ABSTRACT
Attention-deficit/hyperactivity disorder (ADHD) is a complex neurobehavioral disorder that is characterized by attention difficulties, impulsivity, and hyperactivity. A non-stimulant drug, atomoxetine (ATX), which is a selective noradrenaline reuptake inhibitor, is widely used for ADHD because it exhibits fewer adverse effects compared to conventional psychostimulants. However, little is known about the therapeutic mechanisms of ATX. ATX treatment significantly alleviated hyperactivity of pituitary adenylate cyclase-activating polypeptide (PACAP)-deficient (PACAP(-/-)) mice with C57BL/6J and 129S6/SvEvTac hybrid background. ATX also improved impaired novel object recognition memory and prepulse inhibition in PACAP(-/-) mice with CD1 background. The ATX-induced increases in extracellular noradrenaline and dopamine levels were significantly higher in the prefrontal cortex of PACAP(-/-) mice compared to wild-type mice with C57BL/6J and 129S6/SvEvTac hybrid background. These results suggest that ATX treatment-induced increases in central monoamine metabolism may be involved in the rescue of ADHD-related abnormalities in PACAP(-/-) mice. Our current study suggests that PACAP(-/-) mice are an ideal rodent model with predictive validity for the study of ADHD etiology and drug development. Additionally, the potential effects of differences in genetic background of PACAP(-/-) mice on behaviors are discussed.
Subject(s)
Adrenergic Uptake Inhibitors/therapeutic use , Atomoxetine Hydrochloride/therapeutic use , Cognition Disorders/drug therapy , Hyperkinesis/drug therapy , Memory Disorders/drug therapy , Pituitary Adenylate Cyclase-Activating Polypeptide/deficiency , Prepulse Inhibition/drug effects , Acoustic Stimulation , Analysis of Variance , Animals , Biogenic Monoamines/metabolism , Cognition Disorders/genetics , Dose-Response Relationship, Drug , Exploratory Behavior/drug effects , Hyperkinesis/etiology , Memory Disorders/genetics , Mice , Mice, Inbred C57BL , Mice, Knockout , Microdialysis , Pituitary Adenylate Cyclase-Activating Polypeptide/genetics , Recognition, Psychology/drug effectsABSTRACT
Yokukansan (YKS) is a traditional Japanese medicine consisting of seven medicinal herbs that is used for the treatment of neurosis, insomnia, and the behavioral/psychological symptoms of dementia. This study examined the effects of YKS on morphine tolerance and physical dependence in mice. Daily oral administration of YKS (0.5 or 1.0 g/kg) for 3 weeks significantly attenuated morphine tolerance and naloxone-precipitated morphine withdrawal signs (jumps and body weight loss) without affecting the analgesic effect of morphine. The inhibitory effect of YKS on withdrawal jumps in morphine-dependent mice was blocked by a single pretreatment with an α(2)-adrenoceptor antagonist, yohimbine, but not by an α(1)-adrenoceptor antagonist, prazosin. A similar inhibitory effect on withdrawal jumps was observed by repeated administration of yohimbine. The membrane expression of α(2A)-adrenoceptors in the pons/medulla was decreased in morphine withdrawn animals; this reduction was prevented by repeated administration of YKS or yohimbine. Competitive radioligand and [(35)S]guanosine-5'-O-(3-thiotriphosphate) binding assays revealed that YKS and its constituent herbs, Glycyrrhiza (GR) and Uncaria hook (UH), had specific binding affinity for and antagonist activity against the α(2A)-adrenoceptor. Certain chemical constituents, including GR -derived glycyrrhizin and its metabolite, 18ß-glycyrrhetinic acid, and UH-derived geissoschizine methyl ether (GME), shared such activities. Repeated administration of GR, UH, glycyrrhizin or GME significantly inhibited morphine withdrawal signs. These results suggest that YKS and its active constituents inhibit morphine tolerance and physical dependence, and that the latter is due at least in part to the prevention of the decreased membrane expression of the α(2A)-adrenoceptor in the brainstem by its prolonged blockade.
Subject(s)
Behavior, Addictive/drug therapy , Drugs, Chinese Herbal/therapeutic use , Morphine Dependence/drug therapy , Receptors, Adrenergic, alpha-2/metabolism , Adrenergic Agents/pharmacology , Adrenergic alpha-Antagonists/pharmacokinetics , Adrenergic beta-Antagonists/pharmacology , Analysis of Variance , Animals , Disease Models, Animal , Dose-Response Relationship, Drug , Drug Tolerance , Guanosine 5'-O-(3-Thiotriphosphate)/pharmacokinetics , Guanosine Diphosphate/pharmacology , Isotopes/pharmacokinetics , Male , Mice , Norepinephrine Plasma Membrane Transport Proteins/metabolism , Pain Threshold/drug effects , Propranolol/pharmacology , Protein Binding/drug effects , Radioligand Assay , Time Factors , Tropanes/pharmacokineticsSubject(s)
Colonic Neoplasms/pathology , Lipoma/pathology , Neoplasm Regression, Spontaneous/pathology , Adult , Biopsy , Colonoscopy , Humans , MaleABSTRACT
Nonsusceptibility to Bombyx mori densovirus type 2 (BmDNV-2) is controlled by a recessive non-susceptibility gene, nsd-2 (non-susceptibility to DNV-2) in B. mori. Taking advantage of a lack of crossing over in females, reciprocal backcrossed F1 (BF1) progeny were used for linkage analysis and mapping of nsd-2 using silkworm strains C124 and 902, which are classified as being highly susceptible and non-susceptible to DNV-2, respectively. BF1 larvae were inoculated twice with DNV-2 virus at the first and second instar stages. DNA was extracted from each of the surviving fifth instar larvae and analysed by RFLP inheritance patterns using probes specific to each of the 28 linkage groups of B. mori. Our results indicated that the non-susceptibility gene was linked to linkage group 17, since all surviving larvae showed the homozygous profile of strain 902 in their genotype. The other linkage groups showed mixtures of heterozygous and homozygous genotypes, indicating an independent assortment. A linkage map of 30.6 cM was constructed for linkage group 17 with nsd-2 mapped at 24.5 cM and three closely linked cDNA markers were identified.
