title: Altered nocifensive behavior in animal models of autism spectrum disorder: The role of the nicotinic cholinergic system.
abstract: Caretakers and clinicians alike have long recognized that individuals with autism spectrum disorder (ASD) can have altered sensory processing, which can contribute to its core symptoms. However, the pathobiology of sensory alterations in ASD is poorly understood. Here we examined nocifensive behavior in ASD mouse models, the BTBR T+Itpr3tf/J (BTBR) and the fragile-X mental retardation-1 knockout (Fmr1-KO) mice. We also examined the effects of nicotine on nocifensive behavior given that nicotine, a nicotinic cholinergic receptor (nAChR) agonist that has antinociceptive effects, was shown to improve social deficits and decrease repetitive behaviors in BTBR mice. Compared to respective controls, both BTBR and Fmr1-KO had hyporesponsiveness to noxious thermal stimuli and electrical stimulation of C-sensory fibers, normal responsiveness to electrical stimulation of Aβ- and Aδ-fiber, and hyperresponsiveness to visceral pain after acetic acid intraperitoneal injection. In BTBR, nicotine at lower doses increased, whereas at higher doses, it decreased hotplate latency compared to vehicle. In a significantly different effect pattern, in control mice, nicotine had antinociceptive effects to noxious heat only at the high dose. Interestingly, these nocifensive behavior alterations and differential responses to nicotine antinociceptive effects in BTBR mice were associated with significant downregulation of α3, α4, α5, α7, β2, β3, and β4 nAChR subunits in several cerebral regions both, during embryonic development and adulthood. Taken together, these findings further implicate nAChRs in behaviors alterations in the BTBR model and lend support to the hypothesis that nAChRs may be a target for treatment of behavior deficits and sensory dysfunction in ASD.
authors.affiliation: The Sheikh Zayed Institute for Pediatric Surgical Innovation, Children's Research Institute, Division of Anesthesiology, Pain and Perioperative Medicine, Children's National Health System, School of Medicine and Health Sciences, George Washington University, Washington, DC, 20010, USA.
authors.forename: Li
authors.initials: L
authors.lastname: Wang
authors.affiliation: The Sheikh Zayed Institute for Pediatric Surgical Innovation, Children's Research Institute, Division of Anesthesiology, Pain and Perioperative Medicine, Children's National Health System, School of Medicine and Health Sciences, George Washington University, Washington, DC, 20010, USA.
authors.forename: Luis E F
authors.initials: LE
authors.lastname: Almeida
authors.affiliation: The Sheikh Zayed Institute for Pediatric Surgical Innovation, Children's Research Institute, Division of Anesthesiology, Pain and Perioperative Medicine, Children's National Health System, School of Medicine and Health Sciences, George Washington University, Washington, DC, 20010, USA.
authors.forename: Margaret
authors.initials: M
authors.lastname: Nettleton
authors.affiliation: The Sheikh Zayed Institute for Pediatric Surgical Innovation, Children's Research Institute, Division of Anesthesiology, Pain and Perioperative Medicine, Children's National Health System, School of Medicine and Health Sciences, George Washington University, Washington, DC, 20010, USA.
authors.forename: Alfia
authors.initials: A
authors.lastname: Khaibullina
authors.affiliation: The Sheikh Zayed Institute for Pediatric Surgical Innovation, Children's Research Institute, Division of Anesthesiology, Pain and Perioperative Medicine, Children's National Health System, School of Medicine and Health Sciences, George Washington University, Washington, DC, 20010, USA.
authors.forename: Sarah
authors.initials: S
authors.lastname: Albani
authors.affiliation: The Sheikh Zayed Institute for Pediatric Surgical Innovation, Children's Research Institute, Division of Anesthesiology, Pain and Perioperative Medicine, Children's National Health System, School of Medicine and Health Sciences, George Washington University, Washington, DC, 20010, USA.
authors.forename: Sayuri
authors.initials: S
authors.lastname: Kamimura
authors.affiliation: Division of Pulmonary, Allergy and Critical Care Medicine, Department of Medicine, University of Pittsburgh, Pittsburgh, PA, 15213, USA.
authors.forename: Mehdi
authors.initials: M
authors.lastname: Nouraie
authors.affiliation: The Sheikh Zayed Institute for Pediatric Surgical Innovation, Children's Research Institute, Division of Anesthesiology, Pain and Perioperative Medicine, Children's National Health System, School of Medicine and Health Sciences, George Washington University, Washington, DC, 20010, USA; Center for Neuroscience Research, Children's Research Institute, Children's National Health System, School of Medicine and Health Sciences, George Washington University, Washington, DC, 20010, USA. Electronic address: zquezado@childrensnational.org.
authors.forename: Zenaide M N
authors.initials: ZM
authors.lastname: Quezado
mesh_terms: D000818:Animals; D000067877:Autism Spectrum Disorder / Q000503:physiopathology* / Q000523:psychology*; D001362:Avoidance Learning / Q000187:drug effects*; D001921:Brain / Q000196:embryology / Q000378:metabolism; D004195:Disease Models, Animal; D005260:Female; D051860:Fragile X Messenger Ribonucleoprotein 1 / Q000235:genetics; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009538:Nicotine / Q000008:administration & dosage*; D018722:Nicotinic Agonists / Q000008:administration & dosage*; D059225:Nociception / Q000187:drug effects / Q000502:physiology*; D021122:Protein Subunits / Q000378:metabolism; D011978:Receptors, Nicotinic / Q000378:metabolism*
chemical_list: D051860:Fragile X Messenger Ribonucleoprotein 1; D009538:Nicotine; D018722:Nicotinic Agonists; D021122:Protein Subunits; D011978:Receptors, Nicotinic; C497684:Fmr1 protein, mouse
keywords: Autism; BTBR; Nicotine; Nicotine (PubChem CID: 89594); Nicotinic; Nociception; Nocifensive; Pain; Saccharin (PubChem CID: 656582); Social behavior; nAChR