Abstract
Ketamine, principally an antagonist of N-methyl-ᴅ-aspartate receptors, induces schizophrenia-like symptoms in adult humans, warranting its use in the investigation of psychosis-related phenotypes in animal models. Genomic studies further implicate N-methyl-ᴅ-aspartate receptor-mediated processes in schizophrenia pathology, together with more broadly-defined synaptic plasticity and associative learning processes. Strong pathophysiological links have been demonstrated between fear learning and psychiatric disorders such as schizophrenia. To further investigate the impact of ketamine on associative fear learning, we studied the effects of pre- and post-training ketamine on the consolidation and extinction of contextual fear memory in rats. Administration of 25 mg/kg ketamine prior to fear conditioning did not affect consolidation when potentially confounding effects of state dependency were controlled for. Pre-training ketamine (25 mg/kg) impaired the extinction of the conditioned fear response, which was mirrored with the use of a lower dose (8 mg/kg). Post-training ketamine (25 mg/kg) had no effect on the consolidation or extinction of conditioned fear. These observations implicate processes relating to the extinction of contextual fear memory in the manifestation of ketamine-induced phenotypes, and are consistent with existing hypotheses surrounding abnormal associative learning in schizophrenia.
Highlights
Ketamine has been the focus of much research in psychiatry due to its psychotomimetic effects in healthy humans and the fact that it has been shown to augment psychotic symptoms in patient populations (Corlett et al, 2007b, 2016; Javitt and Zukin, 1991; Krystal et al, 1994; Newcomer et al, 1999)
Our results indicate that ketamine impairs between-session extinction of contextual fear memory, but leaves within-session extinction and fear memory conditioning intact
We have observed that systemic administration of the psychotomimetic, ketamine, prior to consolidation generates a statedependent fear memory at 25 mg/kg – that is, rats were better able to recall association information about the context when they were subjected to the same internal context to which the information was acquired in
Summary
Ketamine has been the focus of much research in psychiatry due to its psychotomimetic effects in healthy humans and the fact that it has been shown to augment psychotic symptoms in patient populations (Corlett et al, 2007b, 2016; Javitt and Zukin, 1991; Krystal et al, 1994; Newcomer et al, 1999). Altered associative learning and related plasticity processes have been linked to schizophrenia through behavioural and genomic studies (Diwadkar et al, 2008; Pocklington et al, 2015; Ripke et al, 2014) and have been proposed to contribute to the manifestation of positive symptoms (Corlett et al, 2009; Fletcher and Frith, 2009; Hall et al, 2009; Martins Serra et al, 2001). Extinction results in the loss of the conditioned response Both the consolidation and extinction of a fear memory are considered forms of new learning (Ochs, 1968), yet relate to behaviourally antagonistic components of Pavlovian conditioning (Bouton, 1993; Pavlov, 1927; Rescorla and Heth, 1975). Analysis of genomic data has recently highlighted a particular impact of schizophrenia-related copy number variants on molecular processes underlying fear extinction (Clifton et al, 2017), in line with previous behavioural studies suggesting abnormalities of inhibitory learning in schizophrenia (Holt et al, 2009; Martins Serra et al, 2001; Millan et al, 2012; Pocklington et al, 2015)
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