Elsevier

Behavioural Brain Research

Volume 249, 15 July 2013, Pages 109-115
Behavioural Brain Research

Research report
Effects of a dopamine D1 agonist on ketamine-induced spatial working memory dysfunction in common marmosets

https://doi.org/10.1016/j.bbr.2013.04.012Get rights and content

Highlights

  • Cognitive function was evaluated in common marmosets using the CANTAB SWM test.

  • Subanesthetic doses of ketamine induced cognitive deficiency in the marmosets.

  • A selective dopamine receptor D1 agonist was effective at ameliorating this dysfunction.

  • This model could be useful for predicting the clinical efficacy of treatments for cognitive disorders.

Abstract

It is considered that functional deficiency of the NMDA receptors in the prefrontal cortex (PFC) is one of the causes of the cognitive impairment observed in schizophrenia. As non-human primates display more developed PFC than rodents, they are considered to be useful experimental animals for improving the predictive validity of models used to discover new drugs for treating cognitive dysfunction. The aim of this study was to develop a convenient model of the cognitive impairment observed in schizophrenia using common marmosets and the CANTAB system and to test whether a full agonist of the dopamine D1 receptor (SKF-81297) was effective against the cognitive impairment induced in this model. We administered the NMDA receptor antagonist ketamine (1.5–16 mg/kg, i.m.) to the marmosets to induce cognitive impairment and then evaluated their working memory function using the CANTAB spatial working memory (SWM) test. The marmosets’ working memory was impaired by subanesthetic doses of ketamine. Next, we tested the effect of SKF-81297 (3 or 10 mg/kg, p.o.) on this ketamine-induced cognitive dysfunction. The marmosets were administered SKF-81297 30 min before the ketamine injection. Pretreatment with SKF-81297 reversed the ketamine-induced cognitive deficiency. In this study, we found that a D1 receptor agonist, which has been reported to enhance cognitive function, reversed ketamine-induced cognitive impairment in marmosets, which suggests that our marmoset model could be a useful tool for predicting the clinical efficacy of cognitive-enhancing drugs.

Introduction

In schizophrenia, cognitive impairment is one of the core symptoms affecting functional outcomes such as social adjustment and employment [1], [2]. Therefore, it is very important to improve the cognitive dysfunction of schizophrenia patients; however, atypical antipsychotics have insufficient effects in this patient group [3], [4]. On the other hand, previous preclinical studies have shown that atypical antipsychotics improved cognitive function [5], [6]. In humans, cognitive function is controlled by the prefrontal cortex (PFC), but in rodents it is mainly dependent on the hippocampus. The rodent PFC is not the same as that of primates, for example, the rodent PFC is less developed [7], [8], so it is possible that rodents execute cognitive processes through different neuronal pathways than primates, which might result in differences in drug effects between rodents and humans. To improve the predictive accuracy of models used to assess the clinical effects of drugs on higher brain functions, such as cognition, it is important to evaluate drug effects not only in rodents but also in non-human primates (NHP), whose brain structures are closer to those of humans.

N-methyl-d-aspartic acid (NMDA) receptor antagonists such as ketamine and phencyclidine (PCP) have been found to induce schizophrenia-like symptoms, for example, hallucinations, paranoia, formal thought disorders, and cognitive impairment in healthy human subjects [9], [10]. In addition, in evaluations of cognitive function in human volunteers the administration of NMDA receptor antagonists resulted in worse performance in the n-back test [11], which is PFC-dependent [12], [13], so it is thought that the cognitive dysfunction observed in schizophrenia results from abnormal glutamatergic neuronal transmission due to the hypofunction of NMDA receptors in the PFC. In addition, it has also been reported that NMDA receptor antagonists induce cognitive impairment in NHP [14], [15], [16]. Based on these facts, a NHP model of NMDA receptor antagonist-induced cognitive dysfunction could be a useful tool for translational research. Large monkeys have been used in most previous preclinical studies of cognition; however, they are difficult to handle and require a large quantity of test drugs so in this study we used common marmosets (small monkeys) instead. As the brain anatomy and genetic and immunological characteristics of marmosets are similar to those of humans, they have recently been recognized as useful experimental animals. To the best of our knowledge, no marmoset model of ketamine-induced cognitive dysfunction has been reported although similar models involving rodents and other monkey species have been developed [15], [17], [18].

The Cambridge Neuropsychological Test Automated Battery (CANTAB) is used to evaluate cognitive function and is able to assess memory, attention, and executive function. In this study, we tried to develop a marmoset model of ketamine-induced spatial working memory (SWM) deficiency using the CANTAB SWM test with the aim of constructing a drug evaluation system that is convenient to use and displays a high level of predictive validity. The SWM test is one of the components of the CANTAB and is often used in clinical research [19]. Schizophrenia patients display impairment in the SWM test [20] so it is important to improve this deficit in order to improve their quality of life. In addition, using the abovementioned experimental system, we tested the effects of a selective and full agonist of the dopamine D1 receptor (SKF-81297) on ketamine-induced cognitive dysfunction, as there is a lot of evidence that D1 agonists are effective against cognitive dysfunction in schizophrenia [21], [22], [23].

Section snippets

Effect of training on the marmosets’ success rate in the CANTAB SWM test

At the beginning of the training program, the marmosets could not accurately execute the 2-square task. It took 1–3 months for their success rate to reach a level that would allow them to be used in the subsequent experiments.

Determination of the optimal ketamine dose using the 1-circle task of the CANTAB

Ketamine immediately induced gait disorders after its injection at the dosages described in Table 1, but 30 min later, the gait disorder had disappeared. All of the marmosets were able to complete the 1-circle task within a mean of 60 s in each trial, as shown in Table 1.

Effects of a D1 agonist on ketamine-induced cognitive impairment in the CANTAB SWM test

As

Discussion

In this study, we constructed a model of ketamine-induced spatial working memory deficiency, in which we subjected marmosets to the CANTAB SWM test, with the aim of developing a drug evaluation system that is more convenient than the current methods and has high predictive validity. In addition, we showed that a D1 agonist was effective against ketamine-induced cognitive impairment. To the best of our knowledge, no such ketamine-induced cognitive dysfunction model involving marmosets has been

Animals

Five female adult common marmosets (Callithrix jacchus, 4–10 years old) obtained from CLEA Japan Inc. (Tokyo, Japan) were used in this study. The animals were housed in an air-conditioned room kept at a temperature of 28 ± 2 °C and a humidity of 50 ± 20% under a 12:12 light/dark cycle (lights off at 19:00). Food (CMS-1M, CLEA Japan, Inc.) was administered once daily, and water was available ad libitum. After the end of final experiments, animals were used in other evaluation. All experimental

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