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: Atsuko Kita, Tomoko Kinoshita, Hitoshi Kohayakawa, Kiyoshi Furukawa, Akinori Akaike
• Journal: Progress in neuro-psychopharmacology & biological psychiatry (Prog Neuropsychopharmacol Biol Psychiatry) Vol. 33 Issue 6 Pg. 1040-5 (Aug 31 2009) ISSN: 1878-4216 [Electronic] England
• PMID: 19497344 (Publication Type: Comparative Study, Journal Article)

Chemical References

• Anti-Anxiety Agents
• Bzrp protein, mouse
• Ligands
• N-benzyl-N-ethyl-2-(7,8-dihydro-7-methyl-8-oxo-2-phenyl-9H-purin-9-yl)acetamide
• Purines
• Receptors, GABA

Topics

• Animals
• Anti-Anxiety Agents (administration & dosage, adverse effects)
• Anxiety (chemically induced, metabolism, psychology)
• Drug Tolerance (physiology)
• Ligands
• Male
• Mice
• Purines (administration & dosage, adverse effects, metabolism)
• Receptors, GABA (metabolism)
• Substance Withdrawal Syndrome (metabolism, psychology)