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NEUROPHARMACOLOGY
Division of Neuropsychiatry, Department of Psychiatry, University of Pennsylvania, Philadelphia, Pennsylvania (C.R.M., R.S.E., Y.L., D.T., S.J.K., S.J.S.); and Department of Biology, Rider University, Lawrenceville, New Jersey (J.K.)
Received for publication
June 17, 2005
Accepted
September 27, 2005.
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Abstract |
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; Morgan et al., 2004). Although these drugs produce hallucinations and delusions as well as exacerbating preexisting psychosis, several studies have argued that the psychotic and dissociative features are less prominent than the lasting cognitive disruptions (Malhotra et al., 1997; Morgan et al., 2004). Indeed, the nature of these lasting cognitive deficits remains unclear, and few studies have distinguished the effects of ketamine on the multiple phases of information processing. The current study uses auditory evoked potentials (AEPs) to examine the acute, chronic, and lasting effects of ketamine on various phases of sensory encoding in mice. In so doing, we will further elucidate the precise phases of information processing during which N-methyl-D-aspartate antagonists affect sensory processing.
The physiological and cognitive effects of N-methyl-D-aspartate antagonist drugs of abuse are also relevant to models of schizophrenia. Acute administration of ketamine produces behavioral, cognitive, and physiological AEP changes consistent with schizophrenia (Malhotra et al., 1997; Newcomer et al., 1999; Umbricht et al., 2000; Micallef et al., 2002). Several investigators have proposed that reduced function at N-methyl-D-aspartate receptors may precede overt manifestations of schizophrenia (Newcomer et al., 1999; Greene, 2001). It has been difficult to test such hypotheses in humans because of the inability to identify schizophrenia probands before their first-break episode (McConaghy, 2000). Alternatively, animal studies can measure acute, chronic, and lasting effects of N-methyl-D-aspartate antagonists to evaluate the potential risks of substance abuse and can be used as models for understanding the neurobiology of schizophrenia.
Sensory encoding and information processing have been measured using the P1, N1, and P2 components of AEPs in humans and animals. The P1 reflects precortical processing, whereas the N1 and P2 are cortically generated and can be modulated by directing the subject's attention during the auditory task (Picton et al., 1974; Gallinat et al., 2002). Preliminary studies in humans suggest that these components may have different sensitivities to the effects of acute N-methyl-D-aspartate receptor blockade. For example, one study found that ketamine did not change gating of the human P1, but it did not evaluate amplitude (van Berckel et al., 1998). Another study found increased N1 amplitude with ketamine without alteration of the P2 (Umbricht et al., 2000). Initial studies in rodents suggest that the mouse P1 increases in amplitude following acute ketamine, whereas the mouse and rat P2 decrease in amplitude following acute ketamine exposure (de Bruin et al., 1999; Connolly et al., 2004). Although such studies suggest different sensitivities to acute N-methyl-D-aspartate antagonists among various phases of auditory processing, little is known about the lasting effects of ketamine on such measures.
The current study uses AEPs as physiological measures to elucidate immediate and lasting effects of acute and chronic N-methyl-D-aspartate receptor blockade on multiple phases of auditory processing. The acute exposure studies use four inbred mouse strains to determine genetic vulnerability to ketamine as a predictor of chronic and lasting effects. Subsequent studies to assess the immediate and lasting effects of chronic exposure were then performed using one vulnerable and one resistant inbred strain. The inclusion of such natural genetic variation was intended to provide a foundation for future studies directed at addressing genetic susceptibility to N-methyl-D-aspartate antagonists in humans.
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Materials and Methods |
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Surgery
Animals underwent stereotaxic implantation of electrode assemblies (Plastic Products, Roanoke, VA) for nonanesthetized recording of auditory evoked potentials. The surgical procedure has been reported previously (Connolly et al., 2003, 2004; Siegel et al., 2003; Maxwell et al., 2004a,b). Animals were anesthetized with isoflurane. Unipolar recording electrodes were placed unilaterally in the CA3 hippocampal region, (1.4 mm posterior, 2.65 mm lateral, and 2.75 mm deep relative to bregma) and referenced to the ipsilateral frontal sinus to reflect whole brain electrical activity. The electrode pedestal was secured to the skull using dental cement and Super Glue. Electrode placement was verified to be in the target region using the Perl's iron reaction (LaBossiere and Glickstein, 1976).
AEP Treatment Groups
Acute Study. One hundred twenty-eight mice were used in the AEP portion of this study. In the acute ketamine experiment, 32 mice (eight per strain, four strains) were used in each of the following conditions: vehicle (0 mg/kg), 5 mg/kg ketamine, or 20 mg/kg intraperitoneal ketamine. These animals were tested 2 weeks after electrode surgery.
Chronic Study. The chronic exposure portion of this study used an additional 32 mice to model the effects of repeated ketamine abuse. FVB/Hsd and C3H/HeHsd mice received daily injections of saline (eight FVB/Hsd and eight C3H/HeHsd mice) or 5 mg/kg ketamine (eight FVB/Hsd and eight C3H/HeHsd mice) for 2 weeks. These animals were tested for the effects of chronic ketamine after 2 weeks of exposure and again for the lasting effects of ketamine 7 days later.
Recording. The recording session for the AEP experiments consisted of a baseline, drug-naive trial followed by an i.p. injection of either ketamine or vehicle. The recording parameters for the chronic experiments were identical to those of the acute experiments with recording following the 14th daily injection. Drug exposure trials were recorded 5 min after the injection. Stimuli were generated by Micro1401 hardware and Spike 5 software (Cambridge Electronic Design, Cambridge, UK) and were delivered through speakers attached to the cage top. A series of 50 white noise clicks (10 ms in duration) were presented with a 9-s interstimulus interval at 85 dB compared with background of 70 dB. Waveforms were filtered between 1 and 500 Hz and baseline corrected at stimulus onset. Individual sweeps were rejected for movement artifact based on a criterion of 2 times the root mean squared amplitude per mouse. Average waves were created from 50-ms prestimulus to 200-ms poststimulus (Fig. 1). All recordings were performed within the animal's home cage, which was placed in a Faraday cage 15 min before stimulus onset.
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levels were set at p < 0.05 for all analyses. Serum Half-Life. This experiment determined the serum half-life of ketamine in four mouse strains. Eighty additional mice (four per strain at each of five time points) were injected with 100 mg/kg intraperitoneal ketamine and sacrificed at 5 (n = 16), 10 (n = 16), 20 (n = 16), 30 (n = 16), and 60 (n = 16) min after injection. The dose of 100 mg/kg was used to facilitate a detectable level at 60 min after injection. Serum was pooled to allow for amplification 1 h after injection, which produces a mean value per strain per time point. The HPLC protocol for ketamine extraction in serum is adapted from the phencyclidine extraction protocol provided by Waters (Milford, MA) for use with Breeze software. The wavelength for ketamine was 210 nm with a retention time of 7.4 min. The exponential decay equation x(t) = x(0)eat, where t (time) and x(0) (initial value or x-intercept), was used to calculate the unknown decay constant (a). Once the decay constant (a) is determined, the half-life equation is t1/2 = ln 0.5/a.
Serum and Brain Concentration. Thirty-two mice (eight mice per strain) were injected i.p. with 20 mg/kg acute ketamine to evaluate serum for ketamine and norketamine, a ketamine metabolite, 15 min after injection to determine serum concentration at the time consistent with AEP testing. The ketamine extraction protocol is described above. Norketamine was evaluated using the same parameters with a retention time of 4.6 min. An analysis of variance followed by Fisher's least significant difference post hoc analyses was performed to determine strain differences in metabolism of ketamine and norketamine. Twelve additional FVB/Hsd mice were sacrificed after 15 min of exposure to 0, 5, 20, or 100 mg/kg ketamine. Serum and brain levels were assayed for ketamine and norketamine to determine the correlation between serum and brain ketamine levels at time of AEP testing.
Regional Catecholamine Levels in Brain. The effects of ketamine on brain catecholamine levels in vulnerable (C3H/HeHsd) and resistant (FVB/Hsd) strains were evaluated to investigate a potential neurochemical mechanism by which ketamine alters evoked potentials. Eight FVB/Hsd and eight C3H/HeHsd mice were treated with 0 or 20 mg/kg ketamine to evaluate dopamine, norepinephrine, and epinephrine levels in hypothalamus and hippocampus. Animals were sacrificed using rapid decapitation 15 min after injection. The brains were removed, regionally dissected, and immediately placed in ice-cold 0.1 M HClO4 spiked with an internal standard of 3,4-dihydroxybenzylamine. Samples were frozen at -80°C until catecholamines were assayed by HPLC with electrochemical detection. Briefly, samples were sonicated and centrifuged with aliquots of the supernatants added to sodium phosphate buffer, pH 6.1, 1.5 M Tris-EDTA buffer, pH 8.6, and acid-washed alumina. The alumina was washed in water, and the catecholamines were eluted off the alumina with 0.1 M HClO4. This extract from each sample was manually injected into the HPLC. The HPLC system consisted of pumps (Varian ProStar; Varian, Inc., Palo Alto, CA) and a C18 reverse-phase column (150 mm x 4.6, 5 µm) located in a temperature-controlled housing (27°C) with an electrochemical detector (Varian Star 9080). The system was operated at a flow rate of 1.0 ml/min with the detector potential set at 0.75 V versus a Ag-AgCl reference electrode. The mobile phase buffer consisted of 0.33 M citrate, 0.67 M phosphate, pH 4.5, with 1.2 mM sodium octyl sulfate and 12% methanol. The signal from the detector was recorded by a PC computer (Dell Optiplex) fitted with an ADC controller card using Varian Star Chromatography software version 5.
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Results |
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Acute AEPs
Trends. Main effects of ketamine and interactions between ketamine and strain indicate that ketamine influenced amplitudes and latencies of the P1, N1, and P2. Across all four strains, the main effects of ketamine displayed the following trends: 1) ketamine increased the P1 amplitude and lengthened the P1 latency, 2) ketamine decreased N1 amplitude and shortened N1 latency, and 3) ketamine did not change P2 amplitude but shortened P2 latency. The strain by ketamine interactions described below suggest that there are also strain-dependent vulnerabilities to ketamine (Tables 1 and 2).
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Strain-Specific Findings. C3H/HeHsd. P1 amplitude and latency did not change with ketamine in this strain. The N1 amplitude dose dependently decreased with ketamine administration, whereas the latency remained unchanged. The P2 amplitude did not change with ketamine, but the latency dose dependently decreased (Figs. 3 and 4).
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C57BL/6Hsd. P1 amplitude increased with ketamine exposure, whereas the latency remained unchanged. The N1 amplitude was unchanged with ketamine exposure, whereas the N1 latency decreased. The P2 amplitude was unchanged, whereas the P2 latency decreased at 20 mg/kg.
DBA/2Hsd. The 5-mg/kg dose of ketamine increased the P1 amplitude without changes in latency. The N1 amplitude increased with both doses of ketamine, whereas latency was unchanged. The P2 amplitude was unchanged with ketamine, whereas the P2 latency decreased at both doses.
Regional Catecholamine Analyses. This analysis evaluated dopamine, norepinephrine, and epinephrine levels in hippocampus and hypothalamus in two mouse strains defined to be resistant (FVB/Hsd) and sensitive (C3H/HeHsd) based on acute AEP data. We found that FVB/Hsd mice have more dopamine in hypothalamus compared with C3H/HeHsd, irrespective of ketamine treatment. Also, hippocampus epinephrine levels were reduced with ketamine in C3H/HeHsd mice (p = 0.035) relative to a saline injection in C3H/HeHsd mice but elevated with ketamine in FVB/Hsd mice compared with the FVB/Hsd saline group (p = 0.019) (Table 3; Fig. 5).
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The next series of experiments were performed to evaluate the chronic and lasting effects of ketamine exposure. We selected two strains that differ for the degree of vulnerability to acute ketamine for this analysis. We chose to use C3H/HeHsd and FVB/Hsd mice for this comparison based on their differential effects on the N1 amplitude. Additionally, these strains were selected because they had similar serum levels of both ketamine and norketamine, facilitating a comparison of central nervous system mechanisms of vulnerability without peripheral metabolic variation.
Chronic and Lasting AEPs
In this design, AEPs were recorded from C3H/HeHsd and FVB/Hsd mice after receiving daily ketamine (5 mg/kg) or saline i.p. injections for 14 days. The dose of 5 mg/kg ketamine was chosen based on the acute data in which C3H/HeHsd mice show decreased N1 amplitude at this dose, whereas FVB/Hsd mice did not. Additionally, to determine lasting effects of ketamine, AEPs were recorded on day 21 (7 days after last injection of ketamine or saline).
P1. Chronic and lasting effects. There were no main effects of ketamine or interactions with strain on the amplitude or latency of the P1 after the final daily injection or 7 days later (Table 4).
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N1. Chronic effects. There were no main effects of ketamine or interactions with strain on the amplitude or latency of the N1 after the final daily injection on day 14.
Lasting effects. A main effect of ketamine demonstrated that ketamine treatment produced a reduction of N1 amplitude on day 21 relative to animals that received matched saline injections (Fig. 6). There were no lasting effects on the latency of the N1. Also, there were no interactions between strain and ketamine on either measure of this component.
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Habituation of AEPs
P1. There were no main effects of habituation or interactions with strain and ketamine on the amplitude of the P1 (Table 5).
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N1. An interaction between strain and habituation indicated that C57BL/6Hsd mice showed significantly higher N1 amplitude in response to the last 25 stimuli relative to the first 25 stimuli. No other strains displayed significant differences between the first and last 25 stimuli presented (Table 6). A second interaction between habituation and ketamine demonstrated that the 20-mg/kg ketamine dose significantly decreased the amplitude of response to the first 25 stimuli relative to the last 25 stimuli, suggesting that the inhibitory effects of ketamine were attenuated during progression of the task (Table 7).
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P2. There were no main effects of habituation or interactions with strain and ketamine on the amplitude of the P2 (Table 5).
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Discussion |
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These data suggest that epinephrine is a central factor that could influence strain-specific ketamine vulnerability through alterations in hippocampal catecholamine concentrations. Specifically, ketamine decreases hippocampal epinephrine levels in C3H/HeHsd mice, which have decreased AEP amplitudes, demonstrating a vulnerability to N-methyl-D-aspartate receptor antagonism. Ketamine administration increases epinephrine levels in the ketamine-resistant strain (FVB/Hsd), which show no alterations in AEPs. One rodent study showed systemic epinephrine increased the N1-P2 AEP amplitude, suggesting that epinephrine may modulate late latency AEPs (Berntson et al., 2003). Similarly, human studies have proposed that the hippocampus plays a role in sensory gating of late latency AEPs (Grunwald et al., 2003). To our knowledge, this is the first report of differential AEP sensitivities to acute ketamine in mice that coincide with changes in hippocampal epinephrine concentrations. There are several limitations to the interpretation of this finding. Since other brain regions were not evaluated, a generalized increase in epinephrine concentrations throughout the brain may occur in FVB/Hsd mice with ketamine, and an overall decrease may occur in C3H/HeHsd mice. Similarly, dopamine and norepinephrine levels may be altered with ketamine treatment in other brain regions not examined in this study. Also, our data reflect a snapshot of epinephrine levels at a single time point and therefore cannot distinguish changes in synthesis from changes in release and/or turnover. Future studies will evaluate catecholamine levels in multiple brain regions of animals treated with acute and chronic ketamine to further explore catecholamine modulation of AEPs.
On the basis of acute AEP and pharmacokinetic findings, C3H/HeHsd and FVB/Hsd strains were selected as vulnerable and resistant strains, respectively, to evaluate chronic and lasting alterations following 14 days of repeated low-dose exposure. Interestingly, neither strain displayed alterations in AEP measures directly following the final daily exposure, suggesting adaptation among the previously vulnerable C3H/HeHsd group. Equally intriguing, both groups then demonstrated lasting decrement of the N1 amplitude following 7 days without ketamine exposure, indicating sensitivity to ketamine in FVB/Hsd mice over time. As we demonstrate, the serum half-life for this drug is approximately 13 min in mouse, strongly suggesting that no ketamine remains in the animal at the final time point, which equals 775 half-lives after final administration. Thus, genetic heterogeneity to the physiological effects of ketamine does not seem to protect against the lasting alterations in the neural substrates of sensory encoding of the N1 AEPs.
Acute ketamine exposure in both human and animal literature is also commonly used to model schizophrenia-like deficits in information processing. Multiple studies have shown that decreased N1 amplitude is a reproducible physiological characteristic of schizophrenia (Lifshitz et al., 1987; Boutros et al., 1999, 2004a,b). Additionally, recent data from the clinical Schizophrenia Research Center affiliated with our group demonstrates both decreased N1 amplitude and reduced P2 latency among people with schizophrenia (B. I. Turetsky, S. C. Johnson, S. J. Siegel, and R. E. Gur, unpublished data). Therefore, AEP alterations secondary to reduced N-methyl-D-aspartate-mediated glutamate transmission following acute low-dose ketamine are consistent with the profile seen in schizophrenia. However, these deficits were not found following repeated exposure in mice, suggesting that adaptive changes within the brains of C3H/HeHsd mice may have normalized N-methyl-D-aspartate receptor function in the presence of low-dose ketamine. Such adaptive changes seem to have remained 7 days after the last exposure, resulting in lasting deficits in sensory encoding. These observations (decreased N1 amplitude and decreased P2 latency) are consistent with the idea that N-methyl-D-aspartate hypofunction may be involved in both the cognitive deficits of schizophrenia and among people who abuse ketamine as a recreational drug. Alternatively, the P2 latency shift may not represent an independent phenomenon if it results from a decrease in preceding N1 amplitude. Although this is a concern in most AEP studies, some investigators have made an effort to describe the P2 as an independent component (Crowley and Colrain, 2004).
Secondary analyses of the acute data in this study evaluated the effects of strain and ketamine on habituation to auditory stimuli. Our results indicate that the N1 response in C57BL/6Hsd mice increased over the course of the trial, whereas it did not in other strains. Thus, these data indicate that auditory AEPs do not habituate over the course of a single test session. Also, the amplitude of the N1 was lower for the first 25 responses relative to the second 25 following the 20-mg/kg ketamine dose across all strains, suggesting a loss of inhibition over the course of the task. The loss of ketamine-induced inhibition of the N40 is unlikely to reflect clearance of the active drug because the effect was only manifest on a single component and all testing occurred within one serum half-life for ketamine.
There are a number of limitations to this study. Both C3H/HeHsd and DBA/2Hsd mice display retinal degeneration, which leads to blindness in adult animals (Farber and Lolley, 1973; Schuettauf et al., 2004). This spontaneous visual impairment could promote cortical compensation from the auditory system and may influence the physiological response to auditory stimuli. However, our data indicate that C3H/HeHsd and DBA/2Hsd mice have opposite evoked responses at baseline and during ketamine treatment, suggesting that compensation for visual deficits may not be a major factor influencing the results found in this study. Also, although previous studies propose that the P1 reflects thalamic and early cortical activity, whereas the N1 and P2 reflect higher order processing involving auditory cortex and association cortices, the specific generators of these components are difficult to isolate in mice. Although the direct analogy between human and mouse AEP components is unclear, this study and others provide further support that the human P1, N1, and P2 are analogous to the mouse P1, N1, and P2, respectively (Connolly et al., 2003, 2004; Siegel et al., 2003, 2005; Maxwell et al., 2004a,b; Umbricht et al., 2004). One additional clarification in this study regards the method of chronic ketamine exposure. The chronic portion of this study used repeated daily injections to ketamine rather than continuous exposure from pumps or implants. This paradigm was selected to model chronic ketamine abuse, during which people self-administer acute doses repeatedly over time. However, this may differ from proposed mechanisms of chronic, continuous N-methyl-D-aspartate hypofunction during the schizophrenia prodrome, perhaps limiting generalization to that disease model.
In summary, the current study indicates that inbred mouse strains differ in their physiological AEP response to acute N-methyl-D-aspartate receptor blockade. Our results also support the hypothesis that ketamine acts primarily to reduce cortical processing, but it has the opposite effect on precortical processing. Of note, neither the sensitive nor resistant strains showed alterations following chronic exposure, suggesting the presence of adaptive, compensatory mechanisms in N-methyl-D-aspartate-mediated transmission. Similarly, both strains demonstrated lasting deficits in sensory encoding, suggesting that long-term adaptations to chronic N-methyl-D-aspartate hypofunction occur even in the absence of acute effects.
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Acknowledgements |
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Footnotes |
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Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.
ABBREVIATIONS: AEP, auditory evoked potential; HPLC, high-performance liquid chromatography.
Address correspondence to: Dr. Steven J. Siegel, Division of Neuropsychiatry and Stanley Center for Experimental Therapeutics in Psychiatry, Clinical Research Bldg., Rm. 145a, 415 Ci Blvd., University of Pennsylvania, Philadelphia, PA 19104. E-mail: siegels{at}mail.med.upenn.edu
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indicates significant difference (p < 0.05) from the control condition in the same strain using Fisher's least significant difference post hoc [P1: mean square (MS) = 1401, df = 84; N1: MS = 2146, df = 84; and P2: no interaction].
