Phencyclidine Disrupts the Auditory Steady State Response in Rats

Abstract

The Auditory Steady-State Response (ASSR) in the electroencephalogram (EEG) is usually reduced in schizophrenia (SZ), particularly to 40 Hz stimulation. The gamma frequency ASSR deficit has been attributed to N-methyl-D-aspartate receptor (NMDAR) hypofunction. We tested whether the NMDAR antagonist, phencyclidine (PCP), produced similar ASSR deficits in rats. EEG was recorded from awake rats via intracranial electrodes overlaying the auditory cortex and at the vertex of the skull. ASSRs to click trains were recorded at 10, 20, 30, 40, 50, and 55 Hz and measured by ASSR Mean Power (MP) and Phase Locking Factor (PLF). In Experiment 1, the effect of different subcutaneous doses of PCP (1.0, 2.5 and 4.0 mg/kg) on the ASSR in 12 rats was assessed. In Experiment 2, ASSRs were compared in PCP treated rats and control rats at baseline, after acute injection (5 mg/kg), following two weeks of subchronic, continuous administration (5 mg/kg/day), and one week after drug cessation. Acute administration of PCP increased PLF and MP at frequencies of stimulation below 50 Hz, and decreased responses at higher frequencies at the auditory cortex site. Acute administration had a less pronounced effect at the vertex site, with a reduction of either PLF or MP observed at frequencies above 20 Hz. Acute effects increased in magnitude with higher doses of PCP. Consistent effects were not observed after subchronic PCP administration. These data indicate that acute administration of PCP, a NMDAR antagonist, produces an increase in ASSR synchrony and power at low frequencies of stimulation and a reduction of high frequency (> 40 Hz) ASSR activity in rats. Subchronic, continuous administration of PCP, on the other hand, has little impact on ASSRs. Thus, while ASSRs are highly sensitive to NMDAR antagonists, their translational utility as a cross-species biomarker for NMDAR hypofunction in SZ and other disorders may be dependent on dose and schedule.

Acute Phencyclidine Alters Neural Oscillations Evoked by Tones in the Auditory Cortex of Rats

“…The suppression of high frequency gamma activity by PCP in the present study is similar to several other studies of auditory ERPs in rodents with NMDAr function impaired through genetic manipulations [25] and other NMDAr antagonists, such as MK-801 [30], ketamine [14], and PCP [28]. In contrast, relatively low dose ketamine administration in humans [27] and mice [26] failed to suppress auditory evoked gamma activity.…”

“…Beta neural synchrony (15–30 Hz) has been suggested to be responsible for multi-modal binding across long-range neural networks [41]. The elevated low frequency neural synchrony and power in response to PCP administration is similar to our previous findings with ASSRs [28] and the broadband increase in spontaneous EEG activity commonly elicited by NMDAr antagonists. The cellular mechanisms for a PCP-induced increase in alpha and low gamma range activity generated by auditory stimulation are not well understood.…”

“…The procedure for electrode implantation was completed as described in Leishman et al (2015) [28]. In short, at 12 weeks old (369 ± 6 g), rats were anesthetized and stainless steel screw electrodes were epidurally implanted over the temporal cortex, cerebellum (ground), and frontal sinus (reference).…”

“…One factor that may account for differences among studies is the dose of the NMDAr antagonist or degree of genetically manipulated receptor hypofunction. With auditory steady state responses (ASSRs), for example, high levels of NMDAr blockade may be required to reduce gamma synchrony [14,28]. Secondly, subchronic or chronic administration using either multiple single doses or continuous delivery of NMDAr antagonists may have quite different physiological effects [29].…”

“…Secondly, subchronic or chronic administration using either multiple single doses or continuous delivery of NMDAr antagonists may have quite different physiological effects [29]. Studies using MK-801 [30] and PCP found that acute, but not subchronic administration of a NMDAr antagonist, reduced ASSR gamma phase synchrony in rats [30][28]. …”