Animal models of cognitive dysfunction and negative symptoms of schizophrenia: focus on NMDA receptor antagonism.

Question

1. How long does sertindole take to reverse the cognitive deficit?

2. What is the purpose of the attentional set-shifting task?

3. How long do rats have to respond to the active lever?

4. What is the importance of the duration of each trial?

Accepted Answer

In addition, BL1020, glycine uptake inhibitors and the novel antipsychotic, asenapine also show efficacy to reverse the PCPinduced deficit in this task using a 1 min and 1 hour (for sertindole) ITI.

Accepted Answer

Initial studies using the attentional set-shifting task showed that lesions of the medial prefrontal cortex (mPFC) produce a selective deficit in the EDS phase (Birrell and Brown, 2000), whereas lesions of the orbital prefrontal cortex in male hooded-Lister rats selectively disrupts reversal learning (McAlonan and Brown, 2003).

Accepted Answer

On the following day, rats have 5 mins to respond on the active lever from the previous training day, they then have a 2 min time-out, before the active lever is switched to the opposite lever.

Accepted Answer

The duration of each trial is also important as a preference for the novel object only lasts during the first 1 or 2 minutes, after which time preference diminishes as both objects become familiar and are explored equally.

Accepted Answer

Reversal learning ability can also be assessed using other tasks such as the reversal stages within the attentional set-shifting paradigm.

Accepted Answer

PCP is not the only means of producing a pharmacological deficit in reversal learning, the authors have shown that acute administration of the NMDA antagonists ketamine (15 mg/kg) and MK801 (0.05 mg/kg) produce a selective deficit for the reversal phase of the task (Idris et al., 2006).

Accepted Answer

in both tasks ketamine unexpectedly reduced the number of perseverative errors made compared to the saline-treated group; however in a reversal of the acquired set-shift in the operant procedure, ketamine did produce more perseverative errors than the control group (Floresco et al., 2009).

Accepted Answer

Their laboratory has shown in numerous studies that a sub-chronic PCP treatment regime, specifically, 2 mg/kg twice daily for seven days followed by a seven day washout period, induces a robust cognitive deficit in the NOR paradigm, whereby the ability of rats to discriminate between novel and familiar objects is abolished.

Accepted Answer

The authors have recently shown that acute administration of PCP (1.5-2 mg/kg) to female hoodedLister rats induces a selective and robust impairment in the retention trial of the NOR paradigm, using a 1 min inter-trial interval (ITI), rats were unable to discriminate between the novel and familiar object (Grayson et al., 2004).

Accepted Answer

A single dose of PCP has been shown to produce hallucinations and reduce cognitive function in schizophrenia patients (Krystal et al. 1994; Steinpres 1996).

Accepted Answer

The authors attribute the lack of set-shifting deficit in ketamine-treated rats to a possible lack of training on the initial procedures compared to the attentional set-shifting task described by Birrell and Brown (2000), and due to the shorter duration of action of ketamine compared to PCP, i.e. ketamine-induced neuronal alterations may not have been sufficient to disrupt the mPFC dependent behaviours.

Accepted Answer

The two domains the authors have not yet validated in their laboratory include working memory and verbal learning and memory, with the obvious difficulties of mimicking these deficits in animals.

Accepted Answer

In support of the above findings with PCP, intra-cortical injections of the NMDA receptor antagonist, MK-801 into the mPFC (1 or 3 µg per hemisphere), was shown to produce selective deficits for the set 2 strategy in a maze-based set shifting task in male SpragueDawley rats (this is equivalent to the EDS phase in the perceptual attentional set-shifting task), whereas the AMPA receptor antagonist, LY293558 (1 µg per hemisphere), also impaired the set 1 strategy which represents acquisition of a discrimination rule (Stefani andMoghaddam, 2003).

Accepted Answer

In a reversal-learning task similar to that employed in their laboratory, however, using an innovative touch screen-based system, sub-chronic PCP (5 mg/kg twice daily for 7 days, followed by a 7-day washout period) in male C57BL/6J mice did not affect reversal learning ability (Brigman et al., 2009).

Accepted Answer

The origin of the idea that glutamatergic neurotransmission is disrupted in schizophrenia dates back to the 1950s when it was first reported that the anaesthetic phenylcyclidine (PCP, Sernylan (R) Parke Davis) could produce psychotic effects in people (Luby et al., 1959).

Accepted Answer

It remains to be determined whether the antipsychotic-induced reversal of PCP-induced NOR deficits is mediated by a restoration of prefrontal cortical dopamine.

Accepted Answer

These results suggest that in mice, activation of the NMDA receptors is necessary for encoding of recognition memory but not for consolidation and retrieval processes (Nilsson et al., 2007).

Accepted Answer

Although most commonly used, PCP is not the only pharmacological means of producing cognitive impairments in attentional set-shifting, for example amphetamine sensitised male Sprague-Dawley rats show deficits in this task (Fletcher et al., 2005).

Animal models of cognitive dysfunction and negative symptoms of schizophrenia: focus on NMDA receptor antagonism.

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Most frequently asked questions

1. How long does sertindole take to reverse the cognitive deficit?

2. What is the purpose of the attentional set-shifting task?

3. How long do rats have to respond to the active lever?

4. What is the importance of the duration of each trial?

5. What can be done to improve reversal learning ability?

6. What is the main reason why the reversal learning task is not a pharma?

7. What is the effect of ketamine on set-shifting?

8. How does the rat learn to distinguish between familiar and novel objects?

9. What is the effect of PCP on the retention trial of the NOR paradigm?

10. What is the effect of PCP on schizophrenia?

11. What is the reason for the lack of set-shifting deficit in ketamine-treated?

12. What are the two domains of cognition that the authors have not yet validated in their laboratory?

13. What is the effect of PCP on set-shifting?

14. What is the effect of a reversal learning task?

15. What is the origin of the idea that glutamatergic neurotransmission is disrupted?

16. What is the significance of the reversal of NOR in mice?

17. What is the significance of the NMDA receptors in mice?

18. What is the main reason for the lack of set-shifting deficit in a male Long?

Citations

Animal models of schizophrenia

Altering the course of schizophrenia: progress and perspectives

Update on Typical and Atypical Antipsychotic Drugs

Rapid-acting glutamatergic antidepressants: the path to ketamine and beyond.

Negative symptoms of schizophrenia: clinical characteristics, pathophysiological substrates, experimental models and prospects for improved treatment

References

Behavioural and neurochemical effects of post-weaning social isolation in rodents—Relevance to developmental neuropsychiatric disorders

Ketamine-Induced Exacerbation of Psychotic Symptoms and Cognitive Impairment in Neuroleptic-Free Schizophrenics

The pharmacology, neuroanatomy and neurogenetics of one-trial object recognition in rodents.

Decreased Glutamic Acid Decarboxylase67 Messenger RNA Expression in a Subset of Prefrontal Cortical γ-Aminobutyric Acid Neurons in Subjects With Schizophrenia

Orbital prefrontal cortex mediates reversal learning and not attentional set shifting in the rat

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