Kazuhito Ikeda

Lack of dopamine D4 receptor affinity contributes to the procognitive effect of lurasidone

We previously demonstrated among several antipsychotics exhibiting potent dopamine D2 receptor antagonism that only lurasidone, (1R,2S,3R,4S)-N-[(1R,2R)-2-[4-(1,2-benzisothiazol-3-yl)-1-piperazinylmethyl]-1-cyclohexylmethyl]-2,3-bicyclo[2.2.1] heptanedicarboximide hydrochloride, improved performance in the object retrieval detour (ORD) task by marmosets. The mechanisms by which only lurasidone causes enhancements in cognitive function have not yet been established; however, most antipsychotics, except for lurasidone, have been shown to exhibit potent antagonistic activity against the dopamine D4 receptor. The objectives of this study were to evaluate the role of the dopamine D4 receptor on executive function with the selective agonist, Ro10-5824 and antagonist, L-745,870, and elucidate a possible mechanism for the procognitive effect of lurasidone. The effects of these drugs were evaluated in naïve marmosets using the ORD task. Changes in the success rate during the difficult trial in the task were used to assess the cognitive effect of the drugs. Ro10-5824 (0.3-3 mg/kg) increased the success rate in the difficult trial, potentiated the effect of lurasidone, and reversed the cognitive impairment induced by clozapine. Interestingly, the co-administration of L-745,870 with lurasidone decreased the success rate in the difficult trial, whereas the single administration of L-745,870 had no effect. These results suggest that activation of the dopamine D4 receptor may improve executive function, whereas concomitant blockade of dopamine D4 and D2 receptors may have the opposite effect. In addition to the other unique binding profiles of other monoamine receptors, the lack of affinity for the dopamine D4 receptor by lurasidone could also contribute, at least partly, to its cognitive-enhancing effect.

Effects of lurasidone on ketamine-induced joint visual attention dysfunction as a possible disease model of autism spectrum disorders in common marmosets

Infants with autism have difficulties performing joint visual attention (JVA), defined as following another persons pointing gesture and gaze. Some non-human primates (NHPs) can also perform JVA. Most preclinical research on autism spectrum disorders (ASD) has used rodents as animal models of this social interaction disorder. However, models using rodents fail to capture the complexity of social interactions that are disrupted in ASD. Therefore, JVA impairment in NHPs might be a more useful model of ASD. The aim of this study was to develop an appropriate and convenient ASD model with common marmosets. We first tested whether marmosets were capable of performing JVA. Subsequently, we administered ketamine, an N-methyl-d-aspartate (NMDA) receptor antagonist, to induce JVA impairment and investigated the effects of lurasidone, a newer antipsychotic agent, on the JVA impairments. An apparatus was constructed using 4 white boxes, which were attached to the corners of a frame. All boxes had a hinged door, and marmosets could easily obtain a reward by pushing the door. An experimenter pointed and gazed at the boxes to inform the marmosets which box contained the reward. Their behavior was scored according to the number of incorrect choices. The JVA score was significantly higher in the cued vs. uncued tasks. Ketamine significantly decreased the JVA score, but lurasidone significantly reversed this effect. These findings suggest that this experimental system could be a useful animal model of neuropsychiatric disorders characterized by NMDA-receptor signaling, including ASD, and that lurasidone might be effective for some aspects of ASD.

An eye tracking system for monitoring face scanning patterns reveals the enhancing effect of oxytocin on eye contact in common marmosets

Eye tracking systems are used to investigate eyes position and gaze patterns presumed as eye contact in humans. Eye contact is a useful biomarker of social communication and known to be deficient in patients with autism spectrum disorders (ASDs). Interestingly, the same eye tracking systems have been used to directly compare face scanning patterns in some non-human primates to those in human. Thus, eye tracking is expected to be a useful translational technique for investigating not only social attention and visual interest, but also the effects of psychiatric drugs, such as oxytocin, a neuropeptide that regulates social behavior. In this study, we report on a newly established method for eye tracking in common marmosets as unique New World primates that, like humans, use eye contact as a mean of communication. Our investigation was aimed at characterizing these primates face scanning patterns and evaluating the effects of oxytocin on their eye contact behavior. We found that normal common marmosets spend more time viewing the eyes region in common marmosets picture than the mouth region or a scrambled picture. In oxytocin experiment, the change in eyes/face ratio was significantly greater in the oxytocin group than in the vehicle group. Moreover, oxytocin-induced increase in the change in eyes/face ratio was completely blocked by the oxytocin receptor antagonist L-368,899. These results indicate that eye tracking in common marmosets may be useful for evaluating drug candidates targeting psychiatric conditions, especially ASDs.

The atypical antipsychotic blonanserin reverses (+)-PD-128907- and ketamine-induced deficit in executive function in common marmosets

Antagonism of the dopamine D3 receptor is considered a promising strategy for the treatment of cognitive impairment associated with schizophrenia. We have previously reported that the atypical antipsychotic blonanserin, a dopamine D2/D3 and serotonin 5-HT2A receptor antagonist, highly occupies dopamine D3 receptors at its antipsychotic dose range in rats. In the present study, we evaluated the effects of blonanserin on executive function in common marmosets using the object retrieval with detour (ORD) task. The dopamine D3 receptor-preferring agonist (+)-PD-128907 at 1mg/kg decreased success rate in the difficult trial, but not in the easy trial. Since the difference between the two trials is only cognitive demand, our findings indicate that excess activation of dopamine D3 receptors impairs executive function in common marmosets. Blonanserin at 0.1mg/kg reversed the decrease in success rate induced by (+)-PD-128907 in the difficult trial. This finding indicates that blonanserin has beneficial effect on executive function deficit induced by activation of the dopamine D3 receptor in common marmosets. Next, and based on the glutamatergic hypothesis of schizophrenia, the common marmosets were treated with the N-methyl-d-aspartate (NMDA) receptor antagonist ketamine. Ketamine at sub-anesthetic doses decreased success rate in the difficult trial, but not in the easy trial. Blonanserin at 0.1mg/kg reversed the decrease in success rate induced by ketamine in the difficult trial. The findings of this study suggest that blonanserin might have beneficial effect on executive dysfunction in patients with schizophrenia.

Effects of the 5-HT1A receptor agonists buspirone and 8-OH-DPAT on pupil size in common marmosets

As pupil size is affected by psychotropic drugs in all mammals, it has been used as a well-established clinical indicator for the preclinical and clinical development of novel drugs. It has been reported that activation of the serotonin (5-HT)1A receptor differently affects pupil response in rodents (mydriasis) and humans (miosis). Thus, it is important to establish a quantitative system for measuring pupil size using other species, such as nonhuman primates. Common marmosets have recently attracted a great deal of attention as suitable experimental animals in the psychoneurological field because of handling ease compared with other nonhuman primates and the requirement for small amounts of test drugs. In this study, we constructed a system for measuring changes in pupil size using an infrared eye-tracking camera and evaluated the effects on pupil size of the 5-HT1A receptor agonists buspirone, 8-OH-DPAT and buspirone active metabolite 1-(2-pyrimidinyl) piperazine. Our results show that both buspirone and 8-OH-DPAT significantly decrease pupil size in a dose-dependent manner. The 5-HT1A receptor antagonist WAY 100635 completely blocked both buspirone and 8-OH-DPAT-induced miosis, whereas 1-(2-pyrimidinyl) piperazine had no effect on pupil size. These results suggest that measurement of pupil size may be a useful biomarker for predicting the pharmacodynamics of new 5-HT1A receptor agonists.

Blockade of dopamine D₁ receptors, but not D₂ receptors, decreases motivation in a novel effort-discounting paradigm in common marmosets.

Effort-based decision-making paradigms have recently been used to measure motivation in healthy subjects and patients with neuropsychiatric disorders. In the present study, we developed a novel effort-discounting paradigm using a touch-panel system in common marmosets. Marmosets were trained to choose between a low-reward (a piece of cake) requiring low-effort (one touch response) versus high-reward (three pieces of cake) requiring one of three different effort levels (one, two, or four touch responses). Because the number of trials per session was kept constant, the selection of the high-reward choice was always the optimal strategy to receive the maximum number of rewards. Marmosets’ high-reward rates were reduced as the physical effort requirement was increased, when they were tested using effort discounting in either ascending or descending order of effort intensity. It indicates that marmosets’ decisions could be attributable to cost-benefit evaluation, but not to their fatigue or satisfaction with the reward during the progression of the paradigm. The high dose of dopamine D1 receptor antagonist SCH-39166 (0.03 mg/kg) reduced the high-reward choice rate, only when more effort was required to obtain the high-reward than the low-reward. On the other hand, the D2 receptor antagonist raclopride (0.01 and 0.03 mg/kg) unexpectedly did not affect the high-reward choice rate, but the high dose did increase omission rate. Our finding suggests that dopamine D1 receptor signaling may play a more important role in effort-based decision making than D2 receptor signaling in marmosets. Our novel behavioral paradigm would be useful in translational research focused on motivational deficits.