Differential Effects of Clozapine and Haloperidol on the 40 Hz Auditory Steady State Response-mediated Phase Resetting in the Prefrontal Cortex of the Female Sprague Dawley Rat

Abstract

Background Neural synchrony at gamma frequency (~40 Hz) is important for information processing and is disrupted in schizophrenia. From a drug development perspective, molecules that can improve local gamma synchrony are promising candidates for therapeutic development. Hypothesis Given their differentiated clinical profile, clozapine, and haloperidol may have distinct effects on local gamma synchrony engendered by 40 Hz click trains, the so-called auditory steady-state response (ASSR). Study Design Clozapine and haloperidol at doses known to mimic clinically relevant D2 receptor occupancy were evaluated using the ASSR in separate cohorts of female SD rats. Results Clozapine (2.5–10 mg/kg, sc) robustly increased intertrial phase coherence (ITC), across all doses. Evoked response increased but less consistently. Background gamma activity, unrelated to the stimulus, showed a reduction at all doses. Closer scrutiny of the data indicated that clozapine accelerated gamma phase resetting. Thus, clozapine augmented auditory information processing in the gamma frequency range by reducing the background gamma, accelerating the gamma phase resetting and improving phase precision and signal power. Modest improvements in ITC were seen with Haloperidol (0.08 and 0.24 mg/kg, sc) without accelerating phase resetting. Evoked power was unaffected while background gamma was reduced at high doses only, which also caused catalepsy. Conclusions Using click-train evoked gamma synchrony as an index of local neural network function, we provide a plausible neurophysiological basis for the superior and differentiated profile of clozapine. These observations may provide a neurophysiological template for identifying new drug candidates with a therapeutic potential for treatment-resistant schizophrenia.

Click-train evoked steady state harmonic response as a novel pharmacodynamic biomarker of cortical oscillatory synchrony

“…Lastly, the 40 Hz harmonic took the longest time to emerge, with group-wide synchrony establishing ~ 180 ms from stim onset. This delayed onset of 40 Hz SSHR parallels the slow emergence of the 40 Hz ASSR in humans (Ross et al, 2002), as well as in rodent frontal cortex, as reported recently (Ummear Raza et al, 2023). Thus, it is tempting to speculate that the 40 Hz harmonic may engage the same network or a subset of the network activated by a 40 Hz driving stimulus.…”