title: Quetiapine ameliorates stress-induced cognitive inflexibility in rats.
abstract: The antidepressant action of quetiapine has been demonstrated in clinical and preclinical studies. Nevertheless, little is known about its effectiveness in the treatment of frontal-like cognitive disturbances that may be associated with stress-related disorder. Therefore, the aim of the present study was to investigate whether quetiapine would prevent and/or reverse stress-induced cognitive impairments in a rat model of prefrontal cortex (PFC)-dependent attentional set-shifting task (ASST). Because quetiapine augmentation to selective serotonin reuptake inhibitors (SSRIs) has recently been proven to be beneficial in neuropsychiatric disorders, a separate experiment was designed to assess the impact of combined administration of inactive doses of quetiapine and escitalopram on ASST performance in rats. According to our previous studies, 1 h daily exposure to restraint stress for 7 days significantly and specifically impaired extra-dimensional (ED) set-shifting ability of rats. Quetiapine (2.5 mg/kg, PO) given to rats prior to the restraint sessions completely prevented this stress-induced cognitive inflexibility. Similar effect was demonstrated after pretreatment with the α1-adrenoceptor antagonist, prazosin (1 mg/kg, IP). Moreover, acute administration of quetiapine before the test reversed set-shifting deficits in stressed rats (0.63, 1.25 and 2.5 mg/kg, PO) and improved ED performance of cognitively unimpaired control animals (1.25 and 2.5 mg/kg, PO). Finally, the combined administration of inactive doses of quetiapine (0.63 and 0.3 mg/kg in control and stressed rats, respectively) and escitalopram (0.3 mg/kg, IP) facilitated set-shifting performance in either control or stressed rats. In conclusion, quetiapine administration either prevented or reversed stress-induced cognitive inflexibility in rats. In addition to promoting of set-shifting by itself, quetiapine also enhanced the procognitive efficacy of escitalopram. The potential contribution of the antagonism at α1-adrenoceptors to the mechanisms underlying the protective action of quetiapine requires further evaluation. These findings may have therapeutic implications for the treatment of frontal-like disturbances, particularly cognitive inflexibility, in stress-related psychiatric disorders. This article is part of a Special Issue entitled 'Cognitive Enhancers'.
authors: Department of Behavioral Neuroscience and Drug Development, Institute of Pharmacology, Polish Academy of Sciences, Kraków, Poland. nikifor@if-pan.krakow.pl
authors: Agnieszka
authors: A
authors: Nikiforuk
mesh_terms: D058668:Adrenergic alpha-1 Receptor Antagonists / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D000818:Animals; D018687:Antidepressive Agents, Second-Generation / Q000627:therapeutic use; D001522:Behavior, Animal / Q000187:drug effects; D015283:Citalopram / Q000627:therapeutic use; D003072:Cognition Disorders / Q000188:drug therapy / Q000209:etiology / Q000517:prevention & control*; D003987:Dibenzothiazepines / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004357:Drug Synergism; D004359:Drug Therapy, Combination; D008297:Male; D009474:Neurons / Q000187:drug effects / Q000378:metabolism; D018697:Nootropic Agents / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D058573:Performance-Enhancing Substances / Q000494:pharmacology; D017397:Prefrontal Cortex / Q000187:drug effects / Q000378:metabolism; D000069348:Quetiapine Fumarate; D051381:Rats; D017207:Rats, Sprague-Dawley; D012149:Restraint, Physical; D017367:Selective Serotonin Reuptake Inhibitors / Q000627:therapeutic use; D013312:Stress, Physiological; D013315:Stress, Psychological / Q000503:physiopathology*
chemical_list: D058668:Adrenergic alpha-1 Receptor Antagonists; D018687:Antidepressive Agents, Second-Generation; D015283:Citalopram; D003987:Dibenzothiazepines; D018697:Nootropic Agents; D058573:Performance-Enhancing Substances; D000069348:Quetiapine Fumarate; D017367:Selective Serotonin Reuptake Inhibitors