Asenapine, a novel psychopharmacologic agent: preclinical evidence for clinical effects in schizophrenia.
BACKGROUND
Asenapine is a novel psychopharmacologic agent being developed for the treatment of schizophrenia and bipolar disorder.


METHODS
The present study was undertaken to investigate the effects of asenapine using animal models predictive of antipsychotic efficacy (conditioned avoidance response [CAR]) and extrapyramidal side effects (EPS; catalepsy). In parallel, the effects of asenapine on regional dopamine output using in vivo microdialysis in freely moving rats, dopamine output in the core and shell subregions of nucleus accumbens (NAc) using in vivo voltammetry in anesthetized rats, and N-methyl-D: -aspartate (NMDA)-induced currents in pyramidal neurons of the medial prefrontal cortex (mPFC) using the electrophysiological technique intracellular recording in vitro were assessed.


RESULTS
Asenapine (0.05-0.2 mg/kg, subcutaneous [s.c.]) induced a dose-dependent suppression of CAR (no escape failures recorded) and did not induce catalepsy. Asenapine (0.05-0.2 mg/kg, s.c.) increased dopamine efflux in both the mPFC and the NAc. Low-dose asenapine (0.01 mg/kg, intravenous [i.v.]) increased dopamine efflux preferentially in the shell compared to the core of NAc, whereas at a higher dose (0.05 mg/kg, i.v.), the difference disappeared. Finally, like clozapine (100 nM), but at a considerably lower concentration (5 nM), asenapine significantly potentiated the NMDA-induced responses in pyramidal cells of the mPFC.


CONCLUSIONS
These preclinical data suggest that asenapine may exhibit highly potent antipsychotic activity with very low EPS liability. Its ability to increase both dopaminergic and glutamatergic activity in rat mPFC suggests that asenapine may possess an advantageous effect not only on positive symptoms in patients with schizophrenia, but also on negative and cognitive symptoms.
Frånberg
Olivia
O
Department of Physiology and Pharmacology, Karolinska Institutet, Nanna Svartz väg 2, 171 77, Stockholm, Sweden.
Wiker
Charlotte
C
Marcus
Monica M
MM
Konradsson
Asa
A
Jardemark
Kent
K
Schilström
Björn
B
Shahid
Mohammed
M
Wong
Erik H F
EH
Svensson
Torgny H
TH
D000818:Animals; D014150:Antipsychotic Agents / Q000008:administration & dosage / Q000009:adverse effects / Q000494:pharmacology*; D001362:Avoidance Learning; D002375:Catalepsy / Q000139:chemically induced; D003214:Conditioning, Classical; D003986:Dibenzocycloheptenes; D004195:Disease Models, Animal; D004298:Dopamine / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004594:Electrophysiology; D006576:Heterocyclic Compounds, 4 or More Rings / Q000008:administration & dosage / Q000009:adverse effects / Q000494:pharmacology*; D007279:Injections, Subcutaneous; D008297:Male; D017551:Microdialysis; D009714:Nucleus Accumbens / Q000187:drug effects / Q000378:metabolism; D017397:Prefrontal Cortex / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D012559:Schizophrenia / Q000188:drug therapy*
D014150:Antipsychotic Agents; D003986:Dibenzocycloheptenes; D006576:Heterocyclic Compounds, 4 or More Rings; C522667:asenapine; D004298:Dopamine