Behavioral pharmacology of olanzapine: a novel antipsychotic drug.
BACKGROUND
In this paper, we review the behavioral pharmacology of olanzapine and compare it to its in vitro profile and to clozapine and a number of other antipsychotic agents, and we estimate the likelihood that olanzapine will be an effective and safe antipsychotic with fewer side effects.


METHODS
Since there is no model of schizophrenia, per se, a battery of behavioral assays was used.


RESULTS
Behavioral assays confirmed the in vitro results that olanzapine interacts with dopamine, serotonin, and muscarinic receptor subtypes. Moreover, olanzapine appears to have a clozapine-like atypical profile based on (1) mesolimbic selectivity, (2) blocking 5-HT receptors at a lower dose than dopamine receptors, and (3) inhibiting the conditioned avoidance response (indicative of antipsychotic efficacy) at doses that are lower than those required to induce catalepsy (indicative of extrapyramidal side effects). No only is this profile similar to that of clozapine, but olanzapine has other similarities: olanzapine substitutes for clozapine in a drug discrimination assay; like clozapine and unlike "typical" antipsychotics, olanzapine increases responding in a conflict procedure; and olanzapine, like clozapine, reverses changes induced by antagonists of the NMDA receptor.


CONCLUSIONS
On the basis of these findings, we predict that olanzapine will be an efficacious antipsychotic, active against both positive and negative symptoms, while producing fewer extrapyramidal symptoms than existing treatments.
Moore
N A
NA
Lilly Research Center Ltd., Eli Lilly and Company, Windlesham, Surrey, United Kingdom.
Leander
J D
JD
Benvenga
M J
MJ
Gleason
S D
SD
Shannon
H
H
D000818:Animals; D014150:Antipsychotic Agents / Q000009:adverse effects / Q000494:pharmacology* / Q000627:therapeutic use; D001362:Avoidance Learning / Q000187:drug effects; D001522:Behavior, Animal / Q000187:drug effects*; D001569:Benzodiazepines; D002626:Chemistry, Pharmaceutical; D003024:Clozapine / Q000494:pharmacology; D003216:Conditioning, Operant / Q000187:drug effects; D018492:Dopamine Antagonists / Q000494:pharmacology; D015195:Drug Design; D006801:Humans; D018782:Maze Learning / Q000187:drug effects; D009043:Motor Activity / Q000187:drug effects; D000077152:Olanzapine; D010622:Phencyclidine / Q000494:pharmacology; D010890:Pirenzepine / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D011950:Receptors, Cholinergic / Q000187:drug effects; D011954:Receptors, Dopamine / Q000187:drug effects; D011985:Receptors, Serotonin / Q000187:drug effects; D012702:Serotonin Antagonists / Q000494:pharmacology
D014150:Antipsychotic Agents; D018492:Dopamine Antagonists; D011950:Receptors, Cholinergic; D011954:Receptors, Dopamine; D011985:Receptors, Serotonin; D012702:Serotonin Antagonists; D001569:Benzodiazepines; D010890:Pirenzepine; D010622:Phencyclidine; D003024:Clozapine; D000077152:Olanzapine