Neuropharmacological Evidence Implicating Drug-Induced Glutamate Receptor Dysfunction in Affective and Cognitive Sequelae of Subchronic Methamphetamine Self-Administration in Mice
Methamphetamine (MA) is a highly addictive drug, and MA use disorder is often comorbid with anxiety and cognitive impairment. These comorbid conditions are theorized to reflect glutamate-related neurotoxicity within the frontal cortical regions. However, our prior studies of MA-sensitized mice indic...
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| Format: | Article |
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MDPI AG
2024-02-01
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| Series: | International Journal of Molecular Sciences |
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| Online Access: | https://www.mdpi.com/1422-0067/25/3/1928 |
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| author | Christopher J. E. Denning Lauren E. Madory Jessica N. Herbert Ryan A. Cabrera Karen K. Szumlinski |
| author_facet | Christopher J. E. Denning Lauren E. Madory Jessica N. Herbert Ryan A. Cabrera Karen K. Szumlinski |
| author_sort | Christopher J. E. Denning |
| collection | DOAJ |
| description | Methamphetamine (MA) is a highly addictive drug, and MA use disorder is often comorbid with anxiety and cognitive impairment. These comorbid conditions are theorized to reflect glutamate-related neurotoxicity within the frontal cortical regions. However, our prior studies of MA-sensitized mice indicate that subchronic, behaviorally non-contingent MA treatment is sufficient to dysregulate glutamate transmission in mouse brain. Here, we extend this prior work to a mouse model of high-dose oral MA self-administration (0.8, 1.6, or 3.2 g/L; 1 h sessions × 7 days) and show that while female C57BL/6J mice consumed more MA than males, MA-experienced mice of both sexes exhibited some signs of anxiety-like behavior in a behavioral test battery, although not all effects were concentration-dependent. No MA effects were detected for our measures of visually cued spatial navigation, spatial learning, or memory in the Morris water maze; however, females with a history of 3.2 g/L MA exhibited reversal-learning deficits in this task, and mice with a history of 1.6 g/L MA committed more working-memory incorrect errors and relied upon a non-spatial navigation strategy during the radial-arm maze testing. Relative to naïve controls, MA-experienced mice exhibited several changes in the expression of certain glutamate receptor-related proteins and their downstream effectors within the ventral and dorsal areas of the prefrontal cortex, the hippocampus, and the amygdala, many of which were sex-selective. Systemic pretreatment with the mGlu1-negative allosteric modulator JNJ 162596858 reversed the anxiety-like behavior expressed by MA-experienced mice in the marble-burying test, while systemic pretreatment with NMDA or the NMDA antagonist MK-801 bi-directionally affected the MA-induced reversal-learning deficit. Taken together, these data indicate that a relatively brief history of oral MA is sufficient to induce some signs of anxiety-like behavior and cognitive dysfunction during early withdrawal that reflect, at least in part, MA-induced changes in the corticolimbic expression of certain glutamate receptor subtypes of potential relevance to treating symptoms of MA use disorder. |
| first_indexed | 2024-03-08T03:55:13Z |
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| issn | 1661-6596 1422-0067 |
| language | English |
| last_indexed | 2024-03-08T03:55:13Z |
| publishDate | 2024-02-01 |
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| spelling | doaj.art-fffe02464e334e46a4a58fae725ee58c2024-02-09T15:15:14ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672024-02-01253192810.3390/ijms25031928Neuropharmacological Evidence Implicating Drug-Induced Glutamate Receptor Dysfunction in Affective and Cognitive Sequelae of Subchronic Methamphetamine Self-Administration in MiceChristopher J. E. Denning0Lauren E. Madory1Jessica N. Herbert2Ryan A. Cabrera3Karen K. Szumlinski4Department of Psychological and Brain Sciences, University of California Santa Barbara, Santa Barbara, CA 93106, USADepartment of Psychological and Brain Sciences, University of California Santa Barbara, Santa Barbara, CA 93106, USADepartment of Psychological and Brain Sciences, University of California Santa Barbara, Santa Barbara, CA 93106, USADepartment of Psychological and Brain Sciences, University of California Santa Barbara, Santa Barbara, CA 93106, USADepartment of Psychological and Brain Sciences, University of California Santa Barbara, Santa Barbara, CA 93106, USAMethamphetamine (MA) is a highly addictive drug, and MA use disorder is often comorbid with anxiety and cognitive impairment. These comorbid conditions are theorized to reflect glutamate-related neurotoxicity within the frontal cortical regions. However, our prior studies of MA-sensitized mice indicate that subchronic, behaviorally non-contingent MA treatment is sufficient to dysregulate glutamate transmission in mouse brain. Here, we extend this prior work to a mouse model of high-dose oral MA self-administration (0.8, 1.6, or 3.2 g/L; 1 h sessions × 7 days) and show that while female C57BL/6J mice consumed more MA than males, MA-experienced mice of both sexes exhibited some signs of anxiety-like behavior in a behavioral test battery, although not all effects were concentration-dependent. No MA effects were detected for our measures of visually cued spatial navigation, spatial learning, or memory in the Morris water maze; however, females with a history of 3.2 g/L MA exhibited reversal-learning deficits in this task, and mice with a history of 1.6 g/L MA committed more working-memory incorrect errors and relied upon a non-spatial navigation strategy during the radial-arm maze testing. Relative to naïve controls, MA-experienced mice exhibited several changes in the expression of certain glutamate receptor-related proteins and their downstream effectors within the ventral and dorsal areas of the prefrontal cortex, the hippocampus, and the amygdala, many of which were sex-selective. Systemic pretreatment with the mGlu1-negative allosteric modulator JNJ 162596858 reversed the anxiety-like behavior expressed by MA-experienced mice in the marble-burying test, while systemic pretreatment with NMDA or the NMDA antagonist MK-801 bi-directionally affected the MA-induced reversal-learning deficit. Taken together, these data indicate that a relatively brief history of oral MA is sufficient to induce some signs of anxiety-like behavior and cognitive dysfunction during early withdrawal that reflect, at least in part, MA-induced changes in the corticolimbic expression of certain glutamate receptor subtypes of potential relevance to treating symptoms of MA use disorder.https://www.mdpi.com/1422-0067/25/3/1928NMDA receptorGroup 1 mGluRanxietysex differencesspatial learningworking memory |
| spellingShingle | Christopher J. E. Denning Lauren E. Madory Jessica N. Herbert Ryan A. Cabrera Karen K. Szumlinski Neuropharmacological Evidence Implicating Drug-Induced Glutamate Receptor Dysfunction in Affective and Cognitive Sequelae of Subchronic Methamphetamine Self-Administration in Mice International Journal of Molecular Sciences NMDA receptor Group 1 mGluR anxiety sex differences spatial learning working memory |
| title | Neuropharmacological Evidence Implicating Drug-Induced Glutamate Receptor Dysfunction in Affective and Cognitive Sequelae of Subchronic Methamphetamine Self-Administration in Mice |
| title_full | Neuropharmacological Evidence Implicating Drug-Induced Glutamate Receptor Dysfunction in Affective and Cognitive Sequelae of Subchronic Methamphetamine Self-Administration in Mice |
| title_fullStr | Neuropharmacological Evidence Implicating Drug-Induced Glutamate Receptor Dysfunction in Affective and Cognitive Sequelae of Subchronic Methamphetamine Self-Administration in Mice |
| title_full_unstemmed | Neuropharmacological Evidence Implicating Drug-Induced Glutamate Receptor Dysfunction in Affective and Cognitive Sequelae of Subchronic Methamphetamine Self-Administration in Mice |
| title_short | Neuropharmacological Evidence Implicating Drug-Induced Glutamate Receptor Dysfunction in Affective and Cognitive Sequelae of Subchronic Methamphetamine Self-Administration in Mice |
| title_sort | neuropharmacological evidence implicating drug induced glutamate receptor dysfunction in affective and cognitive sequelae of subchronic methamphetamine self administration in mice |
| topic | NMDA receptor Group 1 mGluR anxiety sex differences spatial learning working memory |
| url | https://www.mdpi.com/1422-0067/25/3/1928 |
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