Severe drug-induced repetitive behaviors and striatal overexpression of VAChT in ChAT-ChR2-EYFP BAC transgenic mice
In drug users, drug-related cues alone can induce dopamine release in the dorsal striatum. Instructive cues activate inputs to the striatum from both dopaminergic and cholinergic neurons, which are thought to work together to support motor learning and motivated behaviors. Imbalances in these neurom...
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| Format: | Article |
| Language: | en_US |
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Frontiers Research Foundation
2014
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| Online Access: | http://hdl.handle.net/1721.1/88039 https://orcid.org/0000-0002-4326-7720 |
| _version_ | 1826200218590248960 |
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| author | Crittenden, Jill R. Lacey, Carolyn J. Lee, Tyrone Bowden, Hilary Ann Graybiel, Ann M. |
| author2 | Massachusetts Institute of Technology. Department of Brain and Cognitive Sciences |
| author_facet | Massachusetts Institute of Technology. Department of Brain and Cognitive Sciences Crittenden, Jill R. Lacey, Carolyn J. Lee, Tyrone Bowden, Hilary Ann Graybiel, Ann M. |
| author_sort | Crittenden, Jill R. |
| collection | MIT |
| description | In drug users, drug-related cues alone can induce dopamine release in the dorsal striatum. Instructive cues activate inputs to the striatum from both dopaminergic and cholinergic neurons, which are thought to work together to support motor learning and motivated behaviors. Imbalances in these neuromodulatory influences can impair normal action selection and might thus contribute to pathologically repetitive and compulsive behaviors such as drug addiction. Dopamine and acetylcholine can have either antagonistic or synergistic effects on behavior, depending on the state of the animal and the receptor signaling systems at play. Semi-synchronized activation of cholinergic interneurons in the dorsal striatum drives dopamine release via presynaptic nicotinic acetylcholine receptors located on dopamine terminals. Nicotinic receptor blockade is known to diminish abnormal repetitive behaviors (stereotypies) induced by psychomotor stimulants. By contrast, blockade of postsynaptic acetylcholine muscarinic receptors in the dorsomedial striatum exacerbates drug-induced stereotypy, exemplifying how different acetylcholine receptors can also have opposing effects. Although acetylcholine release is known to be altered in animal models of drug addiction, predicting whether these changes will augment or diminish drug-induced behaviors thus remains a challenge. Here, we measured amphetamine-induced stereotypy in BAC transgenic mice that have been shown to overexpress the vesicular acetylcholine transporter (VAChT) with consequent increased acetylcholine release. We found that drug-induced stereotypies, consisting of confined sniffing and licking behaviors, were greatly increased in the transgenic mice relative to sibling controls, as was striatal VAChT protein. These findings suggest that VAChT-mediated increases in acetylcholine could be critical in exacerbating drug-induced stereotypic behaviors and promoting exaggerated behavioral fixity. |
| first_indexed | 2024-09-23T11:33:02Z |
| format | Article |
| id | mit-1721.1/88039 |
| institution | Massachusetts Institute of Technology |
| language | en_US |
| last_indexed | 2024-09-23T11:33:02Z |
| publishDate | 2014 |
| publisher | Frontiers Research Foundation |
| record_format | dspace |
| spelling | mit-1721.1/880392022-09-27T20:14:54Z Severe drug-induced repetitive behaviors and striatal overexpression of VAChT in ChAT-ChR2-EYFP BAC transgenic mice Crittenden, Jill R. Lacey, Carolyn J. Lee, Tyrone Bowden, Hilary Ann Graybiel, Ann M. Massachusetts Institute of Technology. Department of Brain and Cognitive Sciences McGovern Institute for Brain Research at MIT Crittenden, Jill R. Lacey, Carolyn J. Lee, Tyrone Bowden, Hilary Ann Graybiel, Ann M. In drug users, drug-related cues alone can induce dopamine release in the dorsal striatum. Instructive cues activate inputs to the striatum from both dopaminergic and cholinergic neurons, which are thought to work together to support motor learning and motivated behaviors. Imbalances in these neuromodulatory influences can impair normal action selection and might thus contribute to pathologically repetitive and compulsive behaviors such as drug addiction. Dopamine and acetylcholine can have either antagonistic or synergistic effects on behavior, depending on the state of the animal and the receptor signaling systems at play. Semi-synchronized activation of cholinergic interneurons in the dorsal striatum drives dopamine release via presynaptic nicotinic acetylcholine receptors located on dopamine terminals. Nicotinic receptor blockade is known to diminish abnormal repetitive behaviors (stereotypies) induced by psychomotor stimulants. By contrast, blockade of postsynaptic acetylcholine muscarinic receptors in the dorsomedial striatum exacerbates drug-induced stereotypy, exemplifying how different acetylcholine receptors can also have opposing effects. Although acetylcholine release is known to be altered in animal models of drug addiction, predicting whether these changes will augment or diminish drug-induced behaviors thus remains a challenge. Here, we measured amphetamine-induced stereotypy in BAC transgenic mice that have been shown to overexpress the vesicular acetylcholine transporter (VAChT) with consequent increased acetylcholine release. We found that drug-induced stereotypies, consisting of confined sniffing and licking behaviors, were greatly increased in the transgenic mice relative to sibling controls, as was striatal VAChT protein. These findings suggest that VAChT-mediated increases in acetylcholine could be critical in exacerbating drug-induced stereotypic behaviors and promoting exaggerated behavioral fixity. Massachusetts Institute of Technology. Simons Center for the Social Brain Cure Huntington’s Disease Initiative, Inc. McGovern Institute for Brain Research at MIT (James and Pat Poitras Research Fund) Eunice Kennedy Shriver National Institute of Child Health and Human Development (U.S.) (R37-HD028341) Nancy Lurie Marks Family Foundation Broad Institute of MIT and Harvard (Stanley Center for Psychiatric Research grant) 2014-06-19T20:01:54Z 2014-06-19T20:01:54Z 2014-05 Article http://purl.org/eprint/type/JournalArticle 1662-5110 http://hdl.handle.net/1721.1/88039 Crittenden, Jill R., Carolyn J. Lacey, Tyrone Lee, Hilary A. Bowden, and Ann M. Graybiel. “Severe Drug-Induced Repetitive Behaviors and Striatal Overexpression of VAChT in ChAT-ChR2-EYFP BAC Transgenic Mice.” Front. Neural Circuits 8 (May 28, 2014). https://orcid.org/0000-0002-4326-7720 en_US http://dx.doi.org/10.3389/fncir.2014.00057 Frontiers in Neural Circuits Article is made available in accordance with the publisher's policy and may be subject to US copyright law. Please refer to the publisher's site for terms of use. application/pdf Frontiers Research Foundation Frontiers Research Foundation |
| spellingShingle | Crittenden, Jill R. Lacey, Carolyn J. Lee, Tyrone Bowden, Hilary Ann Graybiel, Ann M. Severe drug-induced repetitive behaviors and striatal overexpression of VAChT in ChAT-ChR2-EYFP BAC transgenic mice |
| title | Severe drug-induced repetitive behaviors and striatal overexpression of VAChT in ChAT-ChR2-EYFP BAC transgenic mice |
| title_full | Severe drug-induced repetitive behaviors and striatal overexpression of VAChT in ChAT-ChR2-EYFP BAC transgenic mice |
| title_fullStr | Severe drug-induced repetitive behaviors and striatal overexpression of VAChT in ChAT-ChR2-EYFP BAC transgenic mice |
| title_full_unstemmed | Severe drug-induced repetitive behaviors and striatal overexpression of VAChT in ChAT-ChR2-EYFP BAC transgenic mice |
| title_short | Severe drug-induced repetitive behaviors and striatal overexpression of VAChT in ChAT-ChR2-EYFP BAC transgenic mice |
| title_sort | severe drug induced repetitive behaviors and striatal overexpression of vacht in chat chr2 eyfp bac transgenic mice |
| url | http://hdl.handle.net/1721.1/88039 https://orcid.org/0000-0002-4326-7720 |
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