The drug-induced helplessness test: an animal assay for assessing behavioral despair in response to neuroleptic treatment.
BACKGROUND
Neuroleptic dysphoria encompasses a range of unpleasant subjective responses and, as a result, is difficult to study in preclinical animal models.


OBJECTIVE
Based on the learned helplessness model of depression, increases in escape failures (EFs) in the drug-induced helplessness test (DH) are proposed to reflect drug-induced depressive-like state, a contributing factor to neuroleptic dysphoria in humans.


METHODS
Effects of the typical antipsychotic haloperidol and the atypical antipsychotics risperidone, olanzapine, aripiprazole, quetiapine, and clozapine were investigated in the DH test. We further characterized this test by examining compounds affecting motor function, cognition, anxiety, and those with antidepressant activity.


RESULTS
The antipsychotics haloperidol, risperidone, aripiprazole, and olanzapine, all increased EFs, while quetiapine had no effect, and clozapine reduced EFs. Amphetamine, diazepam, and ciproxifan, had no effect on EFs. Scopolamine significantly reduced EFs and MK-801 showed a trend toward reducing EFs at doses not significantly sti mulating locomotor activity. Subchronic, but not acute, imipramine and subchronic fluoxetine significantly reduced EFs at doses significantly suppressing locomotor activity. Dissociation appears to exist between performance in the DH test and compound effects on catalepsy or locomotor activity.


CONCLUSIONS
After discussing potential alternative interpretations of the drug-induced changes of EFs, we propose the DH test as a useful test for assessing a drug-induced, depressive-like state that may contribute to neuroleptic dysphoria.
Ballard
Michael E
ME
Neuroscience Research, Global Pharmaceutical Research and Development, Abbott Laboratories, Abbott Park, IL 60064, USA.
Basso
Ana M
AM
Gallagher
Kelly B
KB
Browman
Kaitlin E
KE
Fox
Gerard B
GB
Drescher
Karla U
KU
Gross
Gerhard
G
Decker
Michael W
MW
Rueter
Lynne E
LE
Zhang
Min
M
D000339:Affect / Q000187:drug effects*; D000818:Animals; D000928:Antidepressive Agents / Q000494:pharmacology*; D014150:Antipsychotic Agents / Q000037:antagonists & inhibitors / Q000633:toxicity*; D001143:Arousal / Q000187:drug effects; D001362:Avoidance Learning / Q000187:drug effects; D001364:Awareness / Q000187:drug effects; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004924:Escape Reaction / Q000187:drug effects*; D006380:Helplessness, Learned; D006801:Humans; D008297:Male; D009042:Motivation; D009043:Motor Activity / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D011930:Reaction Time / Q000187:drug effects
D000928:Antidepressive Agents; D014150:Antipsychotic Agents