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Amphetamine sensitization in mice is sufficient to produce both manic- and depressive-related behaviors as well as changes in the functional connectivity of corticolimbic structures.
- Source :
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Neuropharmacology [Neuropharmacology] 2015 Aug; Vol. 95, pp. 434-47. Date of Electronic Publication: 2015 May 07. - Publication Year :
- 2015
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Abstract
- It has been suggested that amphetamine abuse and withdrawal mimics the diverse nature of bipolar disorder symptomatology in humans. Here, we determined if a single paradigm of amphetamine sensitization would be sufficient to produce both manic- and depressive-related behaviors in mice. CD-1 mice were subcutaneously dosed for 5 days with 1.8 mg/kg d-amphetamine or vehicle. On days 6-31 of withdrawal, amphetamine-sensitized (AS) mice were compared to vehicle-treated (VT) mice on a range of behavioral and biochemical endpoints. AS mice demonstrated reliable mania- and depression-related behaviors from day 7 to day 28 of withdrawal. Relative to VT mice, AS mice exhibited long-lasting mania-like hyperactivity following either an acute 30-min restraint stress or a low-dose 1 mg/kg d-amphetamine challenge, which was attenuated by the mood-stabilizers lithium and quetiapine. In absence of any challenge, AS mice showed anhedonia-like decreases in sucrose preference and depression-like impairments in the off-line consolidation of motor memory, as reflected by the lack of spontaneous improvement across days of training on the rotarod. AS mice also demonstrated a functional impairment in nest building, an ethologically-relevant activity of daily living. Western blot analyses revealed a significant increase in methylation of histone 3 at lysine 9 (H3K9), but not lysine 4 (H3K4), in hippocampus of AS mice relative to VT mice. In situ hybridization for the immediate-early gene activity-regulated cytoskeleton-associated protein (Arc) further revealed heightened activation of corticolimbic structures, decreased functional connectivity between frontal cortex and striatum, and increased functional connectivity between the amygdala and hippocampus of AS mice. The effects of amphetamine sensitization were blunted in C57BL/6J mice relative to CD-1 mice. These results show that a single amphetamine sensitization protocol is sufficient to produce behavioral, functional, and biochemical phenotypes in mice that are relevant to bipolar disorder.<br /> (Copyright © 2015 Elsevier Ltd. All rights reserved.)
- Subjects :
- Anhedonia
Animals
Bipolar Disorder drug therapy
Bipolar Disorder physiopathology
Cerebral Cortex metabolism
Limbic System metabolism
Lithium Compounds pharmacology
Male
Memory Consolidation
Mice
Mice, Inbred C57BL
Motor Activity
Nesting Behavior
Neural Pathways drug effects
Neural Pathways metabolism
Psychotropic Drugs pharmacology
Quetiapine Fumarate pharmacology
Restraint, Physical
Species Specificity
Stress, Psychological physiopathology
Substance Withdrawal Syndrome drug therapy
Substance Withdrawal Syndrome physiopathology
Bipolar Disorder chemically induced
Cerebral Cortex drug effects
Dextroamphetamine administration & dosage
Disease Models, Animal
Limbic System drug effects
Substance Withdrawal Syndrome psychology
Subjects
Details
- Language :
- English
- ISSN :
- 1873-7064
- Volume :
- 95
- Database :
- MEDLINE
- Journal :
- Neuropharmacology
- Publication Type :
- Academic Journal
- Accession number :
- 25959066
- Full Text :
- https://doi.org/10.1016/j.neuropharm.2015.04.026