title: Quetiapine and its metabolite norquetiapine: translation from in vitro pharmacology to in vivo efficacy in rodent models.
abstract: OBJECTIVE
  Quetiapine has a range of clinical activity distinct from other atypical antipsychotic drugs, demonstrating efficacy as monotherapy in bipolar depression, major depressive disorder and generalized anxiety disorder. The neuropharmacological mechanisms underlying this clinical profile are not completely understood; however, the major active metabolite, norquetiapine, has been shown to have a distinct in vitro pharmacological profile consistent with a broad therapeutic range and may contribute to the clinical profile of quetiapine.
  
  
  METHODS
  We evaluated quetiapine and norquetiapine, using in vitro binding and functional assays of targets known to be associated with antidepressant and anxiolytic drug actions and compared these activities with a representative range of established antipsychotics and antidepressants. To determine how the in vitro pharmacological properties translate into in vivo activity, we used preclinical animal models with translational relevance to established antidepressant-like and anxiolytic-like drug action.
  
  
  RESULTS
  Norquetiapine had equivalent activity to established antidepressants at the noradrenaline transporter (NET), while quetiapine was inactive. Norquetiapine was active in the mouse forced swimming and rat learned helplessness tests. In in vivo receptor occupancy studies, norquetiapine had significant occupancy at NET at behaviourally relevant doses. Both quetiapine and norquetiapine were agonists at 5-HT1A receptors, and the anxiolytic-like activity of norquetiapine in rat punished responding was blocked by the 5-HT1A antagonist, WAY100635.
  
  
  CONCLUSIONS
  Quetiapine and norquetiapine have multiple in vitro pharmacological actions, and results from preclinical studies suggest that activity at NET and 5-HT1A receptors contributes to the antidepressant and anxiolytic effects in patients treated with quetiapine.
authors.affiliation: AstraZeneca Neuroscience Innovative Medicines, Cambridge, MA, USA.
authors.forename: A J
authors.initials: AJ
authors.lastname: Cross
authors.affiliation: AstraZeneca Neuroscience Innovative Medicines, Cambridge, MA, USA.
authors.forename: D
authors.initials: D
authors.lastname: Widzowski
authors.affiliation: AstraZeneca Neuroscience Innovative Medicines, Cambridge, MA, USA.
authors.forename: C
authors.initials: C
authors.lastname: Maciag
authors.affiliation: AstraZeneca Neuroscience Innovative Medicines, Cambridge, MA, USA.
authors.forename: A
authors.initials: A
authors.lastname: Zacco
authors.affiliation: AstraZeneca Neuroscience Innovative Medicines, Cambridge, MA, USA.
authors.forename: T
authors.initials: T
authors.lastname: Hudzik
authors.affiliation: AstraZeneca R&D, Shanghai, China.
authors.forename: J
authors.initials: J
authors.lastname: Liu
authors.affiliation: AstraZeneca R&D, Södertälje, Sweden.
authors.forename: S
authors.initials: S
authors.lastname: Nyberg
authors.affiliation: AstraZeneca Neuroscience Innovative Medicines, Cambridge, MA, USA.
authors.forename: M W
authors.initials: MW
authors.lastname: Wood
mesh_terms: D000818:Animals; D014151:Anti-Anxiety Agents / Q000494:pharmacology*; D000928:Antidepressive Agents / Q000494:pharmacology*; D003216:Conditioning, Operant / Q000187:drug effects; D003987:Dibenzothiazepines / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D004195:Disease Models, Animal; D006380:Helplessness, Learned; D006801:Humans; D046353:Immobility Response, Tonic / Q000187:drug effects; D008297:Male; D051379:Mice; D050484:Norepinephrine Plasma Membrane Transport Proteins / Q000378:metabolism; D010879:Piperazines / Q000494:pharmacology; D011678:Punishment; D011725:Pyridines / Q000494:pharmacology; D000069348:Quetiapine Fumarate / Q000494:pharmacology*; D011869:Radioligand Assay; D051381:Rats; D058825:Serotonin 5-HT1 Receptor Agonists / Q000494:pharmacology; D058829:Serotonin 5-HT1 Receptor Antagonists / Q000494:pharmacology
chemical_list: D014151:Anti-Anxiety Agents; D000928:Antidepressive Agents; D003987:Dibenzothiazepines; D050484:Norepinephrine Plasma Membrane Transport Proteins; D010879:Piperazines; D011725:Pyridines; D058825:Serotonin 5-HT1 Receptor Agonists; D058829:Serotonin 5-HT1 Receptor Antagonists; D000069348:Quetiapine Fumarate; C090413:N-(2-(4-(2-methoxyphenyl)-1-piperazinyl)ethyl)-N-(2-pyridinyl)cyclohexanecarboxamide; C572724:norquetiapine