MK-801 disrupts and nicotine augments 40Â Hz auditory steady state responses in the auditory cortex of the urethane-anesthetized rat

- Schizophrenia patients demonstrate 40 Hz auditory steady state response deficits.
- Rats treated with a low dose of NMDA antagonist MK-801 show phase-locking and evoked power deficits to 40 Hz stimulation.
- Nicotine independently augments phase-locking and evoked response to 40 Hz steady state stimulation.
- Nicotine reverses MK-801-induced 40 Hz deficits in a receptor-selective manner.
- The current work offers a translational model to probe specific afferent processing deficits seen in patients.

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.