Royal jelly reduces depression-like behavior through possible effects on adrenal steroidogenesis in a murine model of unpredictable chronic mild stress.

Royal jelly (RJ) is used as a dietary supplement for human health promotion. Recently, a clinical trial has reported that RJ improved mental health. The present study was conducted to experimentally support the clinical effect of RJ on mental health and to further elucidate the mechanisms of action of RJ. RJ and an ethanol extract of RJ, which contains fatty acids but not proteins, inhibited an unpredictable chronic mild stress (UCMS)-induced increase in immobility time, a depression-like behavior, in the tail suspension test. DNA microarray analysis of the adrenal grand revealed that the expression of genes involved in cholesterol metabolism was up-regulated in response to UCMS exposure and that RJ suppressed expression of genes related to cholesterol synthesis and transport. These results suggested that RJ improves stress-induced depression-like behavior by regulating adrenal steroidogenesis and that fatty acids contained in RJ partly contribute to the antidepressant effect of RJ.

Striatal N-Acetylaspartate Synthetase Shati/Nat8l Regulates Depression-Like Behaviors via mGluR3-Mediated Serotonergic Suppression in Mice.

Background: Several clinical studies have suggested that N-acetylaspartate and N-acetylaspartylglutamate levels in the human brain are associated with various psychiatric disorders, including major depressive disorder. We have previously identified Shati/Nat8l, an N-acetyltransferase, in the brain using an animal model of psychosis. Shati/Nat8l synthesizes N-acetylaspartate from L-aspartate and acetyl-coenzyme A. Further, N-acetylaspartate is converted into N-acetylaspartylglutamate, a neurotransmitter for metabotropic glutamate receptor 3. Methods: Because Shati/Nat8l mRNA levels were increased in the dorsal striatum of mice following the exposure to forced swimming stress, Shati/Nat8l was overexpressed in mice by the microinjection of adeno-associated virus vectors containing Shati/Nat8l gene into the dorsal striatum (dS-Shati/Nat8l mice). The dS-Shati/Nat8l mice were further assessed using behavioral and neurochemical tests. Results: The dS-Shati/Nat8l mice exhibited behavioral despair in the forced swimming and tail suspension tests and social withdrawal in the 3-chamber social interaction test. These depression-like behaviors were attenuated by the administration of a metabotropic glutamate receptor 2/3 antagonist and a selective serotonin reuptake inhibitor. Furthermore, the metabolism of N-acetylaspartate to N-acetylaspartylglutamate was decreased in the dorsal striatum of the dS-Shati/Nat8l mice. This finding corresponded with the increased expression of glutamate carboxypeptidase II, an enzyme that metabolizes N-acetylaspartylglutamate present in the extracellular space. Extracellular serotonin levels were lower in the dorsal striatum of the dS-Shati/Nat8l and normal mice that were repeatedly administered a selective glutamate carboxypeptidase II inhibitor. Conclusions: Our findings indicate that the striatal expression of N-acetylaspartate synthetase Shati/Nat8l plays a role in major depressive disorder via the metabotropic glutamate receptor 3-mediated functional control of the serotonergic neuronal system.

Overexpression of Shati/Nat8l, an N-acetyltransferase, in the nucleus accumbens attenuates the response to methamphetamine via activation of group II mGluRs in mice.

A novel N-acetyltransferase, Shati/Nat8l, was identified in the nucleus accumbens (NAc) of mice with methamphetamine (METH) treatment. Previously we reported that suppression of Shati/Nat8l enhanced METH-induced behavioral alterations via dopaminergic neuronal regulation. However, the physiological mechanisms of Shati/Nat8l on the dopaminergic system in the brain are unclear. In this study, we injected adeno-associated virus (AAV) vector containing Shati/Nat8l into the NAc or dorsal striatum (dS) of mice, to increase Shati/Nat8l expression. Overexpression of Shati/Nat8l in the NAc, but not in the dS, attenuated METH-induced hyperlocomotion, locomotor sensitization, and conditioned place preference in mice. Moreover, the Shati/Nat8l overexpression in the NAc attenuated the elevation of extracellular dopamine levels induced by METH in in vivo microdialysis experiments. These behavioral and neurochemical alterations due to Shati/Nat8l overexpression in the NAc were inhibited by treatment with selective group II metabotropic glutamate receptor type 2 and 3 (mGluR2/3) antagonist LY341495. In the AAV vector-injected NAc, the tissue contents of both N-acetylaspartate and N-acetylaspartylglutamate (NAAG), endogenous mGluR3 agonist, were elevated. The injection of peptidase inhibitor of NAAG or the perfusion of NAAG itself reduced the basal levels of extracellular dopamine in the NAc of naive mice. These results indicate that Shati/Nat8l in the NAc, but not in the dS, plays an important suppressive role in the behavioral responses to METH by controlling the dopaminergic system via activation of group II mGluRs.

[The role of a molecule associated with drug dependence, shati/nat8l].

Various molecules are involved in drug addiction induced by drugs of abuse. Therefore, the mechanism of drug addiction is still not clear, and it has been a difficulty in the development of preventive and curative drugs for drug dependence. We tried to identify the molecules associated with drug dependence, and found three molecules including shati/nat81. Recently, it has been demonstrated that the substrate for shati/nat81 is aspaltate and shati/nat8l biosynthesizes N-acetylaspartate, which exists abundantly in the mammalian brain. In this study, we investigated the physiological function of shati/nat81 and the role of shati/nat81 in drug dependence. The overexpression of shati/nat81 in the dorsal striatum of mice led to social abnormality and depression-like behavior, and worsened a part of the motor dysfunction induced by Ca2+ channel agonist BAY-K 8644. The overexpression of shati/nat81 in the nucleus accumbens of mice inhibited methamphetamine-induced behavioral and biochemical abnormalities. These findings suggest that the shati/nat81-associated system could play a role in the regulation of mental activity and motor action, and be a new target in the development of therapeutic drugs for drug dependence.