Ketamine modulates theta and gamma oscillations.

Ketamine, an N-methyl-D-aspartate (NMDA) receptor glutamatergic antagonist, has been studied as a model of schizophrenia when applied in subanesthetic doses. In EEG studies, ketamine affects sensory gating and alters the oscillatory characteristics of neuronal signals in a complex manner. We investigated the effects of ketamine on in vivo recordings from the CA3 region of mouse hippocampus referenced to the ipsilateral frontal sinus using a paired-click auditory gating paradigm. One issue of particular interest was elucidating the effect of ketamine on background network activity, poststimulus evoked and induced activity. We find that ketamine attenuates the theta frequency band in both background activity and in poststimulus evoked activity. Ketamine also disrupts a late, poststimulus theta power reduction seen in control recordings. In the gamma frequency range, ketamine enhances both background and evoked power, but decreases relative induced power. These findings support a role for NMDA receptors in mediating the balance between theta and gamma responses to sensory stimuli, with possible implications for dysfunction in schizophrenia.

Deviance-elicited changes in event-related potentials are attenuated by ketamine in mice.

BACKGROUND: People with schizophrenia exhibit reduced ability to detect change in the auditory environment, which has been linked to abnormalities in N-methyl-D-aspartate (NMDA) receptor-mediated glutamate neurotransmission. This ability to detect changes in stimulus qualities can be measured with electroencephalography using auditory event-related potentials (ERPs). For example, reductions in the N100 and mismatch negativity (MMN), in response to pitch deviance, have been proposed as endophenotypes of schizophrenia. This study examines a novel rodent model of impaired pitch deviance detection in mice using the NMDA receptor antagonist ketamine. METHODS: ERPs were recorded from unanesthetized mice during a pitch deviance paradigm prior to and following ketamine administration. First, N40 amplitude was evaluated using stimuli between 4 and 10 kHz to assess the amplitude of responses across the frequency range used. The amplitude and latency of the N40 were analyzed following standard (7 kHz) and deviant (5-9 kHz) stimuli. Additionally, we examined which portions of the ERP are selectively altered by pitch deviance to define possible regions for the mouse MMN. RESULTS: Mice displayed increased N40 amplitude that was followed by a later negative component between 50 and 75 msec in response to deviant stimuli. Both the increased N40 and the late N40 negativity were attenuated by ketamine. Ketamine increased N40 latency for both standard and deviant stimuli alike. CONCLUSIONS: The mouse N40 and a subsequent temporal region have deviance response properties similar to the human N100 and, possibly, MMN. Deviance responses were abolished by ketamine, suggesting that ketamine-induced changes in mice mimic deviance detection deficits in schizophrenia.

Effects of nicotine vary across two auditory evoked potentials in the mouse.

BACKGROUND: Schizophrenia patients display sensory processing deficits, reduced alpha7-nicotine receptor expression, and increased incidence of smoking, prompting investigation of nicotine receptor agonists as possible treatments. We evaluated the effects of acute and chronic nicotine, using an animal model that incorporates genetic variation for sensory processing and nicotine sensitivity. METHODS: C57BL/6J and DBA/2Hsd mice received 2 weeks of 4.2 mg/kg chronic nicotine or saline. Auditory evoked potentials were recorded before and after acute nicotine injection of 1.05 mg/kg on day 14, with a paired-click paradigm (S1/S2). Amplitude and gating of the P20 and N40 were compared between conditions. RESULTS: Acute nicotine increased the amplitude and gating of the P20 and decreased the amplitude and gating of the N40 across all groups, primarily by acting on S1. Chronic nicotine attenuated the effects of acute nicotine on the N40. CONCLUSIONS: Our data support the notion that the mouse P20 shares pharmacological response properties with the human P50. In addition, findings suggest that nicotine might increase the initial sensory response (S1), with a resulting improvement in gating of some components.

Pharmacokinetic and behavioral characterization of a long-term antipsychotic delivery system in rodents and rabbits.

RATIONALE: Non-adherence with medication remains the major correctable cause of poor outcome in schizophrenia. However, few treatments have addressed this major determinant of outcome with novel long-term delivery systems. OBJECTIVES: The aim of this study was to provide biological proof of concept for a long-term implantable antipsychotic delivery system in rodents and rabbits. MATERIALS AND METHODS: Implantable formulations of haloperidol were created using biodegradable polymers. Implants were characterized for in vitro release and in vivo behavior using prepulse inhibition of startle in rats and mice, as well as pharmacokinetics in rabbits. RESULTS: Behavioral measures demonstrate the effectiveness of haloperidol implants delivering 1 mg/kg in mice and 0.6 mg/kg in rats to block amphetamine (10 mg/kg) in mice or apomorphine (0.5 mg/kg) in rats. Additionally, we demonstrate the pattern of release from single polymer implants for 1 year in rabbits. CONCLUSIONS: The current study suggests that implantable formulations are a viable approach to providing long-term delivery of antipsychotic medications in vivo using animal models of behavior and pharmacokinetics. In contrast to depot formulations, implantable formulations could last 6 months or longer. Additionally, implants can be removed throughout the delivery interval, offering a degree of reversibility not available with depot formulations.

Effects of chronic olanzapine and haloperidol differ on the mouse N1 auditory evoked potential.

Auditory evoked potentials have been used in a variety of animal models to assess information-processing impairments in schizophrenia. Previous mouse models have primarily employed a paired click paradigm to assess the transient measures of auditory gating. The current study uses stimulus trains at varied interstimulus intervals (ISI) between 0.25 and 8 s in mice to assess the effects of chronic olanzapine and haloperidol on auditory processing. Data indicate that olanzapine increases the amplitude of the N40, P80, and P20/N40 components of the auditory evoked potential, whereas haloperidol had no such effect. The ISI paradigm also allowed for an evaluation of several components of the mouse evoked potential to assess those that display response properties similar to the human P50 and N100. Data suggest that the mouse N40 displays an ISI response relationship that shares characteristics with the human N100, whereas the P20 appears more consistent with the human P50 across the ISI range evaluated in this task. This study suggests that olanzapine may help improve N100 impairments seen in schizophrenia, while haloperidol does not.

Inhibition of auditory evoked potentials and prepulse inhibition of startle in DBA/2J and DBA/2Hsd inbred mouse substrains.

Previous data have shown differences among inbred mouse strains in sensory gating of auditory evoked potentials, prepulse inhibition (PPI) of startle, and startle amplitude. These measures of sensory and sensorimotor gating have both been proposed as models for genetic determinants of sensory processing abnormalities in patients with schizophrenia and their first-degree relatives. Data from our laboratory suggest that auditory evoked potentials of DBA/2J mice differ from those previously described for DBA/2Hsd. Therefore, we compared evoked potentials and PPI in these two closely related substrains based on the hypothesis that any observed endophenotypic differences are more likely to distinguish relevant from incidental genetic heterogeneity than similar approaches using inbred strains that vary across the entire genome. We found that DBA/2Hsd substrain exhibited reduced inhibition of evoked potentials and reduced startle relative to the DBA/2J substrain without alterations in auditory sensitivity, amplitude of evoked potentials or PPI of startle. These results suggest that gating of auditory evoked potentials and PPI of startle measure different aspects of neuronal function. The differences between the substrains might reflect genetic drift. Alternatively, differences could arise from different rearing environments or other non-genetic factors. Future studies will attempt to determine the cause of these differences in sensory and sensorimotor processing between these two closely related inbred mouse strains.