title: α₄β₂ Nicotinic receptor stimulation of the GABAergic system within the orbitofrontal cortex ameliorates the severe crossmodal object recognition impairment in ketamine-treated rats: implications for cognitive dysfunction in schizophrenia.
abstract: Schizophrenia is associated with atypical multisensory integration. Rats treated sub-chronically with NMDA receptor antagonists to model schizophrenia are severely impaired on a tactile-to-visual crossmodal object recognition (CMOR) task, and this deficit is reversed by systemic nicotine. The current study assessed the receptor specificity of the ameliorative effect of nicotine in the CMOR task, as well as the potential for nicotinic receptor (nAChR) interactions with GABA and glutamate. Male Long-Evans rats were treated sub-chronically for 10 days with ketamine or saline and then tested on the CMOR task after a 10-day washout. Systemic nicotine given before the sample phase of the CMOR task reversed the ketamine-induced impairment, but this effect was blocked by co-administration of the GABAA receptor antagonist bicuculline at a dosage that itself did not cause impairment. Pre-sample systemic co-administration of the NMDA receptor antagonist MK-801 did not block the remediating effect of nicotine in ketamine-treated rats. The selective α7 nAChR agonist GTS-21 and α4β2 nAChR agonist ABT-418 were also tested, with only the latter reversing the ketamine impairment dose-dependently; bicuculline also blocked this effect. Similarly, infusions of nicotine or ABT-418 into the orbitofrontal cortex (OFC) reversed the CMOR impairment in ketamine-treated rats, and systemic bicuculline blocked the effect of intra-OFC ABT-418. These results suggest that nicotine-induced agonism of α4β2 nAChRs within the OFC ameliorates CMOR deficits in ketamine-treated rats via stimulation of the GABAergic system. The findings of this research may have important implications for understanding the nature and potential treatment of cognitive impairment in schizophrenia.
authors.affiliation: Department of Psychology and Collaborative Neuroscience Program, University of Guelph, Guelph, ON N1G 2W1, Canada.
authors.forename: Jacob M
authors.initials: JM
authors.lastname: Cloke
authors.affiliation: Department of Psychology and Collaborative Neuroscience Program, University of Guelph, Guelph, ON N1G 2W1, Canada. Electronic address: bwinters@uoguelph.ca.
authors.forename: Boyer D
authors.initials: BD
authors.lastname: Winters
mesh_terms: D000818:Animals; D004195:Disease Models, Animal; D018698:Glutamic Acid / Q000378:metabolism; D007649:Ketamine; D008297:Male; D009483:Neuropsychological Tests; D017397:Prefrontal Cortex / Q000187:drug effects / Q000503:physiopathology*; D011897:Random Allocation; D020318:Rats, Long-Evans; D011978:Receptors, Nicotinic / Q000378:metabolism*; D021641:Recognition, Psychology / Q000187:drug effects / Q000502:physiology*; D012559:Schizophrenia / Q000503:physiopathology*; D012565:Schizophrenic Psychology; D005680:gamma-Aminobutyric Acid / Q000378:metabolism*
chemical_list: D011978:Receptors, Nicotinic; C403531:nicotinic receptor alpha4beta2; D018698:Glutamic Acid; D005680:gamma-Aminobutyric Acid; D007649:Ketamine
keywords: Cross-modal object recognition; GABA; Multisensory integration; NMDA receptor; Nicotinic receptors; Orbitofrontal cortex