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Pharmacological profile of encounter-induced hyperactivity in isolation-reared mice
Shigeru Hasebe1, Yukio Ago, Saki Nishiyama
1aLaboratory of Medicinal Pharmacology bLaboratory of Molecular Neuropharmacology ciPS Cell-based Research Project on Brain Neuropharmacology and Toxicology, Graduate School of Pharmaceutical Sciences dUnited Graduate School of Child Development, Osaka University, Kanazawa University, Hamamatsu University School of Medicine, Chiba University and University of Fukui eDepartment of Pharmacology, Graduate School of Dentistry, Osaka University, Osaka, Japan.
Insights
Isolation-reared mice exhibit hyperactivity, which can be reduced by antidepressants and other drugs. This hyperactivity model shows a key role for alpha2 and 5-HT4 receptors in antidepressant effects.
Area of Science:
- Neuroscience
- Pharmacology
- Behavioral Science
Background:
- Isolation rearing in mice induces hyperactivity during intruder encounters.
- The potential of this hyperactivity as a model for psychiatric disorders is unexplored.
Purpose of the Study:
- To investigate the pharmacological profile of encounter-induced hyperactivity in isolation-reared mice.
- To determine if this model can be used for testing antidepressant efficacy.
Main Methods:
- Acute administration of various antidepressants and other drugs to isolation-reared mice.
- Assessment of drug effects on encounter-induced hyperactivity.
- Pharmacological blockade of specific receptor systems to elucidate mechanisms.
Main Results:
- Encounter-induced hyperactivity was significantly reduced by antidepressants (desipramine, fluvoxamine, paroxetine, venlafaxine, duloxetine), the antipsychotic risperidone, and other agents.
- Alpha2 adrenoceptor and 5-HT4 receptor agonists also reduced hyperactivity.
- The effects of desipramine and fluvoxamine were mediated by alpha2 and 5-HT4 receptors, respectively.
- Venlafaxine's effect involved both alpha2 and 5-HT4 receptor pathways.
Conclusions:
- Encounter-induced hyperactivity in isolation-reared mice serves as a valid model for evaluating antidepressant pharmacology.
- The model highlights the critical involvement of alpha2 and 5-HT4 receptors in mediating antidepressant-like effects.
- Further research is needed to explore the full therapeutic potential and limitations of this model.
Abstract:
We have recently found that isolation-reared mice show hyperactivity during an encounter with an intruder. However, it is not known whether encounter-induced hyperactivity may model some aspects of psychiatric disorders. The present study examined the pharmacological profile of encounter-induced hyperactivity in isolation-reared mice. Encounter-induced hyperactivity was reduced by acute administration of various antidepressants including the tricyclic antidepressant desipramine (10 mg/kg), the selective serotonin (5-HT) reuptake inhibitors fluvoxamine (10 mg/kg) and paroxetine (10 mg/kg), the 5-HT/noradrenaline reuptake inhibitors venlafaxine (10 mg/kg) and duloxetine (10 mg/kg), the antipsychotic drug risperidone (0.01 mg/kg), the 5-HT2 antagonist ritanserin (1 mg/kg), and the glucocorticoid receptor antagonist RU-43044 (30 mg/kg). The α2 adrenoceptor agonist clonidine (0.03 mg/kg) and the 5-HT4 receptor agonist BIMU8 (30 mg/kg) also reduced encounter-induced hyperactivity. The effect of desipramine was blocked by the α2 adrenoceptor antagonist idazoxan (0.3 mg/kg). The effect of fluvoxamine was blocked by the 5-HT4 receptor antagonist GR125487 (3 mg/kg), but not the 5-HT1A receptor antagonist WAY100635 (1 mg/kg), the 5-HT3 receptor antagonist azasetron (3 mg/kg), or the 5-HT6 receptor antagonist SB399885 (3 mg/kg). The effect of venlafaxine was blocked by the simultaneous administration of idazoxan (0.3 mg/kg) and GR125487 (3 mg/kg), but not by either compound alone. These findings suggest that encounter-induced hyperactivity in isolation-reared mice is a robust model for testing the pharmacological profile of antidepressants, although the range of antidepressants tested is limited and some non-antidepressants are also effective. The present study also shows a key role of α2 and 5-HT4 receptors in the antidepressant effect in this model.
