The current study examines both immediate and long-lasting effects of chronic ketamine administration on contextual fear conditioning, detection of pitch deviants and auditory gating. Murine studies have repeatedly shown that acute ketamine treatment results in impaired contextual fear conditioning (Pietersen, Bosker et al. 2006
; Pietersen, Bosker et al. 2007
; Calzavara, Medrano et al. 2008
). In those studies, the authors suggest that this deficit is caused by the blockage of NMDA receptors (NMDARs), which are requisite for such Pavlovian conditioning. Additionally, ketamine causes widespread apoptotic neurodegeneration after both single and chronic administrations (Scallet, Schmued et al. 2004
; Wang, Sadovova et al. 2005
; Young, Jevtovic-Todorovic et al. 2005
; Majewski-Tiedeken, Rabin et al. 2008
). Such neurodegeneration has been identified in the thalamus, amygdala, parietal cortex and hippocampus, among other regions. Because all four of these regions are involved in the fear conditioning pathway, it is possible that ketamine-induced cell death, and not only the blockage of NMDARs, in any of these regions can result in fear conditioning impairments (Bissiere, Plachta et al. 2007
; Matus-Amat, Higgins et al. 2007
; Zanoveli, Ferreira-Netto et al. 2007
; Keene and Bucci 2008
). Because experiments in this study were conducted 48 hours after injections and the half-life of ketamine in mice is approximately 13 minutes, it is unlikely that the drug was still bound to NMDARs during data collection (Maxwell, Ehrlichman et al. 2006
). Though the pharmacokinetics of ketamine’s metabolites, norketamine and dehydroketamine, have not been studied in mice, data from other small animals suggest that they are largely cleared within 24 hours (Pedraz, Lanao et al. 1985
; Pypendop and Ilkiw 2005
). Therefore, results in the CFC paradigm support our hypothesis that the detrimental effects of ketamine were caused not by acute NMDAR blockade, but more lasting, potentially apoptotic, mechanisms.
Despite ketamine’s link to impaired fear conditioning, one caveat of the current study is our inability to identify which phase of the learning process was affected by drug. Studies show that the thalamus, hippocampus and sensory cortex are all involved in conditioned response (CR) acquisition, hippocampus and amygdala are important for memory consolidation, and the amygdala is the primary site of conditioned stimulus (CS)-unconditioned stimulus (US) convergence (LeDoux 1995
; Davis and Shi 2000
; Maren 2001
). The hippocampus and amygdala also play a role in the retrieval, or expression, of contextual fear memories, which is one of the physiological functions ultimately being assessed in our two experimental test sessions. Because ketamine-treated mice exhibited normal fear conditioning after two weeks of injections, it appears that they were able to acquire fear memories and retrieve them at that time point. However, because there was only one training session, the task at the second time point was more difficult and isolated to memory retrieval. The selective impairment during the second test session also suggests that ketamine may alter system consolidation, which is the gradual reorganization of brain connections that support memory. This process is generally slower and longer-lasting than synaptic consolidation, which is complete within hours of training and involves changes in more localized circuits. One of the key characteristics of system consolidation is that memories shift from hippocampus- to prefrontal cortex-dependence. The effect of ketamine on CFC two weeks after training may therefore be due to a decreased ability to strengthen the cortical connections involved in this process (Frankland and Bontempi 2005
Though CFC testing was only performed at the two discussed time points, data collected in the gating and novelty paradigms also suggest that repeated ketamine administration has lasting effects on brain functioning. Alternatively, our hypothesis regarding MMN was not supported. The lack of a MMN effect in the current study suggest that the disruption of MMN following acute ketamine is due to receptor blockade, rather than the lasting changes secondary to previous exposure. Despite the lack of effect of chronic ketamine on novelty recognition, the drug did produce the predicted results in terms of several different AEP components. For instance, similar to a previously published study from our laboratory, ketamine caused a significant increase in P20 latency, and generally increased the latencies of the N40 and P80 components, as well (Maxwell, Ehrlichman et al. 2006
). ERP component latency is generally thought to be a measure of processing speed, which is the rate at which a person responds to a given stimulus. As discussed in Amann et al. 2008
, an increase in processing speed would subsequently decrease the likelihood that information held with one’s working memory could be accessed before it is lost or diminished (Fry and Hale 2000
; Amann, Phillips et al. 2008
). The reported effects of chronic ketamine on ERP component latency are therefore consistent with its effects on CFC, and lend further support to the proposed link between the temporal characteristics of electrophysiological recordings and behavioral outcomes.
Similar to its effects on latency, we also found that chronic ketamine had negative consequences in terms of P80 amplitude and gating, as gating was decreased over both test weeks. The mouse P80 displays morphology, relative latency and pharmacological response properties similar to those of the human P200 (Siegel, Connolly et al. 2003
; Maxwell, Liang et al. 2004
). Clinical electrophysiology studies consistently show that the P200 exhibits decreased amplitude and inhibition in patients with schizophrenia (Roth, Pfefferbaum et al. 1981
; Ford, Roth et al. 1999
). Such changes are usually manifest as a reduction in the ability to gate repeated stimuli, as mediated by a decrease in S1 amplitude. Therefore, the effects of chronic ketamine treatment on P80 amplitude and gating support both the NMDAR blockade and chronic ketamine models of abnormal P80/P200 amplitudes after auditory stimuli, as seen in schizophrenia. The P200 has multiple generators and due to their analogous nature, it is believed that the mouse P80 does, as well (Wunderlich and Cone-Wesson 2001
; Sheehan, McArthur et al. 2005
). However, because the recording technique utilized in this study measures whole-brain activity, it is impossible to determine which regions were affected by ketamine and responsible for the gating deficit observed. Because immunohistochemical analyses were not performed, it is also not possible to confirm that the long-lasting effect of ketamine on P80 amplitude, and P20 latency, were due to mechanisms other than NMDAR blockade.
The current study builds upon previous reports assessing the effects of chronic ketamine treatment on the mouse AEP. Until now, such studies have only evaluated these effects immediately and one week after a 14-day daily administration regimen. Therefore, this study demonstrates that continued ketamine administration has even longer lasting effects on AEP components than previously recognized. Such lasting effects also add support to the belief that repeated recreational ketamine use could have long-term effects on brain function and information processing.