Effects of acute and chronic clozapine on D-amphetamine-induced disruption of auditory gating in the rat.
ABSTRACT Auditory gating deficits observed in patients with schizophrenia have been modeled in animals administered the indirect-acting monoaminergic agonist, D-amphetamine (AMPH). The atypical antipsychotic drug clozapine (CLOZ) reverses the disruption of auditory gating in schizophrenic patients. However, its effects on psychostimulant-induced deficits in animals have yet to be assessed.
In the present series of experiments, an auditory evoked potential paradigm was used to: (a) confirm the ability of AMPH to alter auditory gating in the anesthetized rat, (b) specify the nature of the accompanying change(s) in evoked potential waveforms and (c) determine the effects of CLOZ administration on AMPH-induced alterations in auditory gating.
We compared the effects of acute (5 mg/kg, i.p.) and chronic (28 days, 0.5 mg/ml in drinking water) CLOZ on AMPH-induced (1.8 mg/kg, i.p.) alterations in evoked potentials recorded in the hippocampus of anesthetized rats during presentation of a pair of identical tones. Gating was assessed by comparing the amplitude of conditioning and test responses in CLOZ and AMPH-treated rats.
The ratio of test to conditioning response amplitude (T/C ratio) was not altered by vehicle or CLOZ alone. However, T/C ratio was significantly increased following AMPH due to suppression of the conditioning response. Acute but not chronic CLOZ attenuated but did not prevent the increase in T/C ratio.
Qualitative differences between the idiopathic gating deficits observed in schizophrenic patients and AMPH-induced increases in T/C ratio in animals limit this models utility as a means of evaluating the ability of atypical antipsychotic drugs to restore normal sensory gating.
- SourceAvailable from: Robert Andrew Chambers[Show abstract] [Hide abstract]
ABSTRACT: The neonatal ventral hippocampal lesion (NVHL) rat model shows biological and behavioral abnormalities similar to schizophrenia. Disturbed sensory gating reflects a consistent neurobiological abnormality in schizophrenia. Although of critical interest, sensory gating has not been evaluated in the NVHL model. The N40 rat analog of the human P50 was measured to assess sensory response and gating in NVHL and sham rats. Epidural electrodes recorded evoked potentials (EPs), from which amplitudes, latencies, difference scores (S1-S2) and gating ratios (S2/S1) were assessed. Power and phase locking were computed for evoked EEG activity, to test for frequency-specific abnormalities. Prolonged S1 N40 latency was detected in the NVHL group, but amplitude and power measures did not differ. NVHL rats demonstrated disturbed phase-locked sensory gating at theta and beta frequencies, as well as reduced phase-locked gamma activity across stimuli, most robustly at S1. While measures of sensory gating obtained from the EP were relatively insensitive to the NVHL model, phase locking across trials was affected. NVHL rats may have increased evoked response temporal variability, similar to patients with schizophrenia. This pattern of findings likely reflects core developmental NVHL disturbances in dorsal hippocampal circuits associated with temporal and frontal areas.Neuropsychobiology 09/2009; 60(1):12-22. · 2.37 Impact Factor
- [Show abstract] [Hide abstract]
ABSTRACT: Sensory gating can be assessed using an auditory conditioning (C)-test (T) paradigm which measures the reduction in the auditory-evoked response produced by a test stimulus following a conditioning stimulus. Schizophrenic patients demonstrate absence of gating while dysfunction in glutamatergic neurotransmission is implicated in the pathophysiology of schizophrenia. This study examined the effect of the glutamate receptor antagonist, phencyclidine (PCP) on auditory gating in the CA3 region and dentate gyrus (DG) of rat hippocampus and medial prefrontal cortex (mPFC). Local field potential (LFP) activity was recorded simultaneously from CA3, DG and mPFC in isoflurane anaesthetised Lister hooded rats using in vivo electrophysiology. Paired auditory stimuli were presented binaurally over 128 trials. The effect of PCP (1 mg/kg, i.p.) on gating of the N2 LFP wave was assessed as the test:conditioning response amplitude ratio (T/C ratio); a value of < or =50% was indicative of gating. Auditory gating of the N2 wave was observed in the CA3, DG and mPFC. PCP disrupted gating in all three areas with significant increases in test amplitudes (P<0.001). Clozapine (5 mg/kg i.p) prevented the auditory gating deficits induced by PCP in the CA3, DG and mPFC. This study shows that PCP disrupts sensory gating in the CA3, DG and mPFC in the isoflurane anaesthetised rat. Similar deficits are observed in schizophrenic patients and the current method may provide an animal model with good predictive validity, a view substantiated by the fact that clozapine prevented the sensory gating deficits induced by PCP.Brain research 08/2009; 1298:153-60. · 2.46 Impact Factor
- [Show abstract] [Hide abstract]
ABSTRACT: Schizophrenia pathophysiology is associated with alterations in several neurotransmitter systems, particularly dopamine, glutamate and serotonin (5-HT). Schizophrenia patients also have disruptions in sensory gating, a brain information filtering mechanism in response to repeated sensory stimuli. Dopamine and glutamate have been implicated in sensory gating, however little is known about the contribution of serotonin. We therefore investigated the effects of several psychoactive compounds that alter serotonergic neuronal activity on event-related potentials (ERP) to paired auditory pulses. Male Sprague-Dawley rats were implanted with cortical surface electrodes to measure ERPs to 150 presentations of two 85dB bursts of white noise, 500ms apart (S1 and S2). Saline-treated animals suppressed the response to S2 to less than 50% of S1. In contrast, treatment with the serotonin releaser, MDMA (Ecstasy; 2.0mg/kg), the 5-HT2A/2C receptor agonist, DOI (0.5mg/kg), or the 5-HT1A/7 receptor agonist, 8-OH-DPAT (0.5mg/kg), caused an increase in S2/S1 ratios. Analysis of waveform components suggested that the S2/S1 ratio disruption by MDMA was due to subtle effects on the ERPs to S1 and S2; DOI caused the disruption primarily by reducing the ERP to S1; 8-OH-DPAT-induced disruptions were due to an increase in the ERP to S2. These results show that 5-HT receptor stimulation alters S2/S1 ERP ratios in rats. These results may help to elucidate the sensory gating deficits observed in schizophrenia patients.Pharmacology Biochemistry and Behavior 10/2013; · 2.82 Impact Factor