Asenapine, a novel psychopharmacologic agent: preclinical evidence for clinical effects in schizophrenia
Asenapine is a novel psychopharmacologic agent being developed for the treatment of schizophrenia and bipolar disorder.
Materials and 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.
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.
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.
KeywordsAsenapine Schizophrenia Rat Microdialysis CAR Catalepsy Voltammetry Electrophysiology Dopamine Glutamate
This research was supported by the Swedish Research Council (grant no. 4747), the Karolinska Institutet, Organon Laboratories and Pfizer. Drs. Kent Jardemark and Björn Schilström were supported by grants from the Scandinavian College of Neuro-Psychopharmacology and the Lundbeck Foundation. We thank Dr. Marie-Louise Wadenberg for valuable discussions and Mrs. Anna Malmerfelt and Mrs. Ann-Chatrine Samuelsson for skillful technical assistance.
All experiments were approved by, and conducted in accordance with, the local Animal Ethics Committee, Stockholm North, and the Karolinska Institutet, Sweden.
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