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Abstract
Improvement of cognitive impairments represents a high medical need in the development of new antipsychotics. Aberrant EEG gamma oscillations and reductions in the P1/N1 complex peak amplitude of the auditory evoked potential (AEP) are neurophysiological biomarkers for schizophrenia that indicate disruption in sensory information processing. Inhibition of phosphodiesterase (i.e. PDE10A) and activation of metabotropic glutamate receptor (mGluR2) signaling are believed to provide antipsychotic efficacy in schizophrenia, but it is unclear whether this occurs with cognition-enhancing potential. The present study used the auditory paired click paradigm in passive awake Sprague Dawley rats to 1) model disruption of AEP waveforms and oscillations as observed in schizophrenia by peripheral administration of amphetamine and the N-methyl-D-aspartate (NMDA) antagonist phencyclidine (PCP); 2) confirm the potential of the antipsychotics risperidone and olanzapine to attenuate these disruptions; 3) evaluate the potential of mGluR2 agonist LY404039 and PDE10 inhibitor PQ-10 to improve AEP deficits in both the amphetamine and PCP models. PCP and amphetamine disrupted auditory information processing to the first click, associated with suppression of the P1/N1 complex peak amplitude, and increased cortical gamma oscillations. Risperidone and olanzapine normalized PCP and amphetamine-induced abnormalities in AEP waveforms and aberrant gamma/alpha oscillations, respectively. LY404039 increased P1/N1 complex peak amplitudes and potently attenuated the disruptive effects of both PCP and amphetamine on AEPs amplitudes and oscillations. However, PQ-10 failed to show such effect in either models. These outcomes indicate that modulation of the mGluR2 results in effective restoration of abnormalities in AEP components in two widely used animal models of psychosis, whereas PDE10A inhibition does not.
Highlights
Deficits in sensory information processing have been associated with several neuropsychiatric and neurodegenerative disorders
Changes in the amplitudes of auditory evoked potentials (AEP) responses in humans and animals can be demonstrated in the double click paradigm, in which two identical auditory tones are presented in a time window of 500 ms
Schizophrenic patients commonly exhibit deficits in sensory gating in double click paradigms, which can be replicated in animal models of schizophrenia wherein suppression of the response to the second stimulus is reduced [3,4,6,19,20,21,22]
Summary
Deficits in sensory information processing have been associated with several neuropsychiatric and neurodegenerative disorders. The second condition referred as “gating in” is observed when a relatively small amplitude S1 wave occurrs with a fairly normal amplitude S2 wave [14,15,16,17], which reflects an inability of the brain to encode and register novel fetaures of first stimuli These waveform properties of waveforms measured in the paired click paradigm may correlate with the ability of the brain to “gate out” by decreasing the S2 response to repetitive irrelevant stimuli and to “gate in” by increasing the S1 response to novel or changing stimuli [18]. Schizophrenic patients commonly exhibit deficits in sensory gating in double click paradigms, which can be replicated in animal models of schizophrenia wherein suppression of the response to the second stimulus is reduced [3,4,6,19,20,21,22]
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