Nihon shinkei seishin yakurigaku zasshi = Japanese journal of psychopharmacology最新文献

Methamphetamine (METH) dependence show strong familial and genetic influences in family and twin studies. METH exerts its reinforcing effects by modulating monoaminergic transmission, of which dopamine is supposed to be important. Previously, experimental animals were being used to identify mechanisms of action of METH that are related to its abuse and toxicity, and genetic mouse models have also been used to define genes that may predict risk for the development of drug addiction. We found that genetic variances of dopamine transporter, dopamine receptor, micro-opioid receptor, serotonin 1A receptor, serotonin 6 receptor, and adenosine 2A adenosine receptor could be vulnerability factors for METH dependence or psychosis in the Japanese population. Genetic analysis with a genome-wide association study (GWAS)-based approach has been successful for investigating the genetic influences of METH dependence and other complex features. Collaborative studies with JGIDA and NIDA/NIH have obtained the results that the genetic vulnerability to METH dependence contributes to other major drug addiction. The genetic studies for METH dependence might help to identify the risk of individuals and to develop treatments that take advantage of individual genetic information in the future.

Posttraumatic stress disorder (PTSD) is a debilitating psychological condition that develops following exposure to a traumatic event. The characteristic symptoms of PTSD are re-experience, avoidance, psychic numbing and hyper-arousal. The biological PTSD literature has been dramatically growing over the past three decades. PTSD symptoms related to re-experiencing the traumatic event may be conceptualized within a fear conditioning framework. Recent findings suggest that PTSD is associated with a failure of extinction learning of an acquired fear response. A fear-circuit model of PTSD posits that vmPFC fails to inhibit the amygdala, which has a crucial role in fear learning. Exposure therapy currently has the largest number of randomized clinical trials demonstrating its efficacy, and is recommended with substantial clinical confidence in treatment guidelines for PTSD. The efficacy of Prolonged Exposure (PE) was also shown for Japanese PTSD patients in a randomized controlled trial (Asukai et al., 2010). The emotional processing theory that accounts for the treatment mechanism of PE may be consistent with the hypothesis of a neurobiological mechanism in PTSD. D-cycloserine (DCS), an NMDA partial agonist, has been shown to facilitate extinction learning in animals and humans. Clinically, DCS has been shown to be a promising augmentation to PE, particularly for those who need longer treatment.

Neuronal connections are initially redundant, but unnecessary connections are eliminated subsequently during postnatal development. This process, known as 'synapse elimination', is thought to be crucial for establishing functionally mature neural circuits. The climbing fiber (CF) to the Purkinje cell (PC) synapse in the cerebellum is a representative model of synapse elimination. We disclose that one-to-one connection from CF to PC is established through four distinct phases: (1) strengthening of a single CF among multiple CFs in each PC at P3-P7, (2) translocation of a single strengthened CF to PC dendrites from around P9, and (3) early phase (P7 to around P11) and (4) late phase (around P12 to P17) of elimination of weak CF synapses from PC somata. Mice with PC-selective deletion of P/Q-type voltage-dependent Ca2+ channel (VDCC) exhibit severe defects in strengthening of single CFs, dendritic translocation of single CFs and CF elimination from P7. In contrast, mice with a mutation of a single allele for the GABA-synthesizing enzyme GAD67 have a selective impairment of CF elimination from P10 due to reduced inhibition and elevated Ca2+ influx to PC somata. Thus, regulation of Ca2+ influx to PCs is crucial for the four phases of CF synapse elimination.

Genetic factors, personality and environmental factors contribute to the onset of major depression in a classic model. Since the 1980s, several retrospective studies have reported that childhood stress or trauma experiences occur more often in major depressive patients than in healthy controls. However, retrospective studies have a limitation: there is the possibility that depressed individuals may evidence an increased likelihood to recall negative events from their past. In 2003, Caspi et al. reported the prospective cohort study of the birth cohort in Dunedin, New Zealand, in which individuals with one or two copies of the short allele of the 5-HTT promoter polymorphism exhibited more depressive symptoms, diagnosable depression, and suicidality in relation to stressful life events (childhood maltreatment and adult stressful life events) than individuals homozygous for the long allele. This epidemiological study provided evidence of a gene-by-environment interaction (G x E interaction), in which an individual's response to environmental insults is moderated by his or her genetic makeup. Several studies of major depression reported that childhood stress or abuse increases the hypothalamic-pituitary-adrenal axis function and is related to low volume of the hippocampus and anterior cingulate. The authors examine the influence of childhood stress, adult life events and temperament on depression and anxiety in normal adults and mood disorder patients in this study.

Angelman syndrome (AS) is characterized by severe intellectual disability, epilepsy and ataxic motor dysfunction. Paternally imprinted UBE3A, which is located in the imprinted domain of 15q11-q13, is the causative gene of AS. UBE3A is exclusively expressed from the maternally inherited allele only in neurons (neuron-specific imprinting), and is regulated by antisense RNA. UBE3A is an E3 ubiquitin protein ligase and Arc is one of its targets in the brain. Arc is known to regulate AMPA-type glutamate receptor at the post-synaptic membrane. Loss-of-function of UBE3A results in upregulation of Arc and downregulation of AMPA receptors, giving rise to disturbance in experience-dependent synaptic plasticity. Unraveling the pathophysiology of AS will shed light on the development of pharmaceutical agents for genetic intellectual disabilities. Recently, topoisomerase inhibitors were shown to unsilence imprinted Ube3a in a mouse model of AS. This success indicated the possibility of an epigenetic therapy for AS. Therefore, AS is also a good model for the development of epigenetic therapy for genetic intellectual disorders caused by epigenetic dysfunction.

We previously speculated that anticholinergic activity (AA) endogenously appeared in Alzheimer's disease (AD) and accelerated AD pathology. In this article we introduce manuscripts supporting the endogenous appearance of AA in AD and the acceleration of AD pathology. We speculate that acethylcholine (ACh) not only is related to cognitive functions but also regulates the inflammatory system. Therefore in AD, in which the ACh system is down-regulated, the hyperactivity of the inflammatory system may be caused and among cyctokines, substances having anticholinergic properties may appear. We also refer to a case in which serum anticholinergic activity (SAA) disappeared with the prescription of memantine (an antidementia agent that has the property of the N-methyl-D-aspartate (NMDA) receptor blocker) and speculate that because the hyperactivity of the inflammatory system occurs by way of the hyperactivity of NMDA receptor, memantine could abolish the AA.

Recent studies revealed that the subventricular zone (SVZ) in the developing mammalian cerebrum is a source of cortical neurons along with the ventricular zone (VZ), and especially in human SVZ, abundant self-renewal stem cells exist and are thought to largely contribute to the development of huge brain. These studies suggested that the regulations of the number of progenitors or stem cells in the SVZ and their stemness are important issues for understanding the final output of the cortical neurons. We previously reported the migratory difference between the direct progeny of the VZ and the further dividing cells in the SVZ in mice. The former population finishes the cell division in the VZ, stays there for more than 10 hours, and then accumulates in the lower SVZ as multipolar cells. The other exits the VZ earlier than former, distributes widely in the SVZ and divides. These observations showed that the SVZ is divided into two regions; the lower postmitotic cell accumulation region and upper dividing cell-rich region. This model provides the framework for understanding the nature of the SVZ.

In the amygdala, it has been demonstrated that cannabinoid CB1 receptors are particularly enriched in GABAergic axon terminals and moderately expressed on glutamatergic fibers, and involved in the fear coping strategies. In this study, we found predominant neuronal projections of serotonergic, dopaminergic and cholinergic fibers in the basolateral amygdala (BA), and CB1 receptors were frequently localized on serotonergic axons but not dopaminergic, noradrenergic or cholinergic fibers. Furthermore, extracellular release of serotonin was significantly reduced by WIN55212-2, a CB agonist, whereas dopamine concentration was not altered, indicating presynaptic serotonin release is modulated by CB1 receptors. On the other hand, alpha-methyl-5-HT, 5-HT2 receptor agonist decreased the evoked IPSC and EPSC amplitude accompanied with enhancement of paired pulse ratio and induced inward currents from the patch-clamp recording BA pyramidal neurons; these are parameters of presynaptic effect and postsynaptic localization of 5-HT2 receptors, respectively. This suppression of IPSC amplitude was completely blocked by MDL100907, a 5-HT(2A) antagonist, or AM251, a CB1 antagonist. These findings suggest that endocannabinoid is synthesized via activation of postsynaptic 5-HT(2A) receptors, and regulates not only inhibitory presynaptic GABA release but also local serotonergic transmission in the BA.

Emotional disorders and cognitive dysfunctions are important treatment targets in psychiatric clinical settings. The biological mechanisms of emotional disorders have been studied with methods that include fear conditioning, schizophrenia models are studied with methamphetamine-induced reverse tolerance in rats, and dynamic changes in brain neurotransmitters are studied with microdialysis and high-performance liquid chromatography. We combined these methods in order to evaluate dopamine dynamics in the amygdala and the biological bases and relationships of emotional disorder and cognitive dysfunction. Fear-conditioned rats showed freezing behavior and dopamine release in the amygdala in response to conditioned stimuli. Methamphetamine-induced reverse tolerance rats showed increased dopamine release in the amygdala in response to conditioned stimuli. The increased release of dopamine continued after the freezing behavior had ended. This increased and long-lasting dopamine release may reflect abnormal emotional context processing in cognition in schizophrenia. Antipsychotic drugs, such as haloperidol, aripiprazole, and clozapine, suppress this increased release of dopamine in the amygdala in response to conditioned stimuli. These findings suggest that antipsychotic drugs may stabilize abnormal emotional context processing in cognition in this model. We conclude that the significance of pharmacotherapy in schizophrenia is that antipsychotic drugs stabilize the emotional context processing in cognition and adjust the relationship of emotion and cognition.