid cocaine craving cocaine use disorder glutamate resting state magnetic functional resonance imaging |
| url | http://www.sciencedirect.com/science/article/pii/S0011393X24000213 |
| work_keys_str_mv | AT joyamaserms clavulanicacidmediatedincreasesinanteriorcingulateglutamatelevelsareassociatedwithdecreasedcocainecravingandbrainnetworkfunctionalconnectivitychanges AT maryfmorrisonmd clavulanicacidmediatedincreasesinanteriorcingulateglutamatelevelsareassociatedwithdecreasedcocainecravingandbrainnetworkfunctionalconnectivitychanges AT helenephilogenekhalidphd clavulanicacidmediatedincreasesinanteriorcingulateglutamatelevelsareassociatedwithdecreasedcocainecravingandbrainnetworkfunctionalconnectivitychanges AT ronancunningham clavulanicacidmediatedincreasesinanteriorcingulateglutamatelevelsareassociatedwithdecreasedcocainecravingandbrainnetworkfunctionalconnectivitychanges AT daohaiyuphd clavulanicacidmediatedincreasesinanteriorcingulateglutamatelevelsareassociatedwithdecreasedcocainecravingandbrainnetworkfunctionalconnectivitychanges AT mingrewaltersmd clavulanicacidmediatedincreasesinanteriorcingulateglutamatelevelsareassociatedwithdecreasedcocainecravingandbrainnetworkfunctionalconnectivitychanges AT xiaoninglu clavulanicacidmediatedincreasesinanteriorcingulateglutamatelevelsareassociatedwithdecreasedcocainecravingandbrainnetworkfunctionalconnectivitychanges AT nicolasrbolophd clavulanicacidmediatedincreasesinanteriorcingulateglutamatelevelsareassociatedwithdecreasedcocainecravingandbrainnetworkfunctionalconnectivitychanges |