Asenapine effects in animal models of psychosis and cognitive function.
BACKGROUND
Asenapine, a novel psychopharmacologic agent in the development for schizophrenia and bipolar disorder, has high affinity for serotonergic, alpha-adrenergic, and dopaminergic receptors, suggesting potential for antipsychotic and cognitive-enhancing properties.


OBJECTIVE
The effects of asenapine in rat models of antipsychotic efficacy and cognition were examined and compared with those of olanzapine and risperidone.


METHODS
Amphetamine-stimulated locomotor activity (Amp-LMA; 1.0 or 3.0 mg/kg s.c.) and apomorphine-disrupted prepulse inhibition (Apo-PPI; 0.5 mg/kg s.c.) were used as tests for antipsychotic activity. Delayed non-match to place (DNMTP) and five-choice serial reaction (5-CSR) tasks were used to assess short-term spatial memory and attention, respectively. Asenapine doses varied across tasks: Amp-LMA (0.01-0.3 mg/kg s.c.), Apo-PPI (0.001-0.3 mg/kg s.c.), DNMTP (0.01-0.1 mg/kg s.c.), and 5-CSR (0.003-0.3 mg/kg s.c.).


RESULTS
Asenapine was highly potent (active at 0.03 mg/kg) in the Amp-LMA and Apo-PPI assays. DNMTP or 5-CSR performance was not improved by asenapine, olanzapine, or risperidone. All agents (P < 0.01) reduced DNMTP accuracy at short delays; post hoc analyses revealed that only 0.1 mg/kg asenapine and 0.3 mg/kg risperidone differed from vehicle. All active agents (asenapine, 0.3 mg/kg; olanzapine, 0.03-0.3 mg/kg; and risperidone, 0.01-0.1 mg/kg) significantly impaired 5-CSR accuracy (P < 0.05).


CONCLUSIONS
Asenapine has potent antidopaminergic properties that are predictive of antipsychotic efficacy. Asenapine, like risperidone and olanzapine, did not improve cognition in normal rats. Rather, at doses greater than those required for antipsychotic activity, asenapine impaired cognitive performance due to disturbance of motor function, an effect also observed with olanzapine and risperidone.
Marston
Hugh M
HM
Schering-Plough Research Institute, Newhouse, Lanarkshire, UK. hugh.marston@spcorp.com
Young
Jared W
JW
Martin
Frederic D C
FD
Serpa
Kevin A
KA
Moore
Christopher L
CL
Wong
Erik H F
EH
Gold
Lisa
L
Meltzer
Leonard T
LT
Azar
Marc R
MR
Geyer
Mark A
MA
Shahid
Mohammed
M
D000661:Amphetamine / Q000633:toxicity; D000818:Animals; D014150:Antipsychotic Agents / Q000008:administration & dosage / Q000494:pharmacology*; D001058:Apomorphine / Q000633:toxicity; D001288:Attention / Q000187:drug effects; D001569:Benzodiazepines / Q000008:administration & dosage / Q000494:pharmacology; D003071:Cognition / Q000187:drug effects*; D003986:Dibenzocycloheptenes; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D006576:Heterocyclic Compounds, 4 or More Rings / Q000008:administration & dosage / Q000494:pharmacology*; D008297:Male; D000077152:Olanzapine; D011618:Psychotic Disorders / Q000188:drug therapy* / Q000503:physiopathology; D051381:Rats; D017207:Rats, Sprague-Dawley; D018967:Risperidone / Q000008:administration & dosage / Q000494:pharmacology
D014150:Antipsychotic Agents; D003986:Dibenzocycloheptenes; D006576:Heterocyclic Compounds, 4 or More Rings; D001569:Benzodiazepines; D000661:Amphetamine; C522667:asenapine; D018967:Risperidone; D001058:Apomorphine; D000077152:Olanzapine