title: Neuropharmacological modulation of the P3-like event-related potential in a rat two-tone auditory discrimination task with modafinil and NS9283, a positive allosteric modulator of α4β2 nAChRs.
abstract: The P300 (P3) event-related potential (ERP) is a neurophysiological signal believed to reflect cognitive processing of salient cues, and is thus used as a measure of attention and working memory. Additionally, P3 amplitude and latency is altered in neurological diseases and can be pharmacologically modulated. As P3-like ERPs can be recorded in rodents, it may serve as a potential translational biomarker of value for drug discovery. Here we investigated whether a positive allosteric modulator of α4β2 nicotinic acetylcholine receptors, NS9283, and the psychostimulant modafinil could modulate P3-like ERPs in healthy adult rats performing an auditory oddball discrimination task. ERPs were recorded with electroencephalography electrodes implanted into mediodorsal (MD) thalamus, medial prefrontal cortex, hippocampus and auditory cortex (AC). P3-like ERPs were detected in all brain regions, displaying larger amplitudes in target trials compared to non-target trials. Administration of modafinil (64 mg/kg) decreased P3-like ERP latency in MD thalamus and AC, whereas NS9283 augmented P3-like ERP amplitude in MD thalamus at 0.3 mg/kg and in AC at 3.0 mg/kg. Additionally, N1 pre-attention peak amplitude in MD thalamus was increased with 0.3 mg/kg NS9283. Neither of the compounds enhanced task performance. Rather, modafinil lowered correct rejections in non-target trials. In summary, our findings reveal pharmacological modulation of the rat P3-like ERP in cortical and subcortical regions by modafinil and NS9283. These findings encourage further exploration of the rat P3-like ERP in order to promote the understanding of its meaning within cognition, as well as its applicability as a translatable biomarker in drug development.
authors.affiliation: Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, Universitetsparken 2, 2100 Copenhagen, Denmark; Synaptic Transmission 1, H. Lundbeck A/S, Ottiliavej 9, 2500 Valby, Denmark. Electronic address: mortengrupe@gmail.com.
authors.forename: Morten
authors.initials: M
authors.lastname: Grupe
authors.affiliation: Department of Drug Design and Pharmacology, Faculty of Health and Medical Sciences, University of Copenhagen, Universitetsparken 2, 2100 Copenhagen, Denmark; Synaptic Transmission 1, H. Lundbeck A/S, Ottiliavej 9, 2500 Valby, Denmark. Electronic address: mgru@lundbeck.com.
authors.forename: Morten
authors.initials: M
authors.lastname: Grunnet
authors.affiliation: Synaptic Transmission 1, H. Lundbeck A/S, Ottiliavej 9, 2500 Valby, Denmark; Mech-Sense, Department of Gastroenterology, Aalborg University Hospital, Moelleparkvej 4, 9100 Aalborg, Denmark. Electronic address: xbc@lundbeck.com.
authors.forename: Bettina
authors.initials: B
authors.lastname: Laursen
authors.affiliation: Synaptic Transmission 1, H. Lundbeck A/S, Ottiliavej 9, 2500 Valby, Denmark. Electronic address: jfb@lundbeck.com.
authors.forename: Jesper Frank
authors.initials: JF
authors.lastname: Bastlund
mesh_terms: D000161:Acoustic Stimulation; D000818:Animals; D001307:Auditory Perception / Q000187:drug effects* / Q000502:physiology; D001559:Benzhydryl Compounds / Q000494:pharmacology*; D001921:Brain / Q000187:drug effects* / Q000502:physiology; D004192:Discrimination, Psychological / Q000187:drug effects / Q000502:physiology; D004567:Electrodes, Implanted; D004569:Electroencephalography; D005072:Evoked Potentials, Auditory / Q000187:drug effects / Q000502:physiology; D000077408:Modafinil; D009483:Neuropsychological Tests; D018722:Nicotinic Agonists / Q000494:pharmacology*; D010069:Oxadiazoles / Q000494:pharmacology*; D011725:Pyridines / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D011978:Receptors, Nicotinic / Q000378:metabolism; D013647:Task Performance and Analysis; D013997:Time Factors; D064690:Wakefulness-Promoting Agents / Q000494:pharmacology*
chemical_list: C561896:3-(3-(pyridine-3-yl)-1,2,4-oxadiazol-5-yl)benzonitrile; D001559:Benzhydryl Compounds; D018722:Nicotinic Agonists; D010069:Oxadiazoles; D011725:Pyridines; D011978:Receptors, Nicotinic; D064690:Wakefulness-Promoting Agents; C403531:nicotinic receptor alpha4beta2; D000077408:Modafinil
keywords: Alpha4beta2; Event-related potential; Modafinil; NS9283; Nicotinic acetylcholine receptor; Positive allosteric modulator