Ninjin'yoeito, a traditional Japanese medicine, attenuates age-related deficits of muscle performance, self-care motivation, and body temperature in C57BL/6 mice.

As both physiological and psychological factors influence age-associated declines in older people, the development of drug therapy with multifaceted effects is required. To investigate the utility of ninjin'yoeito (NYT) against geriatric syndromes, we evaluated the effects of NYT on age-related declines in old C57BL/6 mice (88-week-old) as a preclinical model of frailty progression. Here, we showed that NYT reversed the decline of rectal temperature in old mice and also improved forelimb grip strength compared with that in the old control group without affecting skeletal muscle loss.

Quantification of central substance P receptor occupancy by aprepitant using small animal positron emission tomography.

Background: Central substance P receptors, termed NK-1 receptors, have been considered as therapeutic targets in the development of drugs against diverse conditions, including emesis, overactive bladder, and depression.

Methods: Here, we applied small animal positron emission tomography (PET) and a radioligand for NK-1 receptors ([(18)F]FE-SPA-RQ) for measuring occupancies of these receptors by a selective antagonist (aprepitant) in order to examine the validity of this in vivo imaging system for preclinical characterization of candidate agents acting on NK-1 receptors, and as a tool for predicting optimal doses in humans.

Results: PET in gerbils depicted high uptake in the striatum and dose-dependent displacement with increasing doses of aprepitant.

Chronic fluoxetine selectively upregulates dopamine D₁-like receptors in the hippocampus.

The dentate gyrus of the hippocampus has been implicated in mechanisms of action of selective serotonin reuptake inhibitors (SSRIs). We have recently demonstrated that the SSRI fluoxetine can reverse the state of maturation of the adult dentate granule cells and enhances serotonin 5-HT₄ receptor-mediated synaptic potentiation at the synapses formed by their mossy fiber axons. Here, we show that fluoxetine can induce long-lasting enhancement of dopaminergic modulation at the mossy fiber synapse.

Reversal of hippocampal neuronal maturation by serotonergic antidepressants.

Serotonergic antidepressant drugs have been commonly used to treat mood and anxiety disorders, and increasing evidence suggests potential use of these drugs beyond current antidepressant therapeutics. Facilitation of adult neurogenesis in the hippocampal dentate gyrus has been suggested to be a candidate mechanism of action of antidepressant drugs, but this mechanism may be only one of the broad effects of antidepressants. Here we show a distinct unique action of the serotonergic antidepressant fluoxetine in transforming the phenotype of mature dentate granule cells.

Quantitative analysis of NK1 receptor in the human brain using PET with 18F-FE-SPA-RQ.

Unlabelled: 18F-fluoroethyl-SPA-RQ (18F-FE-SPA-RQ) was recently developed as a radioligand for the measurement of neurokinin 1 (NK1) receptor with PET. In this study, we used 18F-FE-SPA-RQ with PET to visualize and quantify NK1 receptor in the human brain.

Methods: PET scans were performed on 7 healthy men after intravenous injection of 18F-FE-SPA-RQ.

Chronic fluoxetine bidirectionally modulates potentiating effects of serotonin on the hippocampal mossy fiber synaptic transmission.

Selective serotonin reuptake inhibitors (SSRIs) have been used to treat various psychiatric disorders. Although the cellular mechanisms underlying amelioration of particular symptoms are mostly unknown, recent studies have shown critical importance of the dentate gyrus of the hippocampus in behavioral effects of SSRIs in rodents. Here, we show that serotonin potentiates synaptic transmission between mossy fibers, the sole output of the dentate granule cells, and CA3 pyramidal cells in mouse hippocampal slices.

Phase-dependent roles of reactive microglia and astrocytes in nervous system injury as delineated by imaging of peripheral benzodiazepine receptor.

Elevated levels of peripheral benzodiazepine receptor (PBR) in glia have been documented in diverse nervous system injuries, while the identity and spatiotemporal characteristics of the cells showing upregulation of PBR remain elusive. We examined the astrocytic and microglial expressions of PBR in rat brains during the duration of ethanol-induced neuronal insults in order to clarify the significance of PBR as a biomarker capable of detecting a distinctive subpopulation of these glial cells involved in the impairment and protection of neurons. The levels of PBR, as determined by autoradiographic analysis using a specific radioligand, [11C]DAA1106, began to significantly increase at 3 days after intrastriatal injection of ethanol, and peaked at 7 days.

In vivo mapping of substance P receptors in brains of laboratory animals by high-resolution imaging systems.

Neurotransmission mediated by substance P (SP) and NK(1) receptor has been implicated in the pathophysiology of analgesia, emesis and diverse neuropsychiatric conditions including depression and anxiety disorder. Several lines of clinical trials using NK(1) receptor antagonists have been conducted to date, and the efficiency of preclinical assessments for proof of concept and dose optimization could be greatly increased by configuring an in vivo analytical system that permits quantitative mapping of NK(1) receptors in the brains of small-size laboratory animals expressing "human-like" NK(1) receptors. Hence, we investigated the applicability of experimental animals, ranging from rodents to primates, to positron emission tomographic (PET) measurements with [(18)F]fluoroethyl-SPA-RQ, a modification of a recently established radioligand for NK(1) receptors.

Distribution and pharmacological characterization of primate NK-1 and NK-3 tachykinin receptors in the central nervous system of the rhesus monkey.

Much attention has focused on tachykinin receptors as therapeutic targets for neuropsychiatric disorders, although their expressional distributions in the primate central nervous system (CNS) remain unclear. We cloned the genes encoding the NK-1 and NK-3 tachykinin receptors (referred to as rmNK-1 and rmNK-3) from the rhesus monkey (Macaca mulatta) brain and examined their pharmacological profiles and regional distributions in the CNS. The deduced rmNK-1 amino-acid sequence differed by only two amino acids from the human NK-1 (hNK-1).