Affiliation:
1. Department of Pharmaceutical Sciences, Bill Gatton College of Pharmacy, East Tennessee State University , Johnson City, TN
Abstract
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.
Funder
Bill Gatton College of Pharmacy
East Tennessee State University
Publisher
Oxford University Press (OUP)
Subject
Psychiatry and Mental health