title: Lack of tolerance to anxiolysis and withdrawal symptoms in mice repeatedly treated with AC-5216, a selective TSPO ligand.
abstract: AC-5216, a ligand for the translocator protein (18 kDa) (TSPO), produces anxiolytic-like effects in animal models of anxiety without causing the side effects normally associated with conventional benzodiazepines. This study aimed to investigate whether repeated administration of AC-5216 induces tolerance to anxiolytic-like effects of AC-5216 and produces withdrawal on abrupt cessation, and compare the results with those of diazepam. In the tolerance experiment, AC-5216 (0.1 mg/kg, p.o.) produced significant anxiolytic-like effects in both groups of mice pretreated with the vehicle and AC-5216 twice daily for 14 days. Diazepam (0.1 mg/kg, p.o.) also retained its anxiolytic effects in mice repeatedly treated with diazepam. In the withdrawal experiment, mice were orally treated with either AC-5216 (0.1, 1 or 10 mg/kg; twice daily) or diazepam (0.1, 1 or 10 mg/kg; twice daily) for 14 days, and examined, during a treatment withdrawal period, for anxiogenic-like effects in the social interaction test, and for body weight loss as indices of emotional and somatic withdrawal symptoms, respectively. In AC-5216-treated groups, neither anxiogenic-like effects nor body weight loss was observed upon treatment withdrawal at any of the doses tested. In contrast, in diazepam 1 mg/kg- and 10 mg/kg-treated groups, treatment withdrawal not only induced anxiogenic-like effects on the second day of the withdrawal period, but also decreased body weight gain and brought about body weight loss in mice. These findings indicate that AC-5216 when repeatedly administered does not induce tolerance to its anxiolytic-like effects or withdrawal symptoms.
authors.affiliation: Pharmacology Research Laboratories, Dainippon Sumitomo Pharma Co., Ltd., Japan. atsuko-kita@ds-pharma.co.jp
authors.forename: Atsuko
authors.initials: A
authors.lastname: Kita
authors.forename: Tomoko
authors.initials: T
authors.lastname: Kinoshita
authors.forename: Hitoshi
authors.initials: H
authors.lastname: Kohayakawa
authors.forename: Kiyoshi
authors.initials: K
authors.lastname: Furukawa
authors.forename: Akinori
authors.initials: A
authors.lastname: Akaike
mesh_terms: D000818:Animals; D014151:Anti-Anxiety Agents / Q000008:administration & dosage / Q000009:adverse effects; D001007:Anxiety / Q000139:chemically induced / Q000378:metabolism* / Q000523:psychology; D004361:Drug Tolerance / Q000502:physiology*; D008024:Ligands; D008297:Male; D051379:Mice; D011687:Purines / Q000008:administration & dosage / Q000009:adverse effects* / Q000378:metabolism*; D018079:Receptors, GABA / Q000378:metabolism*; D013375:Substance Withdrawal Syndrome / Q000378:metabolism* / Q000523:psychology
chemical_list: D014151:Anti-Anxiety Agents; C463819:Bzrp protein, mouse; D008024:Ligands; C502525:N-benzyl-N-ethyl-2-(7,8-dihydro-7-methyl-8-oxo-2-phenyl-9H-purin-9-yl)acetamide; D011687:Purines; D018079:Receptors, GABA