Agomelatine in the tree shrew model of depression: effects on stress-induced nocturnal hyperthermia and hormonal status

Eur Neuropsychopharmacol. 2014 Mar;24(3):437-47. doi: 10.1016/j.euroneuro.2013.07.010. Epub 2013 Aug 2.

Abstract

The antidepressive drug agomelatine combines the properties of an agonist of melatonergic receptors 1 and 2 with an antagonist of the 5-HT2C receptor. We analyzed the effects of agomelatine in psychosocially stressed male tree shrews, an established preclinical model of depression. Tree shrews experienced daily social stress for a period of 5 weeks and were concomitantly treated with different drugs daily for 4 weeks. The effects of agomelatine (40 mg/kg/day) were compared with those of the agonist melatonin (40 mg/kg/day), the inverse 5-HT2C antagonist S32006 (10mg/kg/day), and the SSRI fluoxetine (15 mg/kg/day). Nocturnal core body temperature (CBT) was recorded by telemetry, and urinary norepinephrine and cortisol concentrations were measured. Chronic social stress induced nocturnal hyperthermia. Agomelatine normalized the CBT in the fourth week of the treatment (T4), whereas the other drugs did not significantly counteract the stress-induced hyperthermia. Agomelatine also reversed the stress-induced reduction in locomotor activity. Norepinephrine concentration was elevated by the stress indicating sympathetic hyperactivity, and was normalized in the stressed animals treated with agomelatine or fluoxetine but not in those treated with melatonin or S32006. Cortisol concentration was elevated by stress but returned to basal levels by T4 in all animals, irrespective of the treatment. These observations show that agomelatine has positive effects to counteract stress-induced physiological processes and to restore the normal rhythm of nocturnal CBT. The data underpin the antidepressant properties of agomelatine and are consistent with a distinctive profile compared to its constituent pharmacological components and other conventional agents.

Keywords: Cortisol; Fluoxetine; Melatonin; Norepinephrine; S32006; Telemetry.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acetamides / pharmacology*
  • Animals
  • Antidepressive Agents / pharmacology*
  • Antidepressive Agents, Second-Generation / pharmacology
  • Body Temperature / drug effects
  • Body Weight / drug effects
  • Central Nervous System Depressants / pharmacology
  • Circadian Rhythm / drug effects
  • Depressive Disorder / drug therapy*
  • Depressive Disorder / physiopathology*
  • Fever / drug therapy*
  • Fever / physiopathology
  • Fluoxetine / pharmacology
  • Hydrocortisone / urine
  • Indoles / pharmacology
  • Male
  • Melatonin / pharmacology
  • Motor Activity / drug effects
  • Norepinephrine / urine
  • Pyridines / pharmacology
  • Serotonin 5-HT2 Receptor Antagonists / pharmacology
  • Stress, Psychological / drug therapy*
  • Stress, Psychological / physiopathology
  • Tupaiidae

Substances

  • Acetamides
  • Antidepressive Agents
  • Antidepressive Agents, Second-Generation
  • Central Nervous System Depressants
  • Indoles
  • Pyridines
  • S32006
  • Serotonin 5-HT2 Receptor Antagonists
  • Fluoxetine
  • S 20098
  • Melatonin
  • Hydrocortisone
  • Norepinephrine