ABSTRACT
Genetic abnormalities in amyloid precursor protein (APP) are associated with Down's syndrome and familial Alzheimer's disease where hallmark plaques contain A beta peptides derived from APP. Both APP and its derivatives are implicated in neurodegenerative processes and may play important physiological and pathophysiological roles in synaptic function. Here, we show that young APP23 transgenic mice overexpressing human APP with the Swedish double mutation display altered novelty seeking behavior before the age of plaque onset. Using short interfering RNA (siRNA) targeted against APP, we investigate the direct contribution of APP and its derivatives to this behavioral deficit. After validating siRNAs targeting human APP in vitro, siRNAs were infused directly into the brain of APP23 mice for 2 weeks. Behavioral analysis shows that infusion of siRNA targeted against APP completely reverses increased exploratory activity in APP23 mice. Collectively, these data suggest that excessive APP and/or its derivatives, causes a hyperactive phenotype in APP23 mice when placed in a novel environment, which is fully reversible and not linked to plaque deposits.
Subject(s)
Amyloid beta-Protein Precursor/antagonists & inhibitors , Behavior, Animal/physiology , Brain/metabolism , Exploratory Behavior/physiology , Psychomotor Agitation/genetics , RNA, Small Interfering/pharmacology , Alzheimer Disease/genetics , Alzheimer Disease/metabolism , Alzheimer Disease/physiopathology , Amyloid beta-Protein Precursor/genetics , Animals , Behavior, Animal/drug effects , Brain/drug effects , Brain/physiopathology , CHO Cells , Cricetinae , Cricetulus , Disease Models, Animal , Down-Regulation/drug effects , Down-Regulation/genetics , Environment , Exploratory Behavior/drug effects , Genetic Therapy/methods , Humans , Male , Mice , Mice, Inbred C57BL , Mice, Inbred DBA , Mice, Transgenic , Mutation/genetics , Plaque, Amyloid/genetics , Plaque, Amyloid/metabolism , Psychomotor Agitation/metabolism , Psychomotor Agitation/physiopathology , RNA Interference/physiology , RNA, Small Interfering/therapeutic useABSTRACT
Classical benzodiazepines such as diazepam are widely used tranquillisers and hypnotics in various neuropsychiatric diseases including alcohol-related disorders. One of the major drawbacks of benzodiazepine therapy, however, is an exacerbation of the sedative and hypnotic effects associated with alcohol intake, even at low doses. Even though the gamma-aminobutyric acid (GABA)A receptor complex is a common target for the actions of both classes of drugs, the molecular mechanisms underlying the enhanced pharmacological properties of the combined use of benzodiazepines and alcohol remain to be identified. The present experiments aimed at clarifying which of the GABAA receptor subtypes mediate the augmented hypnotic-like and sedative effects of combined diazepam and alcohol using the righting reflex and motor activity assays, respectively, in histidine-to-arginine point mutated mice that possess diazepam-insensitive alpha1-, alpha2-, alpha3- or alpha5-GABAA receptors. The combination of diazepam (2 or 3 mg/kg) and ethanol (3 g/kg) induced loss of righting reflex with a significantly dose-dependent increase of the latency to its full recovery in wild-type, alpha1(H101R), alpha3(H126R) and alpha5(H105R) but not in alpha2(H101R) mice. A combined treatment with diazepam (1 mg/kg) and ethanol (2.5 g/kg) precipitated motor inhibition similarly in wild-type and alpha2(H101R) mice. Responsiveness of the alpha2(H101R) mice to ethanol alone was similar to that of wild-type mice. These results demonstrate that induction of loss of righting reflex by combined diazepam and alcohol is closely dependent on the activation of the alpha2-GABAA receptors by the benzodiazepine whereas precipitation of sedation involves GABAA receptors other than the alpha2-GABAA receptors.
Subject(s)
Anesthesia , Central Nervous System Depressants/pharmacology , Conscious Sedation , Diazepam/pharmacology , Ethanol/pharmacology , GABA Modulators/pharmacology , Hypnotics and Sedatives/pharmacology , Receptors, GABA-A/metabolism , Animals , Arginine/genetics , Behavior, Animal , Histidine/genetics , Male , Mice , Mice, Mutant Strains , Motor Activity/drug effects , Point Mutation , Reflex/drug effectsABSTRACT
The open field is a very popular animal model of anxiety-like behavior. An overview of the literature on the action elicited by effective or putative anxiolytics in animal subjected to this procedure indicates that classical treatments such as benzodiazepine receptor full agonists or 5-HT(1A) receptor full or partial agonists elicit an anxiolytic-like effect in this procedure in most cases (approximately 2/3). However, compounds (triazolobenzodiazepines such as adinazolam and alprazolam, selective serotonin reuptake inhibitors) that have a different spectrum of therapeutic efficacy in anxiety disorders such as panic attacks, generalized anxiety disorder or obsessive-compulsive disorder were poorly effective as anxiolytics in the open field test, suggesting that this paradigm may not model features of anxiety disorders. The procedure is also relevant for the study of compounds endowed with anxiogenic effects, as such effects were detected after treatments with benzodiazepine receptor inverse agonists or with corticotropin releasing factor (CRF) receptor agonists.
