title: 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.
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.
authors.affiliation: University of South Carolina School of Medicine, Columbia, SC 29209, USA.
authors.forename: G
authors.initials: G
authors.lastname: Pathak
authors.affiliation: University of South Carolina School of Medicine, Columbia, SC 29209, USA.
authors.forename: B A
authors.initials: BA
authors.lastname: Ibrahim
authors.affiliation: Pfizer, Neuroscience, Groton, CT 06340, USA.
authors.forename: S A
authors.initials: SA
authors.lastname: McCarthy
authors.affiliation: Pfizer, Neuroscience, Groton, CT 06340, USA.
authors.forename: K
authors.initials: K
authors.lastname: Baker
authors.affiliation: University of South Carolina School of Medicine, Columbia, SC 29209, USA. Electronic address: Michy.Kelly@uscmed.sc.edu.
authors.forename: M P
authors.initials: MP
authors.lastname: Kelly
mesh_terms: D059445:Anhedonia; D000818:Animals; D001714:Bipolar Disorder / Q000139:chemically induced* / Q000188:drug therapy / Q000503:physiopathology; D002540:Cerebral Cortex / Q000187:drug effects* / Q000378:metabolism; D003913:Dextroamphetamine / Q000008:administration & dosage*; D004195:Disease Models, Animal; D008032:Limbic System / Q000187:drug effects* / Q000378:metabolism; D018020:Lithium Compounds / Q000494:pharmacology; D008297:Male; D000069077:Memory Consolidation; D051379:Mice; D008810:Mice, Inbred C57BL; D009043:Motor Activity; D009425:Nesting Behavior; D009434:Neural Pathways / Q000187:drug effects / Q000378:metabolism; D011619:Psychotropic Drugs / Q000494:pharmacology; D000069348:Quetiapine Fumarate / Q000494:pharmacology; D012149:Restraint, Physical; D013045:Species Specificity; D013315:Stress, Psychological / Q000503:physiopathology; D013375:Substance Withdrawal Syndrome / Q000188:drug therapy / Q000503:physiopathology / Q000523:psychology*
chemical_list: D018020:Lithium Compounds; D011619:Psychotropic Drugs; D000069348:Quetiapine Fumarate; D003913:Dextroamphetamine
keywords: Bipolar disorder; Cognitive deficits; Dextroamphetamine, d-Amphetamine, Dexamphetamine (PubChem CID: 5826); Dopamine; Lithium chloride (PubChem CID: 433294); Mouse model; Nesting; Procedural learning; Quetiapine (PubChem ID: 5002)