title: Adjunctive treatment with asenapine augments the escitalopram-induced effects on monoaminergic outflow and glutamatergic neurotransmission in the medial prefrontal cortex of the rat.
abstract: BACKGROUND
  Substantial clinical data support the addition of low doses of atypical antipsychotic drugs to selective serotonin reuptake inhibitors (SSRIs) to rapidly enhance the antidepressant effect in treatment-resistant depression. Preclinical studies suggest that this effect is at least partly explained by an increased catecholamine outflow in the medial prefrontal cortex (mPFC).
  
  
  METHODS
  In the present study we used in vivo microdialysis in freely moving rats and in vitro intracellular recordings of pyramidal cells of the rat mPFC to investigate the effects of adding the novel atypical antipsychotic drug asenapine to the SSRI escitalopram with regards to monoamine outflow in the mPFC and dopamine outflow in nucleus accumbens as well as glutamatergic transmission in the mPFC.
  
  
  RESULTS
  The present study shows that addition of low doses (0.05 and 0.1 mg/kg) of asenapine to escitalopram (5 mg/kg) markedly enhances dopamine, noradrenaline, and serotonin release in the rat mPFC as well as dopamine release in the nucleus accumbens. Moreover, this drug combination facilitated both N-methyl-d-Aspartate (NMDA)- and α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)-induced currents as well as electrically evoked excitatory postsynaptic potentials in pyramidal cells of the rat mPFC.
  
  
  CONCLUSIONS
  Our results support the notion that the augmentation of SSRIs by atypical antipsychotic drugs in treatment-resistant depression may, at least in part, be related to enhanced catecholamine output in the prefrontal cortex and that asenapine may be clinically used to achieve this end. In particular, the subsequent activation of the D1 receptor may be of importance for the augmented antidepressant effect, as this mechanism facilitated both NMDA and AMPA receptor-mediated transmission in the mPFC. Our novel observation that the drug combination, like ketamine, facilitates glutamatergic transmission in the mPFC may contribute to explain the rapid and potent antidepressant effect obtained when atypical antipsychotic drugs are added to SSRIs.
authors.affiliation: Department of Physiology and Pharmacology, Section of Neuropsychopharmacology, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Carl
authors.initials: C
authors.lastname: Björkholm
authors.affiliation: Department of Physiology and Pharmacology, Section of Neuropsychopharmacology, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Olivia
authors.initials: O
authors.lastname: Frånberg
authors.affiliation: Department of Physiology and Pharmacology, Section of Neuropsychopharmacology, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Anna
authors.initials: A
authors.lastname: Malmerfelt
authors.affiliation: Department of Physiology and Pharmacology, Section of Neuropsychopharmacology, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Monica M
authors.initials: MM
authors.lastname: Marcus
authors.affiliation: Department of Physiology and Pharmacology, Section of Neuropsychopharmacology, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Åsa
authors.initials: Å
authors.lastname: Konradsson-Geuken
authors.affiliation: Department of Physiology and Pharmacology, Section of Neuropsychopharmacology, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Björn
authors.initials: B
authors.lastname: Schilström
authors.affiliation: Department of Physiology and Pharmacology, Section of Neuropsychopharmacology, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Kent
authors.initials: K
authors.lastname: Jardemark
authors.affiliation: Department of Physiology and Pharmacology, Section of Neuropsychopharmacology, Karolinska Institutet, Stockholm, Sweden. torgny.svensson@ki.se.
authors.forename: Torgny H
authors.initials: TH
authors.lastname: Svensson
mesh_terms: D000818:Animals; D014150:Antipsychotic Agents / Q000494:pharmacology*; D001552:Benzazepines / Q000494:pharmacology; D001640:Bicuculline / Q000494:pharmacology; D015306:Biogenic Monoamines / Q000378:metabolism*; D015283:Citalopram / Q000494:pharmacology*; D003986:Dibenzocycloheptenes; D018492:Dopamine Antagonists / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D018683:Excitatory Amino Acid Agents / Q000494:pharmacology; D019706:Excitatory Postsynaptic Potentials / Q000187:drug effects; D058787:GABA-A Receptor Antagonists / Q000494:pharmacology; D018698:Glutamic Acid / Q000378:metabolism*; D006576:Heterocyclic Compounds, 4 or More Rings / Q000494:pharmacology*; D008297:Male; D009474:Neurons / Q000187:drug effects; D017397:Prefrontal Cortex / Q000166:cytology / Q000187:drug effects*; D051381:Rats; D017208:Rats, Wistar; D017367:Selective Serotonin Reuptake Inhibitors / Q000494:pharmacology*; D009435:Synaptic Transmission / Q000187:drug effects*; D013997:Time Factors
chemical_list: D014150:Antipsychotic Agents; D001552:Benzazepines; D001640:Bicuculline; D015306:Biogenic Monoamines; D015283:Citalopram; D003986:Dibenzocycloheptenes; D018492:Dopamine Antagonists; D018683:Excitatory Amino Acid Agents; D058787:GABA-A Receptor Antagonists; D018698:Glutamic Acid; D006576:Heterocyclic Compounds, 4 or More Rings; D017367:Selective Serotonin Reuptake Inhibitors; C534628:SCH 23390; C522667:asenapine
keywords: atypical antipsychotics; depression; dopamine-glutamate interactions; prefrontal cortex; selective serotonin reuptake inhibitor