A frightening view on schizophrenia. Combining fear conditioning and ketamine administration to investigate emotional blunting in an animal model of schizophrenia (original) (raw)
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An Animal Model of Emotional Blunting in Schizophrenia
PLoS ONE, 2007
Schizophrenia is often associated with emotional blunting-the diminished ability to respond to emotionally salient stimuliparticularly those stimuli representative of negative emotional states, such as fear. This disturbance may stem from dysfunction of the amygdala, a brain region involved in fear processing. The present article describes a novel animal model of emotional blunting in schizophrenia. This model involves interfering with normal fear processing (classical conditioning) in rats by means of acute ketamine administration. We confirm, in a series of experiments comprised of cFos staining, behavioral analysis and neurochemical determinations, that ketamine interferes with the behavioral expression of fear and with normal fear processing in the amygdala and related brain regions. We further show that the atypical antipsychotic drug clozapine, but not the typical antipsychotic haloperidol nor an experimental glutamate receptor 2/3 agonist, inhibits ketamine's effects and retains normal fear processing in the amygdala at a neurochemical level, despite the observation that fear-related behavior is still inhibited due to ketamine administration. Our results suggest that the relative resistance of emotional blunting to drug treatment may be partially due to an inability of conventional therapies to target the multiple anatomical and functional brain systems involved in emotional processing. A conceptual model reconciling our findings in terms of neurochemistry and behavior is postulated and discussed.
Deficits in emotional learning and memory in an animal model of schizophrenia
Behavioural Brain Research, 2012
Alterations in N-methyl-D-aspartate (NMDA) receptor function have been linked to numerous behavioral deficits and neurochemical alterations. Recent investigations have begun to explore the role of NMDA receptor function on principally inhibitory neurons and their role in network function. One of the prevailing models of schizophrenia proposes a reduction in NMDA receptor function on inhibitory interneurons and the resulting disinhibition may give rise to aspects of the disorder. Studies using NMDA receptor antagonists such as PCP and ketamine have induced schizophrenia-like behavioral deficits in animal model systems as well as changes in inhibitory circuits. The current study investigated whether the administration of a subanesthetic dose of ketamine (8 mg/kg subcutaneously), that disrupts sensorimotor gating, also produces impairments in a Pavlovian emotional learning and memory task. We utilized both standard delay and trace cued and contextual fear conditioning (CCF) paradigms to examine if ketamine produces differential effects when the task is more difficult and relies on connectivity between specific brain regions. Rats administered ketamine displayed no significant deficits in cued or contextual fear following the delay conditioning protocol. However, ketamine did produce a significant impairment in the more difficult trace conditioning protocol. Analyses of tissue from the hippocampus and amygdala indicated that the administration of ketamine produced an alteration in GABA receptor protein levels differentially depending on the task. These data indicate that 8 mg/ kg of ketamine impairs learning in the more difficult emotional classical conditioning task and may be related to altered signaling in GABAergic systems.
Progress in Neuro-Psychopharmacology and Biological Psychiatry, 2006
The neurotransmitter glutamate and its associated receptors perform an important role in the brain circuitry underlying normal fear processing. The glutamate NMDA receptor, in particular, is necessary for the acquisition and recollection of conditioned-fear responses. Here the authors examine how acute blockage of the NMDA receptor with sub-aesthetic doses of ketamine affect behavioural assays of fear-conditioned stress (e.g. freezing) and cFos expression in a network of brain areas that have previously been implicated in fear processing.
Expression of c-Fos and CRF in the brains of rats differing in the strength of a fear response
Behavioural brain …, 2008
The aim of the study was to examine the neurochemical background of differences in the individual responses to conditioned aversive stimuli, using the strength of a rat conditioned freezing response (the contextual fear test), as a discriminating variable. It was shown that low responders (LR), i.e. rats with duration of a freezing response one standard error, or more, below the mean value, had a higher activity of the M2 cortical area, and the median raphe nucleus (c-Fox expression), in comparison to the high responders (HR), i.e. rats with the duration of a freezing response one standard error, or more, above the mean value. These animals had also stronger 5-HT-and CRF-related immunostaining in the M2 area, and increased concentration of GABA in the basolateral nucleus of amygdala (in vivo microdialysis). The LR group vocalized more during test session in the aversive band, and had higher serum levels of corticosterone, examined 10 min after test session. It was shown that different natural patterns of responding to conditioned aversive stimuli are associated with different involvement of brain structures and with dissimilar neurochemical mechanisms.
Behavioural and Motor Responses to Induced Fear in Wistar Rats
American Journal of PharmTech Research, 2018
This study investigated the behavioral and motor responses of induced fear in Wistar rats. Twentyfive wister rats used in this experiment were divided into five groups with each group comprising of five rats. Group I received low dose of glutamate receptor antagonist (GRA), Group II received high dose of GRA, Group III were given low dose of adrenaline, Group IV were given high dose of adrenaline while Group V (control group) were given normal saline. These animals were made to undergo two sets of tests viz; One, Induced Fear and Emotional Reactivity (IFER) Test using light/dark automatic reflex conditioned box to test for their threshold for fear shortly after induction using foot-shock method. The degree of passivity, grooming and escape attempt were noted and recorded and their respective cognitive recovery potentials were measured. Two, the Elevated Plus Maze (EPM) Test was employed to assess their level of fear expression under drug influence. The results and extrapolations suggested that groups administered with glutamate receptor antagonist in both low and high concentrations expressed less enhanced alertness, mental cognition and general awareness in both the light and dark compartments on a short time basis with activities characterized with passivity, grooming and attempt to escape when compared with those sets of observations in the adrenaline-administered groups both in short and long term durations with much significant influence (p< 0.05). The results of the elevated maze plus (EPM) test followed the same pattern. The present results indicate that induced fear significantly interfered with cognitive activities and normal patterned behaviour in animals and the consequence of this psychic interference played out apparently in after-fear potential (a set of relatively new set of behavioural patterns. The cognitive recovery potential was significantly (p< 0.05) slowest in the glutamate antagonist groups and fastest (p< 0.05) in the adrenaline groups. These observations suggest that excitatory agonists like thiopental (glutamate receptor antagonist) may lack the ability to ameliorate stress-laden influence on brain cognitive circuitry but stress hormones such as adrenaline do in extremely significant fashion.
Rodent doxapram model of panic: behavioral effects and c-Fos immunoreactivity in the amygdala
Biological Psychiatry, 2003
Panic attacks, the hallmark of panic disorder, are often characterized by hyperventilation. Existing animal models of anxiety have not addressed the effects of the hyperventilation on anxiety-related behaviors. Doxapram is a respiratory stimulant that reliably evokes panic attacks in patients with panic disorder. We examined doxapram in four rodent models of anxiety and sought to identify brain regions involved in its behavioral effects. The effects of doxapram were determined for cue and contextual fear conditioning, the open field test, and the social interaction test. The effect of doxapram on c-Fos-like immunoreactivity was examined in three brain regions. Doxapram at 4 mg/kg increased anxiety-related behaviors in all four anxiety models. An inverted U-shaped dose-response curve was identified for fear conditioning to cue. Doxapram induced c-Fos-like immunoreactivity in the central nucleus of the amygdala but not the lateral nucleus or the nucleus tractus solitarius. Doxapram enhanced anxiety-related behaviors in four animal models of anxiety that involve conditioning or spontaneous avoidance. The effect of doxapram may result from activation of neurons in the amygdala. Doxapram, by inducing hyperventilation, may be a useful adjunct to existing animal anxiety models for improving validity for panic anxiety.
Progress in Neuro-Psychopharmacology and Biological Psychiatry, 2004
Previously, it was shown that subchronic application of the NMDA receptor antagonist ketamine (Ket) induces schizophrenia-related alterations, e.g. decreased non-aggressive behaviour in the social interaction test, which might be a useful animal model in the study of negative symptoms of this disease. In order to further evaluate the predictive validity of this model, the anxioloytic diazepam, the classic neuroleptic haloperidol and the atypical neuroleptics clozapine and risperidone were tested after acute and subchronic treatment. The experiments demonstrated that haloperidol did not normalise the behavioural effects of Ket. After acute administration, diazepam was ineffective in control animals but increased non-aggressive behaviour in Ket-treated animals. Similar effects were found in animals injected with either clozapine or risperidone. Twenty-four hours after discontinuation of subchronic treatment with both substances, there was an increase in the percentage of non-aggressive behaviour in the ketamine group and a decrease in the control animals. This decrease was explained in terms of withdrawal. Different effects in the control groups and the Ket groups were found when the test was performed 1 h after subchronic clozapine or risperidone treatment. The data suggest that atypical antipsychotic drugs (APD) effectively counteract Ket-induced alterations in social behaviour. Regarding false-positive effects by anxiolytic drugs without antipsychotic efficacy, this model may have some predictive validity for identifying anxiolytic effects of novel antipsychotic compounds. D
Brain c-Fos immunocytochemistry and cytochrome oxidase histochemistry after a fear conditioning task
Psicothema, 2007
The involvement of the basolateral and the medial amygdala in fear conditioning was evaluated using different markers of neuronal activation. The method described here is a combination of cytochrome oxidase (CO) histochemistry and c-Fos immunocytochemistry on fresh frozen brain sections. Freezing behavior was used as an index of auditory and contextual fear conditioning. As expected, freezing scores were significantly higher in rats exposed to tone-shock pairings in a distinctive environment (conditioned; COND), as compared to rats that did not receive any shocks (UNCD). CO labeling was increased in the basolateral and medial amygdala of the COND group. Conversely, c-Fos expression in the basolateral and medial amygdala was lower in the COND group as compared to the UNCD group. Furthermore, c-Fos expression was particularly high in the medial amygdala of the UNCD group. The data provided by both techniques indicate that these amygdalar nuclei could play different roles on auditory a...
The effects of FG7142 on overexpectation of Pavlovian fear conditioning.
Behavioral neuroscience, 2009
Six experiments studied the role of GABA A receptor activation in expression of overexpectation of Pavlovian fear conditioning. After separate pairings of CSA and CSB with shock in Stage I, rats received pairings of the compound AB with shock in Stage II, producing overexpectation of fear. The expression of overexpectation was attenuated, in a dose-dependent manner, by the benzodiazepine partial inverse agonist FG7142. FG7142 had no effect on responding to a CS paired with a low magnitude US or a CS subjected to associative blocking. These results suggest that the negative prediction error generated during overexpectation training may impose a mask on fear rather than erasing the original fear learning. They support claims that overexpectation shares features with extinction.