ABSTRACT
This review presents an overview of some of the pre-clinical and clinical issues that have contributed to the failures of potential novel neuropsychiatric drugs, which have prompted a re-examination of the role of animal models of neuropsychiatric disorders. Advances both in basic neuroscience and technology have driven the development of animal models of aspects of neuropsychiatric disorders. Genetics and environmental factors have been the primary contributors to the development of new animal models. Neuroimaging has contributed to the search for biomarkers by which neuropsychiatric disorders may be identified and differentiated, its progression monitored and that the effects of therapy assessed. Parallel to these theoretical and practical advancements have been the changes in the diagnosis and classification of neuropsychiatric disorders from DSM-4 to DSM-5, and emergence of the NIH initiatives such as MATRICS; CNTRICS and RDoC. These latter changes are shifting our concepts of neuropsychiatric disorders away from phenomenology to their biology and thus aligning physiology with psychology.
Subject(s)
Drug Discovery , Animals , Biomarkers , Humans , Models, Animal , Neuroimaging , Translational Research, BiomedicalABSTRACT
The limited effect of AChE inhibitors and NMDA receptor antagonists for the treatment of the cognitive symptoms of Alzheimer's disease has prompted the search for new drugs that are capable not only of treating behavioral symptoms, but also of modifying the disease process. Considerable research efforts have been focused on orthosteric muscarinic M1 functional agonists during the past decade to address both these strategies. Part of this research has included the use of non-human primates as models of cognitive impairment to demonstrate preclinical efficacy. No M1 functional agonist has been successfully registered for the treatment of Alzheimer's disease, mostly because of mechanism-related adverse side effects and marginal cognitive effects. However, the M1 agonist xanomeline exhibited preclinical and clinical efficacy for the treatment of the negative and cognitive symptoms of schizophrenia. These results prompted renewed interest in repositioning compounds such as sabcomeline (Proximagen Group plc) for this indication, as well as developing allosteric muscarinic M1 ligands to improve efficacy while reducing side-effect-related attrition. This review discusses preclinical and clinical data from orthosteric M1 functional agonists, focusing on target validation in primate cognition studies, and provides recommendations for testing a new generation of M1 ligands and compounds with novel mechanisms of action.
Subject(s)
Alzheimer Disease/drug therapy , Cognition/drug effects , Muscarinic Agonists/pharmacology , Muscarinic Agonists/therapeutic use , Receptor, Muscarinic M1/agonists , Animals , Clinical Trials as Topic , Disease Models, Animal , Humans , Primates , Validation Studies as TopicABSTRACT
The need for treatment of obesity and obesity-related diseases, such as type 2 diabetes, has been intensified by the epidemic rise of obesity. Recent advances make possible continuous monitoring of metabolically relevant functions in animals to identify novel thermogenic and anorectic compounds. This unit describes non-invasive in vivo calorimetric assessment of energy expenditure using measurements of oxygen consumption and carbon dioxide production, complemented by telemetric monitoring of body core temperature and locomotor activity in mice and rats. Reference compounds are used to illustrate the determination of substance-specific parameters, such as the dose that produces the half-maximal effect (ED(50)), the maximal effect, as well as the time of onset and duration of compound action. Indirect calorimetry performed at different temperatures provides information on several other well-defined parameters, including resting metabolic rate, basal metabolic rate, lower critical temperature, temperature sensitivity, defended body temperature, and respiratory quotient.
Subject(s)
Calorimetry, Indirect , Energy Metabolism/physiology , Animals , Behavior, Animal , Body Temperature/physiology , Calorimetry, Indirect/instrumentation , Calorimetry, Indirect/methods , Diabetes Mellitus, Type 2/etiology , Diabetes Mellitus, Type 2/metabolism , Diabetes Mellitus, Type 2/physiopathology , Disease Models, Animal , Male , Mice , Mice, Inbred Strains , Mice, Obese , Mice, Transgenic , Motor Activity/physiology , Oxygen Consumption , Protein Tyrosine Phosphatase, Non-Receptor Type 1/geneticsABSTRACT
The need for treatment of obesity and obesity-related diseases, such as type 2 diabetes, has been intensified by the epidemic rise of obesity. Recent advances make possible continuous monitoring of metabolically relevant functions in animals to identify novel thermogenic and anorectic compounds. This unit describes non-invasive in vivo calorimetric assessment of energy expenditure using measurements of oxygen consumption and carbon dioxide production, complemented by telemetric monitoring of body core temperature and locomotor activity in mice and rats. Reference compounds are used to illustrate the determination of substance-specific parameters, such as the dose that produces the half-maximal effect (ED(50)), the maximal effect, as well as the time of onset and duration of compound action. Indirect calorimetry performed at different temperatures provides information on several other well-defined parameters, including resting metabolic rate, basal metabolic rate, lower critical temperature, temperature sensitivity, defended body temperature, and respiratory quotient.
Subject(s)
Diabetes Mellitus/drug therapy , Energy Metabolism , Obesity/drug therapy , Animals , Carbon Dioxide/metabolism , Energy Metabolism/drug effects , Male , Mice , Mice, Inbred C57BL , Oxygen Consumption , TemperatureABSTRACT
Because of the dramatic increase in obesity and related conditions, such as type 2 diabetes, efforts have intensified to develop medications to assist in losing weight or in minimizing weight gain. To this end, methods that allow for the continuous monitoring of metabolically relevant functions in laboratory animals have been developed to help identify novel anorectic and thermogenic agents. Described in this unit is an in vivo procedure for simultaneous recording of feeding, drinking, and motor activity in mice. Data obtained using reference compounds are presented to illustrate how results are calculated, including the minimum effective dose and the dose producing a half-maximal effect (ED(50)), as well as the time of onset and duration of action. Information derived from this procedure reveals the specificity of an anorectic effect, which, when combined with parameters of meal patterns, allows for inferences to be made about the effects of test compounds on satiety and hunger.
