Guanfacine treatment improves ADHD phenotypes of impulsivity and hyperactivity in a neurofibromatosis type 1 mouse model.

Autor: Lukkes JL; Department of Psychiatry, Indiana University School of Medicine, Indianapolis, IN, 46202, USA. jodiburk@iu.edu.; Stark Neurosciences Research Institute, Indiana University School of Medicine, 320 West 15th Street, Indianapolis, IN, 46202, USA. jodiburk@iu.edu., Drozd HP; Stark Neurosciences Research Institute, Indiana University School of Medicine, 320 West 15th Street, Indianapolis, IN, 46202, USA.; Program in Medical Neurosciences, Indiana University School of Medicine, Indianapolis, IN, USA., Fitz SD; Department of Psychiatry, Indiana University School of Medicine, Indianapolis, IN, 46202, USA.; Stark Neurosciences Research Institute, Indiana University School of Medicine, 320 West 15th Street, Indianapolis, IN, 46202, USA., Molosh AI; Department of Psychiatry, Indiana University School of Medicine, Indianapolis, IN, 46202, USA.; Stark Neurosciences Research Institute, Indiana University School of Medicine, 320 West 15th Street, Indianapolis, IN, 46202, USA., Clapp DW; Stark Neurosciences Research Institute, Indiana University School of Medicine, 320 West 15th Street, Indianapolis, IN, 46202, USA.; Wells Center for Pediatric Research, Department of Pediatrics, Indiana University School of Medicine, Indianapolis, IN, USA.; Department of Microbiology and Immunology, Indiana University School of Medicine, Indianapolis, IN, USA., Shekhar A; Department of Psychiatry, Indiana University School of Medicine, Indianapolis, IN, 46202, USA.; Stark Neurosciences Research Institute, Indiana University School of Medicine, 320 West 15th Street, Indianapolis, IN, 46202, USA.; Program in Medical Neurosciences, Indiana University School of Medicine, Indianapolis, IN, USA.; Department of Pharmacology and Toxicology, Indiana University School of Medicine, Indianapolis, IN, USA.; Indiana Clinical and Translation Sciences Institute, Indiana University School of Medicine, Indianapolis, IN, USA.
Jazyk: angličtina
Zdroj: Journal of neurodevelopmental disorders [J Neurodev Disord] 2020 Jan 15; Vol. 12 (1), pp. 2. Date of Electronic Publication: 2020 Jan 15.
DOI: 10.1186/s11689-019-9304-y
Abstrakt: Background: Neurofibromatosis type 1 (NF1) is an autosomal dominant disorder with a mutation in one copy of the neurofibromin gene (NF1 +/- ). Even though approximately 40-60% of children with NF1 meet the criteria for attention deficit hyperactivity disorder (ADHD), very few preclinical studies, if any, have investigated alterations in impulsivity and risk-taking behavior. Mice with deletion of a single NF1 gene (Nf1 +/- ) recapitulate many of the phenotypes of NF1 patients.
Methods: We compared wild-type (WT) and Nf1 +/- mouse strains to investigate differences in impulsivity and hyperactivity using the delay discounting task (DDT), cliff avoidance reaction (CAR) test, and open field. We also investigated whether treatment with the clinically effective alpha-2A adrenergic receptor agonist, guanfacine (0.3 mg/kg, i.p.), would reverse deficits observed in behavioral inhibition.
Results: Nf1 +/- mice chose a higher percentage of smaller rewards when both 10- and 20-s delays were administered compared to WT mice, suggesting Nf1 +/- mice are more impulsive. When treated with guanfacine (0.3 mg/kg, i.p.), Nf1 +/- mice exhibited decreased impulsive choice by waiting for the larger, delayed reward. Nf1 +/- mice also exhibited deficits in behavioral inhibition compared to WT mice in the CAR test by repetitively entering the outer edge of the platform where they risk falling. Treatment with guanfacine ameliorated these deficits. In addition, Nf1 +/- mice exhibited hyperactivity as increased distance was traveled compared to WT controls in the open field. This hyperactivity in Nf1 +/- mice was reduced with guanfacine pre-treatment.
Conclusions: Overall, our study confirms that Nf1 +/- mice exhibit deficits in behavioral inhibition in multiple contexts, a key feature of ADHD, and can be used as a model system to identify alterations in neural circuitry associated with symptoms of ADHD in children with NF1.
Databáze: MEDLINE
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