Four-week repeated oral dose toxicity study of zinc maltol in rats.

Zinc (Zn) is one of the trace elements, and Zn deficiency causes many adverse effects. Zn complexes are used for Zn supplementation, but there are few toxicity reports. Zn maltol (ZM) was orally administered for 4 weeks to male rats at a dose of 0, 200, 600, or 1000 mg/kg to assess its toxicity. As a ligand group, maltol was administered at a dose of 800 mg/kg/day. General conditions, ophthalmology, hematology, blood biochemistry, urinalysis, organ weights, necropsy, histopathology, and plasma Zn concentration were investigated. Plasma Zn concentration increased with dose levels of ZM. The following toxicities were observed at 1000 mg/kg. Pancreatitis was observed with histopathological lesions and increases in white blood cell parameters and creatine kinase. Anemia was observed with changes in red blood cell parameters and extramedullary hematopoiesis in the spleen. Decreases in the trabecula and growth plate in the femur were observed. On the other hand, no toxicities were observed in the ligand group. In conclusion, these toxicities induced by ZM have been reported as Zn-related toxicities. It was considered that these results will be helpful for a creation and development of new Zn complexes as well as supplements.

Comparative study on detectability of learning and memory disorder between two water maze tests commonly used in juvenile rat toxicity studies using isoflurane inhaled rat model.

Evaluation of learning and memory is crucial in juvenile animal toxicity studies (JAS) during the development of CNS active drugs, but there are no currently recommended test methods. We compared the ability of the Morris water maze (MWM) and the Biel water maze (BWM) to detect learning and memory disorder (LMD) using rats inhaled isoflurane (IFN). Rats were treated with 1% IFN using inhalation on postnatal day (PND) 7 for 6 h. All rats were subjected to the MWM on PND 33 and the BWM on PND 55/57 (Experiment 1), or the BWM on PND 32/33 and the MWM on PND 54/55 (Experiment 2). On PND 70, the brain was weighed and then neurohistopathology was conducted. There were no IFN-related changes in clinical signs and body weight. In the tests beginning on PND 32/33, the MWM clearly detected IFN-related LMD in both sexes whereas the BWM detected LMD only in males. With an additional benefit of a simpler procedure, the MWM was considered superior to the BMW for JAS. LMD was not detected in both mazes tested from PND 54/55/57, which was considered due to weak effect and/or recovery of brain function with growth. Single IFN inhalation on PND 7 was considered useful as positive control to induce LMD caused by postnatal exposure in rats, but stronger treatment regimens was recommended.

The effect of 5-HT1A receptor antagonist on reward-based decision-making.

When choosing the best action from several alternatives, we compare each value that depends on the balance between benefit and cost. Previous studies have shown that animals and humans with low brain serotonin (5-HT) level tend to choose smaller immediate reward. We used a decision-making schedule task to investigate whether 5-HT1A receptor is responsible for the decisions related to reward. In this task, the monkeys chose either of two different alternatives that were comprised of 1-4 drops of liquid reward (benefit) and 1-4 repeats of a color discrimination trial (workload cost), then executed the chosen schedule. By the administration of 5-HT1A antagonist, WAY100635, the choice tendency did not change, however, the sensitivity to the amount of reward in the schedule part was diminished. The 5-HT1A could have a role in maintaining reward value to keep track with the promised reward rather than modulating workload discounting of reward value.

Neurons in the monkey orbitofrontal cortex mediate reward value computation and decision-making.

Choice reflects the values of available alternatives; more valuable options are chosen more often than less valuable ones. Here we studied whether neuronal responses in orbitofrontal cortex (OFC) reflect the value difference between options, and whether there is a causal link between OFC neuronal activity and choice. Using a decision-making task where two visual stimuli were presented sequentially, each signifying a value, we showed that when the second stimulus appears many neurons encode the value difference between alternatives. Later when the choice occurs, that difference signal disappears and a signal indicating the chosen value emerges. Pharmacological inactivation of OFC neurons coding for choice-related values increases the monkey's latency to make a choice and the likelihood that it will choose the less valuable alternative, when the value difference is small. Thus, OFC neurons code for value information that could be used to directly influence choice.

Self-choice enhances value in reward-seeking in primates.

When an individual chooses one item from two or more alternatives, they compare the values of the expected outcomes. The outcome value can be determined by the associated reward amount, the probability of reward, and the workload required to earn the reward. Rational choice theory states that choices are made to maximize rewards over time, and that the same outcome values lead to an equal likelihood of choices. However, the theory does not distinguish between conditions with the same reward value, even when acquired under different circumstances, and does not always accurately describe real behavior. We have found that allowing a monkey to choose a reward schedule endows the schedule with extra value when compared to performance in an identical schedule that is chosen by another agent (a computer here). This behavior is not consistent with pure rational choice theory. Theoretical analysis using a modified temporal-difference learning model showed an enhanced schedule state value by self-choice. These results suggest that an increased reward value underlies the improved performances by self-choice during reward-seeking behavior.