title: The α4β2 nicotinic acetylcholine receptor modulates autism-like behavioral and motor abnormalities in pentylenetetrazol-kindled mice.
abstract: Epilepsy is associated with several psychiatric disorders, including cognitive impairment, autism and attention deficit/hyperactivity disorder (ADHD). However, the psychopathology of epilepsy is frequently unrecognized and untreated in patients. In the present study, we investigated the effects of ABT-418, a neuronal nicotinic acetylcholine receptor agonist, on pentylenetetrazol (PTZ)-kindled mice with behavioral and motor abnormalities. PTZ-kindled mice displayed impaired motor coordination (in the rotarod test), anxiety (in the elevated plus maze test) and social approach impairment (in the three-chamber social test) compared with control mice. ABT-418 treatment (0.05 mg/kg, intraperitoneally) alleviated these behavioral abnormalities in PTZ-kindled mice. Immunolabeling of tissue sections demonstrated that expression of the α4 nicotinic acetylcholine receptor subunit in the medial habenula was similar in control and PTZ-kindled mice. However, expression was significantly decreased in the piriform cortex in PTZ-kindled mice. In addition, we examined the expression of the synaptic adhesion molecule neuroligin 3 (NLG3). NLG3 expression in the piriform cortex was significantly higher in PTZ-kindled mice compared with control mice. Collectively, our findings suggest that ADHD-like or autistic-like behavioral abnormalities associated with epilepsy are closely related to the downregulation of the α4 nicotinic receptor and the upregulation of NLG3 in the piriform cortex. In summary, this study indicates that ABT-418 might have therapeutic potential for attentional impairment in epileptic patients with psychiatric disorders such as autism and ADHD.
authors: Division of Pharmacy, Ehime University Hospital, Shitsukawa, Toon, Ehime 791-0295, Japan. Electronic address: dph20010@s.okadai.jp.
authors: Kenshi
authors: K
authors: Takechi
authors: School of Pharmacy, Shujitsu University, 1-6-1 Nishikawara, Naka-ku, Okayama 703-8516, Japan.
authors: Katsuya
authors: K
authors: Suemaru
authors: Integrated Center for Science, Ehime University, Shitsukawa, Toon, Ehime 791-0295, Japan.
authors: Takeshi
authors: T
authors: Kiyoi
authors: Division of Pharmacy, Ehime University Hospital, Shitsukawa, Toon, Ehime 791-0295, Japan.
authors: Akihiro
authors: A
authors: Tanaka
authors: Division of Pharmacy, Ehime University Hospital, Shitsukawa, Toon, Ehime 791-0295, Japan.
authors: Hiroaki
authors: H
authors: Araki
mesh_terms: D000818:Animals; D014151:Anti-Anxiety Agents / Q000494:pharmacology / Q000627:therapeutic use; D001007:Anxiety / Q000188:drug therapy / Q000378:metabolism; D001321:Autistic Disorder / Q000188:drug therapy / Q000378:metabolism; D001522:Behavior, Animal / Q000187:drug effects; D003292:Convulsants; D004195:Disease Models, Animal; D007555:Isoxazoles / Q000494:pharmacology / Q000627:therapeutic use; D007696:Kindling, Neurologic; D008297:Male; D008813:Mice, Inbred ICR; D009043:Motor Activity / Q000187:drug effects; D018722:Nicotinic Agonists / Q000494:pharmacology / Q000627:therapeutic use; D010433:Pentylenetetrazole; D011597:Psychomotor Performance / Q000187:drug effects; D011759:Pyrrolidines / Q000494:pharmacology / Q000627:therapeutic use; D011978:Receptors, Nicotinic / Q000378:metabolism*; D045442:Rotarod Performance Test; D012640:Seizures / Q000139:chemically induced / Q000188:drug therapy / Q000378:metabolism; D012919:Social Behavior
chemical_list: D014151:Anti-Anxiety Agents; D003292:Convulsants; D007555:Isoxazoles; D018722:Nicotinic Agonists; D011759:Pyrrolidines; D011978:Receptors, Nicotinic; C403531:nicotinic receptor alpha4beta2; C088383:3-methyl-5-(1-methyl-2-pyrrolidinyl)isoxazole; D010433:Pentylenetetrazole
keywords: ABT-418; Epilepsy; Neuroligin; Nicotine; Psychiatric disorders