Electrophysiological characterization of the effects of asenapine at 5-HT(1A), 5-HT(2A), alpha(2)-adrenergic and D(2) receptors in the rat brain.
Asenapine is a psychopharmacologic agent being developed for schizophrenia and bipolar disorder. This study electrophysiologically characterized the in vivo effects of asenapine at dorsal raphe nucleus (DRN) and hippocampus serotonin-1A (5-HT(1A)), ventral tegmental area D(2), locus coeruleus 5-HT(2A,) and alpha(2)-adrenergic receptors in anesthetized rats. Asenapine displayed potent antagonistic activity at alpha(2)-adrenoceptors (ED(50), 85+/-2 microg/kg), 5-HT(2A) (ED(50), 75+/-2 microg/kg) and D(2) receptors (ED(50), 40+/-2 microg/kg) as evidenced by its reversal of clonidine-, DOI-, and apomorphine-induced inhibition of norepinephrine and dopamine neurons. In contrast, asenapine acted as a partial agonist at 5-HT(1A) receptors in DRN and hippocampus, as indicated by blockade of its inhibitory effect on neuronal firing by the 5-HT(1A) antagonist WAY 100635 and the partial inhibition of the suppressant action of 5-HT when co-applied by microiontophoresis. These results confirm that asenapine displays potent antagonistic activity at 5-HT(2A), D(2), alpha(2)-adrenergic receptors and provide evidence to support its 5-HT(1A) partial agonistic activity.
Ghanbari
Ramez
R
University of Ottawa Institute of Mental Health Research, 1145 Carling Avenue, Ottawa, Ontario K1Z7K4, Canada. ramez.ghanbari@rohcg.on.ca
El Mansari
Mostafa
M
Shahid
Mohammed
M
Blier
Pierre
P
D017371:8-Hydroxy-2-(di-n-propylamino)tetralin / Q000494:pharmacology; D000200:Action Potentials / Q000187:drug effects; D058647:Adrenergic alpha-2 Receptor Agonists; D000662:Amphetamines / Q000494:pharmacology; D000818:Animals; D001058:Apomorphine / Q000494:pharmacology; D001921:Brain / Q000166:cytology*; D003000:Clonidine / Q000494:pharmacology; D003986:Dibenzocycloheptenes; D004305:Dose-Response Relationship, Drug; D006576:Heterocyclic Compounds, 4 or More Rings / Q000494:pharmacology*; D008297:Male; D009474:Neurons / Q000187:drug effects* / Q000502:physiology; D051381:Rats; D017207:Rats, Sprague-Dawley; D044282:Receptor, Serotonin, 5-HT1A / Q000502:physiology*; D044402:Receptor, Serotonin, 5-HT2A / Q000502:physiology*; D018341:Receptors, Adrenergic, alpha-2 / Q000502:physiology*; D017448:Receptors, Dopamine D2 / Q000819:agonists; D058825:Serotonin 5-HT1 Receptor Agonists; D058826:Serotonin 5-HT2 Receptor Agonists
C547770:Adra2a protein, rat; D058647:Adrenergic alpha-2 Receptor Agonists; D000662:Amphetamines; D003986:Dibenzocycloheptenes; D006576:Heterocyclic Compounds, 4 or More Rings; D044402:Receptor, Serotonin, 5-HT2A; D018341:Receptors, Adrenergic, alpha-2; D017448:Receptors, Dopamine D2; D058825:Serotonin 5-HT1 Receptor Agonists; D058826:Serotonin 5-HT2 Receptor Agonists; D044282:Receptor, Serotonin, 5-HT1A; D017371:8-Hydroxy-2-(di-n-propylamino)tetralin; C522667:asenapine; D003000:Clonidine; D001058:Apomorphine; C015952:4-iodo-2,5-dimethoxyphenylisopropylamine