Tonic immobility in guinea pigs: a behavioural response for detecting an anxiolytic-like effect?
Tonic immobility (TI) is considered to be an innate fear response characterized by a temporary state of profound and reversible motor inhibition. TI occurs in a wide range of species in a predator-prey confrontation and is hypothesized to be a terminal defence response occurring when there is physical contact between prey and predator. The objective of the present study was to investigate the validity of the TI model in guinea pigs for detection of anxiolytic and/or antidepressant drug activity. Compounds that reduced TI include the serotonin (5-HT) releaser fenfluramine, the 5-HT(1A) receptor agonists 8-hydroxy-2-(di-n-propylamino)tetralin (8-OH-DPAT) and buspirone, the 5-HT(2C/2B) receptor antagonist SB206553, the 5-HT(2A) receptor antagonist MDL 100.151 -- but only at doses thought also to inhibit 5-HT(2C) receptors--the noradrenaline (NA) reuptake inhibitor desipramine, the benzodiazepine inverse agonist FG-7142, the alpha(2)-adrenergic receptor antagonist yohimbine, the neurokinin (NK)(1) receptor antagonist L-733.060, and the NK(2) receptor antagonist SR-48968. Compounds that increased TI include the benzodiazepine agonists diazepam and alprazolam, and the alpha(2)-adrenergic receptor agonist clonidine. The selective 5-HT reuptake inhibitors citalopram, paroxetine and fluoxetine, the 5-HT(1A) receptor antagonist WAY100.635, the 5-HT(2C) receptor agonist MK-212, the 5-HT/NA reuptake inhibitor imipramine, the NA reuptake inhibitor talopram, the benzodiazepine antagonist flumazenil, the alpha(2)-adrenergic receptor antagonist idazoxan and the psychostimulant amphetamine did not have any effect. These findings indicate that the serotonergic, noradrenergic and neurokinin systems are involved in mediating or modulating TI behaviour in guinea pigs. The potential of TI as a behaviour for detecting anxiolytic-like effect may be questioned due to the contradictory effect of the benzodiazepine ligands, which may be attributed to the sedative and/or ataxic effects of the compounds. Nevertheless, there is preclinical evidence suggesting that 5-HT(1A) receptor agonists, 5-HT(2C) receptor antagonists and NK(1) and NK(2) receptor antagonists possess anxiolytic potential. Only when results of clinical investigations of the anxiolytic potential of non-benzodiazepine ligands (for example the NK receptor antagonists) are available, will it be possible to determine fully the predictive validity of the TI model.
Olsen
C K
CK
Pharmalogical Research, H. Lundbeck A/S, Valby, Copenhagen, Denmark. ckol@lundbeck.com
Hogg
S
S
Lapiz
M D S
MD
D018663:Adrenergic Agents / Q000494:pharmacology; D000818:Animals; D014151:Anti-Anxiety Agents / Q000494:pharmacology*; D001522:Behavior, Animal / Q000187:drug effects* / Q000502:physiology; D018757:GABA Modulators / Q000494:pharmacology; D006168:Guinea Pigs; D007103:Immobilization; D008024:Ligands; D008297:Male; D023421:Models, Animal; D009043:Motor Activity / Q000187:drug effects* / Q000502:physiology; D011619:Psychotropic Drugs / Q000494:pharmacology*; D018040:Receptors, Neurokinin-1 / Q000187:drug effects; D018041:Receptors, Neurokinin-2 / Q000187:drug effects; D012702:Serotonin Antagonists / Q000494:pharmacology; D017366:Serotonin Receptor Agonists / Q000494:pharmacology; D017367:Selective Serotonin Reuptake Inhibitors / Q000494:pharmacology
D018663:Adrenergic Agents; D014151:Anti-Anxiety Agents; D018757:GABA Modulators; D008024:Ligands; D011619:Psychotropic Drugs; D018040:Receptors, Neurokinin-1; D018041:Receptors, Neurokinin-2; D012702:Serotonin Antagonists; D017366:Serotonin Receptor Agonists; D017367:Selective Serotonin Reuptake Inhibitors