The multi‐acting receptor targeted antipsychotics (MARTA) are useful for treating schizophrenia because they are effective on not only positive symptoms but also negative symptoms. However, it is known that MARTA including olanzapine increase body weight and blood glucose levels, which often disturbs its treatment. We have shown that central administration of olanzapine causes hyperglycemia through activation of sympathetic nerves. In addition, stimulations of central dopamine D2 receptors, histamine H1 receptors and α1 adrenoceptors increase blood glucose levels. Moreover, stimulation of central dopamine D2 receptors increases blood glucose levels by increasing hepatic glucose production. Taken together, it is suggested that olanzapine activates sympathetic nerves by antagonizing central dopamine D2 receptors, which causes hyperglycemia through increase of hepatic glucose production. The research examining the mechanism how MARTA disturbs glucose metabolism contributes not only to the appropriate treatment of schizophrenia using MARTA but also to understanding the regulation of blood glucose regulation by the central nervous system.
Dopaminergic neurotransmission is considered to play a wide range of important roles in such as motor control, cognition, motivation, learning, and memory. Dopamine activates the direct pathway via the D1 receptor (D1R) and suppresses the indirect pathway via the D2 receptor (D2R) in the basal ganglia circuit. To clarify D1R or D2R‐mediated dopaminergic neurotransmission in more detail, we investigated the role of dopaminergic neurotransmission via dopamine D1Rs in motor function and aversive memory formation using conditional D1R knockdown (D1RcKD) mice, in which the expression of D1Rs can conditionally and reversibly be controlled by doxycycline treatment. It was revealed that dopaminergic neurotransmission via dopamine D1Rs maintains information transmission of the direct pathway of the basal ganglia circuit and promotes motor function. Furthermore, our findings indicated that D1R‐mediated dopaminergic transmission is critical for aversive memory formation, specifically by influencing Arc expression in the cerebral cortex. Here, we mainly present motor control and aversive memory formation using D1RcKD mice, including our recent findings.
It has been established that the selective α2A adrenoceptor agonist guanfacine re‐duces hyperactivity and improves cognitive impairment in patients with attention‐deficit/hyperactivity disorder (ADHD) . The major mechanisms of guanfacine are considered to be involved in the activation of the postsynaptic α2A adrenoceptor of glutamatergic pyramidal neurons in the orbitofrontal cortex, but the effects of chronic guanfacine administration on catecholaminergic and glutamatergic transmissions in the orbitofrontal cortex remained to be clarified. Therefore, the present report discussed with pathophysiology of ADHD via effects of selective α2A adrenoceptor agonist, guanfacine, on noradrenergic, GABAergic and glutamatergic transmission.
The nucleus accumbens (NAc) is a terminal area of mesolimbic dopaminergic neurons that originate in the ventral tegmental area. Additionally, the NAc contains GABAergic neurons that interact with dopaminergic neurons. This review describes the GABAergic neural mechanisms in NAc that regulate increases in accumbal dopamine (DA) efflux induced by selective stimulation of delta‐ and mu‐opioid receptor (‐R) subtypes in freely moving rats, focusing on findings from experiments using in vivo microdialysis techniques. First, we consider how endogenous GABA exerts inhibition of accumbal DA efflux through GABA‐R subtypes, namely GABAA‐ and GABAB‐Rs. The NAc contains GABAergic neurons that express delta‐ or mu‐opioid‐Rs, hence decreases in GABA input to GABAA‐ and/or GABAB‐Rs on dopaminergic nerve endings could mediate delta‐ or mu‐opioid‐R‐mediated increases in accumbal DA efflux. Therefore, we summarize the effects of selective GABAA‐ and GABAB‐R ligands on delta‐ and mu‐opioid‐R subtype‐mediated accumbal DA efflux. This is to increase understanding of the mechanisms of interaction between GABAergic neurons that contain delta‐ or mu‐opioid‐Rs and dopaminergic neurons in NAc. Finally, we provide a synaptic network to explain the interactions among delta‐ or mu‐opioid‐R subtypes, GABAergic neurons, GABA‐R subtypes and dopaminergic neurons in NAc.
Patients with mental disorders and their families would suffer not only from the disadvantages caused by the mental disorder itself, but also from the distress caused by attributing the cause of the disorders to their own “nature” and “nurture” (i. e. their parents and themselves) . In addition, treatments based on the pathogenesis of mental disorders have yet to be developed. In this situation, there are increasing expectations for psychiatric genomic research. Genomic studies of mental disorders have revealed that specific genomic information does not explain specific mental disorders in general, and that various factors are involved in their pathogenesis. Some new genomic insights can be used directly in the diagnosis and treatment of mental disorders. It is necessary to improve the psychiatrists’ literacy of genomic medicine so that they can provide appropriate genetic counseling in psychiatric clinical situation. Furthermore, it is essential to elucidate the pathogenesis of psychiatric disorders and to conduct drug discovery research based on the pathogenesis, which is the sincerest wish of patients and their families for psychiatric research, and it is necessary to promote the development of human resources for this purpose.
Mental disorders cause not only a great pain and loss of quality of life for the patients themselves but also enormous losses for the society. However, the pathogenesis of mental disorders has yet to be elucidated, and the development of fundamental treatments has not been realized. One of the reasons for this is that it is difficult to establish experimental models which make it possible to analyze and verify the pathological mechanisms of mental disorders. To overcome this, iPS cells have been attracting attention. Looking back at the early days when iPS cell technology was applied to investigate the pathogenesis of mental disorders, most studies simply compared “healthy subjects vs. patients with mental disorders.” In recent years, the approach has shifted to be based on risk genomic variants for the development of mental disorders. Here, we introduce our research with the combined use of genomic information and iPS cells, and discuss pons and cons of iPS cells, as well as the potential of iPS cells in elucidating the pathogenesis of mental disorders and in drug discovery.
Advances in the researches regarding genome for psychiatric disorders would expected to avoid prejudice against the mental illness and to innovate treatment and prevention against the disorders. Genomic information, on the other hand, may raises significant concerns about the potential onsets of individuals and their relatives as well. Therefore, the handling of the genomic information requires the utmost care with psychiatric care and psychological support and assurance. This review also outlines the transitional medicine from pediatric to adult care for the psychiatric symptoms of patients with hereditary and chromosomal disorders, and in general the literacy required of psychiatrists regarding genetic counseling for psychiatric disorders as common diseases.
High‐throughput sequencing has greatly contributed to precision medicine.
On the other hand, comprehensive whole‐genome analysis has raised a new issue of disclosure of secondary findings, which is different from the original purpose of the analysis, and the response to this issue has been discussed. In Japan, guidelines for secondary findings have been developed, and the disclosure of germline genetic variants, such as cancer genome profiling, is already being performed in clinical practice. However, challenges remain in reporting secondary findings (SF) of germline pathogenic variants and managing the affected patients.
In this paper, we described the prospects and challenges of disclosing genetic information to patients, genetic counseling in Japan, and returning genomic research results to clinical practice, based on our experience in conducting clinical genomic research.