Neurochemical responses to antidepressants in the prefrontal cortex of mice and their efficacy in preclinical models of anxiety-like and depression-like behavior: a comparative and correlational study.
BACKGROUND
Marble burying and forced swimming behavior are widely used and sensitive tests for identifying clinically effective antidepressant drugs, although the underlying neurobiology of these behaviors is not fully elucidated.


OBJECTIVE
The objective of this study was to determine the relationship between the behavioral effects of antidepressant drugs and their ability to modulate extracellular neurotransmitter levels in the prefrontal cortex.


METHODS
The effects of fluoxetine, fluvoxamine, citalopram, imipramine, and desipramine (0 to 60 mg/kg by oral gavage, except fluoxetine at 0 to 40 mg/kg) were studied independently in CD-1 mice in the marble-burying task, forced swim task and on extracellular concentrations of serotonin, norepinephrine, and dopamine in the prefrontal cortex by freely moving microdialysis.


RESULTS
Fluvoxamine, fluoxetine, and citalopram all suppressed marble-burying behavior, but produced no change in immobility time in the forced swim test. In contrast, imipramine and desipramine suppressed both marble-burying behavior and increased swimming time in the forced swim test, although desipramine mildly suppressed locomotor activity at the maximal dose. Fluvoxamine, fluoxetine, and citalopram all increased extracellular levels of cortical serotonin. Desipramine and imipramine increased extracellular dopamine levels. Fluoxetine, desipramine, and imipramine increased extracellular norepinephrine levels. Correlational analysis revealed a positive correlation between efficacy of drugs in the forced swim test and cortical extracellular dopamine levels, whereas a positive correlation was found between efficacy in the marble-burying test and extracellular serotonin levels.


CONCLUSIONS
Although marble burying and forced swimming behavior have strong predictive validity in tests of antidepressant action, each assay appears to be underpinned by entirely different neurochemical systems.
Kobayashi
Tomohiro
T
Department of Pharmacology, Tsukuba Research Laboratories, High Throughput Biology, Discovery Research, GlaxoSmithKline, 43 Wadai, Tsukuba, Ibaraki 300-4247, Japan. Tomohiro_Kobayashi2@nts.toray.co.jp
Hayashi
Etsuko
E
Shimamura
Midori
M
Kinoshita
Mine
M
Murphy
Niall P
NP
D000818:Animals; D000928:Antidepressive Agents / Q000494:pharmacology*; D001007:Anxiety / Q000503:physiopathology* / Q000523:psychology*; D001522:Behavior, Animal / Q000187:drug effects* / Q000502:physiology*; D003863:Depression / Q000503:physiopathology* / Q000523:psychology*; D004195:Disease Models, Animal; D004298:Dopamine / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004353:Drug Evaluation, Preclinical; D006380:Helplessness, Learned; D008297:Male; D051379:Mice; D009042:Motivation; D009043:Motor Activity / Q000187:drug effects; D018377:Neurotransmitter Agents / Q000378:metabolism*; D009638:Norepinephrine / Q000378:metabolism; D017397:Prefrontal Cortex / Q000187:drug effects* / Q000503:physiopathology; D012701:Serotonin / Q000378:metabolism; D013223:Statistics as Topic; D013239:Stereotyped Behavior / Q000187:drug effects / Q000502:physiology; D013550:Swimming
D000928:Antidepressive Agents; D018377:Neurotransmitter Agents; D012701:Serotonin; D004298:Dopamine; D009638:Norepinephrine