PCP-based mice models of schizophrenia: differential behavioral, neurochemical and cellular effects of acute and subchronic treatments

Castañé, Anna; Santana, Noemí; Artigas, Francesc

doi:10.1007/s00213-015-3946-6

Cited by 63 publications

(53 citation statements)

References 70 publications

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“…dopamine (DA) levels in the striatum (Castañé et al, 2015) and induces minor changes in D 2 receptors (Hesselink et al, 1999), while not changing the binding of D 1 receptors in several brain areas (Becker and Grecksch, 2004). Taken together, this evidence supports the hypothesis that both acute and subchronic ketamine administration exerts dopaminergic hyperactivity, which could be related to an increase in climbing.…”

Section: Discussionmentioning

confidence: 72%

Effect of ketamine administration, alone and in combination with E-6837, on climbing behavior

Briones-Aranda

Suárez-Santiago

Picazo

et al. 2016

Behavioural Pharmacology

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Some types of schizophrenia have been associated with repetitive movements lacking specific purpose, also known as stereotyped behavior. Dopamine agonists (D2) and noncompetitive N-methyl-D-aspartate receptor antagonists (e.g. ketamine) have been administered in rodent models to induce stereotyped behavior that resembles some motor symptoms of schizophrenia. Recently, a relationship has been found between 5-HT6 receptors (5-HT6Rs) and dopaminergic activity. The present study evaluates the effect of ketamine (5 and 10 mg/kg), alone and in combination with the 5-HT6R agonist E-6837, on the climbing behavior of male mice. Ketamine was administered with an acute (1 day) and subchronic (5 day) scheme. Later, these doses and schemes were combined with an acute scheme of E-6837 (5 and 10 mg/kg). With both the acute and the subchronic schemes, ketamine increased climbing behavior at a dose of 10 mg/kg, and this effect was reversed by E-6837 (at 5 and 10 mg/kg). The present results suggest that there is an interaction between N-methyl-D-aspartate and 5-HT6 receptors in the regulation of climbing behavior. Further research is necessary to provide more evidence on this interaction.

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Section: Discussionmentioning

confidence: 72%

Effect of ketamine administration, alone and in combination with E-6837, on climbing behavior

Briones-Aranda

Suárez-Santiago

Picazo

et al. 2016

Behavioural Pharmacology

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“…Impaired performance in the Spontaneous Alternation task can result from lesions of the medial PFC or corticolimbic pathways that lead to behavioral disinhibition (Lalonde, 2002), and lower alternation scores have been taken to indicate impairments in spatial working memory (Stefani and Moghaddam, 2005; Castañé et al, 2015; Grayson et al, 2016). Subchronic (but not acute) PCP treatment in adult animals impairs performance in spontaneous alternation (Castañé et al, 2015; Grayson et al, 2016). Similarly, perinatal MK-801 treatment in rats also leads to impaired spontaneous alternation in adults (Stefani and Moghaddam, 2005).…”

Section: Discussionmentioning

confidence: 99%

“…Early postnatal blockade of N-methyl-D-aspartic acid (NMDA) receptors provides a widely used rodent model for studying the neurodevelopmental consequences of NMDA receptor (NMDAR) dysfunction, which are at the center of glutamate hypotheses of schizophrenia (Javitt and Zukin, 1991; du Bois and Huang, 2007; Castañé et al, 2015). These hypotheses developed out of the observation that NMDAR antagonists induce core symptoms of the illness, including cognitive deficits, both in healthy humans (Javitt and Zukin, 1991; Krystal et al, 2002) and in animals (Amitai et al, 2007; Coleman et al, 2009; Chatterjee et al, 2011), and that they exacerbate symptoms in schizophrenic patients (Lahti et al, 1995; Malhotra et al, 1997).…”

Section: Introductionmentioning

confidence: 99%

Antioxidant Treatment with N-acetyl Cysteine Prevents the Development of Cognitive and Social Behavioral Deficits that Result from Perinatal Ketamine Treatment

Phensy

Duzdabanian

Brewer

et al. 2017

Front. Behav. Neurosci.

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Alterations of the normal redox state can be found in all stages of schizophrenia, suggesting a key role for oxidative stress in the etiology and maintenance of the disease. Pharmacological blockade of N-methyl-D-aspartic acid (NMDA) receptors can disrupt natural antioxidant defense systems and induce schizophrenia-like behaviors in animals and healthy human subjects. Perinatal administration of the NMDA receptor (NMDAR) antagonist ketamine produces persistent behavioral deficits in adult mice which mimic a range of positive, negative, and cognitive symptoms that characterize schizophrenia. Here we tested whether antioxidant treatment with the glutathione (GSH) precursor N-acetyl-cysteine (NAC) can prevent the development of these behavioral deficits. On postnatal days (PND) 7, 9 and 11, we treated mice with subanesthetic doses (30 mg/kg) of ketamine or saline. Two groups (either ketamine or saline treated) also received NAC throughout development. In adult animals (PND 70–120) we then assessed behavioral alterations in a battery of cognitive and psychomotor tasks. Ketamine-treated animals showed deficits in a task of cognitive flexibility, abnormal patterns of spontaneous alternation, deficits in novel-object recognition, as well as social interaction. Developmental ketamine treatment also induced behavioral stereotypy in response to an acute amphetamine challenge, and it impaired sensorimotor gating, measured as reduced prepulse inhibition (PPI) of the startle response. All of these behavioral abnormalities were either prevented or strongly ameliorated by NAC co-treatment. These results suggest that oxidative stress is a major factor for the development of the ketamine-induced behavioral dysfunctions, and that restoring oxidative balance during the prodromal stage of schizophrenia might be able to ameliorate the development of several major symptoms of the disease.

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“…Critically, PCP-induced deficits in rodents are still present after prolonged drug-free periods (1 week and longer) and thus reflect enduring functional changes rather than acute drug effects. PCP-pre-treated animals exhibit impaired performance on novel object recognition, spontaneous alternation, and pre-pulse inhibition, which are believed to model cognitive and negative symptoms of human schizophrenia (Castane et al 2015 ; Grayson et al 2015 ; Jorgensen et al 2015 ). The mechanisms through which PCP produces behavioral impairments are largely unknown, but neurophysiological and immunochemical results point to the involvement of prefrontal cortical circuits (Kargieman et al 2012 ; Piyabhan et al 2013 ; Young et al 2015 ).…”

Section: Introductionmentioning

confidence: 99%

Altered cortico-striatal crosstalk underlies object recognition memory deficits in the sub-chronic phencyclidine model of schizophrenia

et al. 2017

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The neural mechanisms underlying cognitive deficits in schizophrenia are poorly understood. Sub-chronic treatment with the NMDA antagonist phencyclidine (PCP) produces cognitive abnormalities in rodents that reliably model aspects of the neurocognitive alterations observed in schizophrenia. Given that network activity across regions encompassing medial prefrontal cortex (mPFC) and nucleus accumbens (NAc) plays a significant role in motivational and cognitive tasks, we measured activity across cortico-striatal pathways in PCP-treated rats to characterize neural enabling and encoding of task performance in a novel object recognition task. We found that PCP treatment impaired task performance and concurrently (1) reduced tonic NAc neuronal activity, (2) desynchronized cross-activation of mPFC and NAc neurons, and (3) prevented the increase in mPFC and NAc neural activity associated with the exploration of a novel object in relation to a familiar object. Taken together, these observations reveal key neuronal and network-level adaptations underlying PCP-induced cognitive deficits, which may contribute to the emergence of cognitive abnormalities in schizophrenia.

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PCP-based mice models of schizophrenia: differential behavioral, neurochemical and cellular effects of acute and subchronic treatments

Cited by 63 publications

References 70 publications

Effect of ketamine administration, alone and in combination with E-6837, on climbing behavior

Effect of ketamine administration, alone and in combination with E-6837, on climbing behavior

Antioxidant Treatment with N-acetyl Cysteine Prevents the Development of Cognitive and Social Behavioral Deficits that Result from Perinatal Ketamine Treatment

Altered cortico-striatal crosstalk underlies object recognition memory deficits in the sub-chronic phencyclidine model of schizophrenia

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