Behavioral and pharmacological validation of the gerbil forced-swim test: effects of neurokinin-1 receptor antagonists.
Several studies have suggested that neurokinin-1 (NK1) receptor antagonists may have therapeutic potential as novel antidepressant drugs. To test these compounds preclinically, gerbils have become one of the preferred species in that they demonstrate close NK1 receptor homology with humans and bind NK1 antagonists with higher affinity than rats and mice. The intent of the present study was to determine whether the forced-swim test (FST), one of the most commonly used animal tests of antidepressant-like activity, could be adapted for use with the gerbil. Critical factors in the establishment of this assay included swim tank diameter, weight, and sex of the animals tested. Pharmacological validation of the FST using standard antidepressant compounds (eg fluoxetine, paroxetine, desipramine) resulted in decreased immobility time during the test, indicative of an antidepressant-like effect. Similar to results reported for the rat and mouse FST, the antipsychotic drug haloperidol increased immobility, whereas the psychostimulant, amphetamine decreased immobility, and anxiolytic drugs (eg buspirone) had no effect. Investigation into the locomotor effects of all compounds tested was consistent with previous reports in other species, with the exception of paroxetine, which produced hyperactivity at therapeutically effective doses in gerbils. In addition to standard antidepressants, NK1 antagonists (L-733060, MK-869, and CP-122721) all reduced immobility in the gerbil FST without affecting locomotor activity. Overall, these results suggest that the gerbil is an ideal species for use in the FST, and that this paradigm may have predictive validity for identifying novel antidepressant compounds.
Wallace-Boone
Tanya L
TL
Neuroscience Drug Discovery, Bristol-Myers Squibb Pharmaceutical Research Institute, Wallingford, CT, USA. tanya.wallace.tw1@roche.com
Newton
Amy E
AE
Wright
Robert N
RN
Lodge
Nicholas J
NJ
McElroy
John F
JF
D018759:Adrenergic Uptake Inhibitors / Q000627:therapeutic use; D000661:Amphetamine / Q000627:therapeutic use; D000818:Animals; D000928:Antidepressive Agents / Q000627:therapeutic use*; D018687:Antidepressive Agents, Second-Generation / Q000627:therapeutic use; D000929:Antidepressive Agents, Tricyclic / Q000627:therapeutic use; D014150:Antipsychotic Agents / Q000494:pharmacology; D001835:Body Weight / Q000187:drug effects; D000697:Central Nervous System Stimulants / Q000627:therapeutic use; D003627:Data Interpretation, Statistical; D003866:Depressive Disorder / Q000188:drug therapy* / Q000523:psychology*; D005260:Female; D005849:Gerbillinae; D008297:Male; D009043:Motor Activity / Q000187:drug effects; D064729:Neurokinin-1 Receptor Antagonists; D015203:Reproducibility of Results; D017367:Selective Serotonin Reuptake Inhibitors / Q000627:therapeutic use; D012727:Sex Characteristics; D013550:Swimming / Q000523:psychology*
D018759:Adrenergic Uptake Inhibitors; D000661:Amphetamine; D000928:Antidepressive Agents; D018687:Antidepressive Agents, Second-Generation; D000929:Antidepressive Agents, Tricyclic; D014150:Antipsychotic Agents; D000697:Central Nervous System Stimulants; D064729:Neurokinin-1 Receptor Antagonists; D017367:Selective Serotonin Reuptake Inhibitors