Effects of psychostimulants on locomotor activity in the BTBR T+ Itpr3tf/J mouse: implications for comorbid autism spectrum disorder and attention deficit hyperactivity disorder.
William E Fantegrossi, Hannah E Shaw, Stephen A Fagot, Kamryn Thomas, Harpreet Kaur
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引用次数: 0
Abstract
Rationale: People with autism spectrum disorder (ASD) often have psychiatric comorbidities, with attention deficit hyperactivity disorder (ADHD) being the most common. Psychostimulants used as ADHD treatments are less effective in these dual diagnosis individuals, with lower rates of symptom improvement and a higher incidence of adverse drug effects. The mutant BTBR T+ Itpr3tf/J mouse (BTBR) may serve as a model for comorbid ADHD and ASD, however, few studies have assessed the effects of psychostimulants in these animals.
Objectives: We determined dose-effect curves for locomotor effects of 10 different psychostimulants in adult male BTBR and C57Bl/6 N (C57) mice, including amphetamine and other monoamine releasers, methylphenidate and other reuptake inhibitors, as well as some drugs with a mixed profile of monoamine release and reuptake inhibition.
Methods: Mice were surgically implanted with radiotelemetry probes which measured locomotor activity within the home cage.
Results: A robust strain difference was typically observed at large doses, wherein C57 mice entered motor stereotypy while BTBRs did not. This resistance to stereotypy in BTBR mice resulted in dramatically increased locomotor stimulant effects across drugs.
Conclusions: Because resistance to locomotor stereotypy in BTBRs was observed among psychostimulants with distinct mechanisms of action and selectivities for monoamine transporters, it is likely that pervasive neurobiological and/or metabolic differences in BTBR mice mediate this effect. Further studies to determine the mechanisms underlying the exaggerated locomotor responses to psychostimulants in BTBR mice are needed. Results of these studies may guide drug development efforts toward identifying more effective and better-tolerated medications for comorbid ASD with ADHD.
期刊介绍：
Official Journal of the European Behavioural Pharmacology Society (EBPS)
Psychopharmacology is an international journal that covers the broad topic of elucidating mechanisms by which drugs affect behavior. The scope of the journal encompasses the following fields:
Human Psychopharmacology: Experimental
This section includes manuscripts describing the effects of drugs on mood, behavior, cognition and physiology in humans. The journal encourages submissions that involve brain imaging, genetics, neuroendocrinology, and developmental topics. Usually manuscripts in this section describe studies conducted under controlled conditions, but occasionally descriptive or observational studies are also considered.
Human Psychopharmacology: Clinical and Translational
This section comprises studies addressing the broad intersection of drugs and psychiatric illness. This includes not only clinical trials and studies of drug usage and metabolism, drug surveillance, and pharmacoepidemiology, but also work utilizing the entire range of clinically relevant methodologies, including neuroimaging, pharmacogenetics, cognitive science, biomarkers, and others. Work directed toward the translation of preclinical to clinical knowledge is especially encouraged. The key feature of submissions to this section is that they involve a focus on clinical aspects.
Preclinical psychopharmacology: Behavioral and Neural
This section considers reports on the effects of compounds with defined chemical structures on any aspect of behavior, in particular when correlated with neurochemical effects, in species other than humans. Manuscripts containing neuroscientific techniques in combination with behavior are welcome. We encourage reports of studies that provide insight into the mechanisms of drug action, at the behavioral and molecular levels.
Preclinical Psychopharmacology: Translational
This section considers manuscripts that enhance the confidence in a central mechanism that could be of therapeutic value for psychiatric or neurological patients, using disease-relevant preclinical models and tests, or that report on preclinical manipulations and challenges that have the potential to be translated to the clinic. Studies aiming at the refinement of preclinical models based upon clinical findings (back-translation) will also be considered. The journal particularly encourages submissions that integrate measures of target tissue exposure, activity on the molecular target and/or modulation of the targeted biochemical pathways.
Preclinical Psychopharmacology: Molecular, Genetic and Epigenetic
This section focuses on the molecular and cellular actions of neuropharmacological agents / drugs, and the identification / validation of drug targets affecting the CNS in health and disease. We particularly encourage studies that provide insight into the mechanisms of drug action at the molecular level. Manuscripts containing evidence for genetic or epigenetic effects on neurochemistry or behavior are welcome.
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