title: MK-801 disrupts and nicotine augments 40 Hz auditory steady state responses in the auditory cortex of the urethane-anesthetized rat.
abstract: Patients with schizophrenia show marked deficits in processing sensory inputs including a reduction in the generation and synchronization of 40 Hz gamma oscillations in response to steady-state auditory stimulation. Such deficits are not readily demonstrable at other input frequencies. Acute administration of NMDA antagonists to healthy human subjects or laboratory animals is known to reproduce many sensory and cognitive deficits seen in schizophrenia patients. In the following study, we tested the hypothesis that the NMDA antagonist MK-801 would selectively disrupt steady-state gamma entrainment in the auditory cortex of urethane-anesthetized rat. Moreover, we further hypothesized that nicotinic receptor activation would alleviate this disruption. Auditory steady state responses were recorded in response to auditory stimuli delivered over a range of frequencies (10-80 Hz) and averaged over 50 trials. Evoked power was computed under baseline condition and after vehicle or MK-801 (0.03 mg/kg, iv). MK-801 produced a significant attenuation in response to 40 Hz auditory stimuli while entrainment to other frequencies was not affected. Time-frequency analysis revealed deficits in both power and phase-locking to 40 Hz. Nicotine (0.1 mg/kg, iv) administered after MK-801 reversed the attenuation of the 40 Hz response. Administered alone, nicotine augmented 40 Hz steady state power and phase-locking. Nicotine's effects were blocked by simultaneous administration of the α4β2 antagonist DHßE. Thus we report for the first time, a rodent model that mimics a core neurophysiological deficit seen in patients with schizophrenia and a pharmacological approach to alleviate it.
authors.affiliation: Neuroscience Biology, Bristol Myers Squibb Company, 3CD-422, 5 Research Parkway, Wallingford, CT 06492, USA. siva.digavalli@bms.com
authors.forename: Digavalli V
authors.initials: DV
authors.lastname: Sivarao
authors.forename: Mikhail
authors.initials: M
authors.lastname: Frenkel
authors.forename: Ping
authors.initials: P
authors.lastname: Chen
authors.forename: Francine L
authors.initials: FL
authors.lastname: Healy
authors.forename: Nicholas J
authors.initials: NJ
authors.lastname: Lodge
authors.forename: Robert
authors.initials: R
authors.lastname: Zaczek
mesh_terms: D000161:Acoustic Stimulation; D018686:Anesthetics, Intravenous / Q000494:pharmacology; D000818:Animals; D001303:Auditory Cortex / Q000187:drug effects* / Q000502:physiology; D058256:Brain Waves / Q000187:drug effects* / Q000502:physiology; D004079:Dihydro-beta-Erythroidine / Q000494:pharmacology; D016291:Dizocilpine Maleate / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D005072:Evoked Potentials, Auditory / Q000187:drug effects / Q000502:physiology; D018691:Excitatory Amino Acid Antagonists / Q000494:pharmacology; D008297:Male; D009538:Nicotine / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D018722:Nicotinic Agonists / Q000494:pharmacology; D018733:Nicotinic Antagonists / Q000494:pharmacology; D051381:Rats; D014520:Urethane / Q000494:pharmacology
chemical_list: D018686:Anesthetics, Intravenous; D018691:Excitatory Amino Acid Antagonists; D018722:Nicotinic Agonists; D018733:Nicotinic Antagonists; D004079:Dihydro-beta-Erythroidine; D014520:Urethane; D016291:Dizocilpine Maleate; D009538:Nicotine
keywords: 40 Hz; Auditory steady state response; MK801; NMDA; Nicotine; Schizophrenia