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

The nucleus accumbens (NAc), the ventral part of the striatum, plays a critical role in motivation, learning, and cognition in the basal ganglia circuit. Outputs of the NAc are transmitted through two parallel direct and indirect pathways. We have developed a reversible neurotransmission blocking (RNB) technique, in which neurotransmission of each pathway in the NAc is selectively blocked by specific expression of a transmission-blocking tetanus toxin (D-RNB or I-RNB). In visual cue and reversal tasks in the cross-maze, the NAc direct pathway was critical for learning acquisition. In contrast, the NAc indirect pathway was essential not only for learning flexibility, but also for subsequent acquisition of a new strategy. In place discrimination and serial reversal learning tasks in the IntelliCage, we showed that the NAc indirect pathway controls behavioral flexibility by suppressing the influence of previously correct behavioral strategies during the reversal stage. These basal ganglia circuit mechanisms provide new insight into pathophysiologies associated with compulsive behaviors, including addiction and obesity.

Visual cortical neurons selectively respond to particular features of visual stimuli. Selective visual responsiveness is modified by visual expe- rience during development. We report that fine-scale networks of precisely interconnected excitatory neurons were embedded in the rat visual cortex and suggest that this network could be a functional unit for visual information processing. We also investigated the effects of visual dep- rivation on the development of visual cortical circuits. We used two kinds of deprivation, binocular deprivation and dark rearipg, which allowed visual inputs with only diffuse light and no visual input, respectively. The probability and strength of excitatory connections t layer 2/3 pyrami- dal cells increased during the 2 weeks after eye opening, and these changes were prevented by dark rearing, but not binocular eprivation. Fine- scale networks were absent just after eye opening and established during the following 2 weeks in rats reared with normal visual experience, but not with either type of deprivation. These results indicate that patterned vision is required for the emergence of the fine-scale network, whereas diffuse light stimulation is sufficient for the mituration of individual synapses. The critical role of early sensory experience may be to organize cell assemblies underlying visual information processing in the visual cortex.

Psychiatric disorders such as schizophrenia and depression are considered to be complex diseases that result from an interaction of many ge- netic and environmental risk factors associated with the diseases. The underlying molecular mechanisms, however, remain largely unknown and there are conditions, the treatment of which is not necessarily satisfactory due to inadequate therapeutic effect or treatment resistance. Therefore, scientific research on the brain functions and dysfunctions as well as development of better treatments is crucially important. In the present review, I will attempt to discuss such a research using animal disease models together with genetic studies in human disorders and point out future directions of the translational research on psychiatric disorders.

Cocaine-induced neuroplasticity in brain reward circuitry consisting of the ventral tegmental area (VTA), nucleus accumbens and medial pre- frontal cortex is critical for developing cocaine addiction. Recent studies have investigated the involvement of brain areas in addition to the mesocorticolimbic circuitry in cocaine addiction. One such area is the laterodorsal tegmental nucleus (LDT). Cholinergic neurons in the LDT project to the VTA and regulate the activity of dopaminergic neurons. Using the cocaine-induced conditioned place preference (CPP) paradigm in rats, we found that the activity of LDT cholinergic neurons and cholinergic transmission-from the LDT to VTA are critical for the acquisition and expression of cocaine CPP. Moreover, ex vivo electrophysiological analyses revealed that chronic cocaine administration induces plasticity in excitatory synaptic transmission and membrane excitability of LDT cholinergic neurons. Furthermore, noradrenaline, which is released from locus coeruleus axon terminals, attenuated inhibitory synaptic transmission in LDT cholinergic neurons which were obtained from rats that had received chronic cocaine but not saline administrations. This cocaine-induced plasticity in LDT cholinergic neurons may enhance the excitability of these neurons, resulting in changes in the reward circuit activity that might be associated with the development of addicted behaviors induced by cocaine.

Recent advances in neuroimaging studies enable us to measure brain function non-invasively. Over the past several decades, neuroimaging measurement has been substantially applied to elucidate the neurobiological mechanisms underlying major depressive disorder (MDD). Since MDD is a wide spectrum which consists of various symptoms such as low mood or loss of interest and is considered to affect a biologically het- erogeneous population, we have not yet elucidated the biological underpinnings of MDD. It seems to be more promising to consider MDD as an integral network abnormality instead of deficits in specific brain regions or neurotransmitters. We firstly provide a comprehensive review of the extant neuroimaging literature including structural and functional magnetic resonance imaging, magnetic resonance spectroscopy, single pho- ton emission computed tomography, and positron emission tomography studies. Then we show our neuroimaging studies for MDD toward po- tential application as a biomarker for diagnosis and treatment. We believe it will facilitate the development, of a more integrative model of neural dysfunction in MDD.

Aripiprazole once-monthly (AOM) was previously approved for treatment of schizophrenia as monthly injections in the gluteal muscle. The deltoid muscle provides a more accessible injection site. The present study was conducted in Japanese schizophrenia patients as a 24-week, open-label trial that assessed the pharmacokinetics and safety of 5 sequential doses of AOM 400 mg (AOM 400) once every 4 weeks administered in the deltoid muscle. Patients treated with an oral atypical antipsychotic (other than aripiprazole) continued to receive their pre-study medication up to 14 days after the first AOM 400 injection. The completion rate was 76.5% (n = 13/17). Mean aripiprazole plasma C(min) almost reached steady-state by the fourth AOM 400 injection. After the fifth AOM 400 injection, mean aripiprazole AUC(28d), C(max) and C(min) were 165 μg x h/ml, 331 ng/ml and 201 ng/ml, respectively, which were similar to previously published pharmacokinetic parameters after the fifth gluteal injection of AOM 400. The most common treatment-emergent adverse event (TEAE) was injection site pain (35.3%). Most TEAEs were classified as mild in intensity. In conclusion, the deltoid injection of AOM can be considered an alternative route of administration, as deltoid and gluteal injections are interchangeable in terms of aripiprazole plasma concentrations, with no additional safety issues.

Family, twin and adoption studies have revealed genetic factors involved in suicide, while the accumulation of stress and mental illnesses are major contributing factors of suicide. Since higher lethality of suicidal behavior is considered to increase familial liability to suicidal behavior, we believe biological research of completed suicide is most important for a better understanding of the pathophysiology in suicide. Dysregulated hypothalamic-pituitary-adrenal axis has gained a special interest in the neurobiology of suicide, mostly because of the findings using a dexamethasone suppression test (DST), in which DST non-suppressors show a nearly 10-fold higher risk of completed suicide than DST suppressors in a depressed cohort. Other data mainly from postmortem brain studies indicate abnormalities of the noradrenergic-locus coeruleus system, serotonergic system, endogenous opioid system, brain-derived neurotrophic factor, inflammatory cytokines and omega-3 fatty acid in completed suicide. However, genetic research of complete suicide is behind other mental problems because it is extremely difficult to obtain tissue samples of completed suicide. Under the difficult situation, we now retain over 800 blood samples of suicide completers thanks to bereaved families' cooperation. We are actively working on the research of suicide, for instance, by performing a GWAS using 500 samples of suicide completers.

The current nomenclature is based on clinical indications; for example, drugs used for mania and psychosis are classified as "mood stabilizers" and "antipsychotic drugs", respectively. This discrepancy between their names and indications often confuses patients and their caregivers and sometimes leads to a misunderstanding of the effects of prescribed medications. In addition, up-to-date scientific knowledge on these drugs has not been reflected in the current nomenclature. To overcome these limitations of the current nomenclature, following an initiative of the European Congress of Neuropsychopharmacology (ECNP), a taskforce for psychotropic nomenclature was established with representatives from 5 international organizations, including the Asian College of Neuropsychopharmacology (AsCNP). The mission of this taskforce is to provide a pharmacologically-driven (rather than indication-based) nomenclature, which is now referred to as Neuroscience-based Nomenclature (NbN). The NbN project has just started. Since it always takes time to change the culture, we understand the transition will likely involve some expected and unexpected responses from the field. However, we believe that such responses and feedback will surely improve the quality of the NbN, which in turn will be beneficial for clinicians, researchers, and patients as well as their caregivers.

Capsaicin receptor TRPV1 and wasabi receptor TRPA1 are expressed in the unmyelinated C fiber nociceptors and activated by various nociceptive stimuli causing pain in our body. Their involvement in nociception was proven with behavior studies using mice lacking TRPV1 and TRPA1. TRPV1 was found to interact with a calcium-activated chloride channel, anoctamin1 (ANO1), and calcium ions entering the primary sensory neurons activated ANO1, leading to chloride efflux which resulted in further depolarization. This is a novel pain-enhancing mechanism. A splicing variant of mouse TRPA1 (TRPA1b) was identified, and TRPA1b was found to bind to the full length TRPA1 (TRPA1a) and enhance the translocation of TRPA1a to the plasma membrane, leading to the increase in TRPA1 activity. The increase in TRPA1b transcript in the inflammatory and neuropathic pain conditions suggests the involvement of TRPA1b in the increased pain sensation under pathological conditions. Regulation of TRPV1/ANO1 complex formation or TRPA1b production could be a promising way to develop novel analgesic agents.

The positive outcome that hypothermia contributes to brain and cardiac protection following ischemia has stimulated research in the development of pharmacological approaches to induce a hypothermic/hypometabolic state. Pharmacological manipulation of central autonomic thermoregulatory circuits could represent a potential target for the induction of a hypothermic state. Here we present a brief description of the CNS thermoregulatory centers and how the manipulation of these circuits can be useful in the treatment of pathological conditions such as stroke or brain hemorrhage.