Oscillations in the brain’s electrical potential, recorded through the technique of electroencephalography (EEG), reflect the ensemble activity of a large population of neurons. Auditory steady-state response (ASSR) is the time-locked entrainment in EEG to an auditory stimulus such as a train of clicks. ASSR to a 40 Hz (gamma frequency) click train is especially reduced in schizophrenia patients, reflecting the sensory processing deficits that impact real-world functional outcomes. Since the 40 Hz ASSR is demonstrable across species and is responsive to pharmacological treatments, it can be a translational biomarker for drug development studies. Prototypical antipsychotic drugs (APDs) like haloperidol and clozapine are examples of typical and atypical classes used to treat schizophrenia patients. While both are D2 receptor blockers, they have additional pharmacological effects that may differentiate them. Here, we investigated the acute effect of clozapine (atypical) or haloperidol (typical) on the 40 Hz ASSR, in two independent studies. The doses for the two drugs were chosen to reflect comparable in vivo D2 receptor occupancy. We used female Sprague-Dawley rats implanted with epidural EEG recording electrodes. In the first experiment, vehicle or clozapine 2.5, 5, and 10 mg/kg were administered (sc) and the 40 Hz ASSR paradigm (65 dB, 40 clicks for 1 second, 2-sec inter-stimulus interval) was used to record responses at 30, 60, 90 and 120 minutes post-drug. Resting-state EEG was recorded at 60 minutes post-treatment. Treatment effects were evaluated on the evoked power and phase-locking factor (PLF), a measure of trial-to-trial consistency of the 40 Hz ASSR. Clozapine improved both measures in a dose and time-dependent manner. Clozapine also tended to reduce the resting-state gamma (30-100 Hz) power, a hallmark of cortical noise. However, the effect was not significant (P>0.05). Next, we tested the effect of haloperidol on the 40 Hz ASSR. Doses of 0.02 mg/kg -0.08 mg/kg (sc) were evaluated at 30, 60, 90 and 120-minutes post-injection. Haloperidol failed to improve the 40 Hz ASSR (evoked power and PLF). Moreover, it had no discernible effect on the resting-state gamma. These results show that despite the comparable blockade of D2 receptors, the putative target for these APDs, clozapine, and haloperidol have different effects on the 40 Hz ASSR. We conclude that the effects of clozapine on 40 Hz ASSR may be unrelated to its affinity to D2 receptors and may be mediated through other pharmacological mechanisms.
| Identifer | oai:union.ndltd.org:ETSU/oai:dc.etsu.edu:asrf-1770 |
| Date | 18 March 2021 |
| Creators | Raza, Muhammad Ummear, Dakota, Rorie, Makki, Michael, Tabor, Sydney Faith, Plsek, Caige Gaylon, Sivarao, Digavalli V |
| Publisher | Digital Commons @ East Tennessee State University |
| Source Sets | East Tennessee State University |
| Detected Language | English |
| Type | text |
| Source | Appalachian Student Research Forum |
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