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: Maarten van den Buuse
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- "Preclinical studies have attempted to delineate the neuronal pathways that mediate N40 gating and have implicated dopamine and glutamate (Adler et al., 1986; Swerdlow et al., 2006), GABA (Ma and Leung, 2011), noradrenaline (Adler et al., 1988; Keedy et al., 2007) and acetylcholine (Luntzleybman et al., 1992; Stevens et al., 1995). For example, drugs that increase dopamine receptor signalling, such as the dopamine releaser, amphetamine, disrupt N40 sensory gating (Adler et al., 1986), an effect which can be attenuated by antipsychotic drugs such as haloperidol and clozapine (Adler et al., 1988, 1986; Joy et al., 2004). Similarly, the glutamate NMDA receptor antagonist, phencyclidine, was shown to cause a disruption of N40 sensory gating (Adler et al., 1986; Swerdlow et al., 2006). "
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; 112. DOI:10.1016/j.pbb.2013.09.016 · 2.82 Impact Factor
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- "The N40 wave demonstrates a diminished response to the test stimuli (T/C B 50%) in healthy controls (Miller et al. 1992) while disrupted gating has been shown in pharmacological models (e.g. following phencyclidine and amphetamine administration) of schizophrenia (Miller et al. 1992; Joy et al. 2004). An example of sensory gating is illustrated in Fig. 1, showing average auditory evoked LFPs recorded from the hippocampal CA3 region of an anesthetized rat. "
ABSTRACT: Gating of sensory information can be assessed using an auditory conditioning-test paradigm which measures the reduction in the auditory evoked response to a test stimulus following an initial conditioning stimulus. Recording brainwaves from specific areas of the brain using multiple electrodes is helpful in the study of the neurobiology of sensory gating. In this paper, we use such technology to investigate the role of cannabinoids in sensory gating in the CA3 region of the rat hippocampus. Our experimental results show that application of the exogenous cannabinoid agonist WIN55,212-2 can abolish sensory gating. We have developed a phenomenological model of cannabinoid dynamics incorporated within a spiking neural network model of CA3 with synaptically interacting pyramidal and basket cells. Direct numerical simulations of this model suggest that the basic mechanism for this effect can be traced to the suppression of inhibition of slow GABA(B) synapses. Furthermore, by working with a simpler mathematical firing rate model we are able to show the robustness of this mechanism for the abolition of sensory gating.Cognitive Neurodynamics 07/2008; 2(2):159-70. DOI:10.1007/s11571-008-9050-4 · 1.77 Impact Factor
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- "However, few studies have investigated the neurophysiological properties of psychostimulants, such as MPD, in intact humans or animals , especially its behavioral effects and alteration of sensory evoked neuronal activity in brain regions that are involved in the mesocorticolimbic DA system. Most neurophysiological studies that investigated psychostimulants have been conducted in vivo in the presence of anesthesia [4,31,32], which is known to interfere with CNS activity , or obtained in vitro on brain slices [34-38]. A valuable method to studying the mechanistic action of psychostimulants, such as MPD, on neuronal population is to record neuronal activity before and after administration of the psychostimulant in an intact, non-anesthetized, freely behaving subject through sensory-evoked field responses following sensory stimulation. "
ABSTRACT: Methylphenidate (MPD) is a psychostimulant commonly prescribed for attention deficit/hyperactivity disorder. The mode of action of the brain circuitry responsible for initiating the animals' behavior in response to psychostimulants is not well understood. There is some evidence that psychostimulants activate the ventral tegmental area (VTA), nucleus accumbens (NAc), and prefrontal cortex (PFC). The present study was designed to investigate the acute dose-response of MPD (0.6, 2.5, and 10.0 mg/kg) on locomotor behavior and sensory evoked potentials recorded from the VTA, NAc, and PFC in freely behaving rats previously implanted with permanent electrodes. For locomotor behavior, adult male Wistar-Kyoto (WKY; n = 39) rats were given saline on experimental day 1 and either saline or an acute injection of MPD (0.6, 2.5, or 10.0 mg/kg, i.p.) on experimental day 2. Locomotor activity was recorded for 2-h post injection on both days using an automated, computerized activity monitoring system. Electrophysiological recordings were also performed in the adult male WKY rats (n = 10). Five to seven days after the rats had recovered from the implantation of electrodes, each rat was placed in a sound-insulated, electrophysiological test chamber where its sensory evoked field potentials were recorded before and after saline and 0.6, 2.5, and 10.0 mg/kg MPD injection. Time interval between injections was 90 min. Results showed an increase in locomotion with dose-response characteristics, while a dose-response decrease in amplitude of the components of sensory evoked field responses of the VTA, NAc, and PFC neurons. For example, the P3 component of the sensory evoked field response of the VTA decreased by 19.8% +/- 7.4% from baseline after treatment of 0.6 mg/kg MPD, 37.8% +/- 5.9% after 2.5 mg/kg MPD, and 56.5% +/- 3.9% after 10 mg/kg MPD. Greater attenuation from baseline was observed in the NAc and PFC. Differences in the intensity of MPD-induced attenuation were also found among these brain areas. These results suggest that an acute treatment of MPD produces electrophysiologically detectable alterations at the neuronal level, as well as observable, behavioral responses. The present study is the first to investigate the acute dose-response effects of MPD on behavior in terms of locomotor activity and in the brain involving the sensory inputs of VTA, NAc, and PFC neurons in intact, non-anesthetized, freely behaving rats previously implanted with permanent electrodes.Behavioral and Brain Functions 02/2006; 2(1):3. DOI:10.1186/1744-9081-2-3 · 2.00 Impact Factor