A nonbenzodiazepine partial agonist, S-(+)-DN-2327, has minimal physical dependence-producing liability, but shows cross-dependence on barbital in rats.
1. Physical dependence and cross-physical dependence on barbital of the benzodiazepine receptor partial agonist S-(+)-DN-2327 and the benzodiazepine receptor full agonist diazepam were compared in male Fischer 344 rats. 2. In the physical dependence study, rats were treated with S-(+)-DN-2327 (30, 100, 300 and 1000 mg/kg/day) or diazepam (30, 100 and 300 mg/kg/day) for 4 weeks by the drug admixed with food method. After stopping the treatment, the body weight and food consumption in the diazepam 100 and 300 mg/kg groups tended to decrease or decreased to values lower than those in the control group, whereas these parameters in the S-(+)-DN-2327 30, 100 and 300 mg/kg groups were comparable to the control group values. 3. In the cross-dependence study, rats were treated with increasing doses of barbital by admixing the drug with food for 4 weeks, after which the diet admixed with barbital was replaced by basal diet alone or admixed with S-(+)-DN-2327 or diazepam (target doses: 100 and 300 mg/kg/day for each compound). During the substitution period, the decreases in body weight and food consumption in both S-(+)-DN-2327 and both diazepam groups were suppressed compared with those in the basal diet group. 4. These results suggest that S-(+)-DN-2327 possesses minimal physical dependence-producing liability, but shows cross-dependence on barbital, as do benzodiazepine receptor full agonists.
Inui
Y
Y
Drug Safety Research Laboratories, Takeda Chemical Industries Ltd., Osaka, Japan.
Yamamoto
M
M
Awasaki
Y
Y
Nishida
N
N
D000818:Animals; D014151:Anti-Anxiety Agents / Q000008:administration & dosage / Q000494:pharmacology*; D019540:Area Under Curve; D001462:Barbital / Q000009:adverse effects; D001522:Behavior, Animal / Q000187:drug effects; D001667:Binding, Competitive / Q000187:drug effects; D001835:Body Weight / Q000187:drug effects; D003975:Diazepam / Q000009:adverse effects / Q000494:pharmacology; D004435:Eating / Q000187:drug effects; D058785:GABA-A Receptor Agonists; D006993:Hypnotics and Sedatives / Q000009:adverse effects; D054833:Isoindoles; D008297:Male; D009287:Naphthyridines / Q000008:administration & dosage / Q000494:pharmacology*; D051381:Rats; D011916:Rats, Inbred F344; D013141:Spiro Compounds / Q000008:administration & dosage / Q000494:pharmacology*; D013375:Substance Withdrawal Syndrome / Q000523:psychology; D019966:Substance-Related Disorders / Q000523:psychology*
D014151:Anti-Anxiety Agents; D058785:GABA-A Receptor Agonists; D006993:Hypnotics and Sedatives; D054833:Isoindoles; D009287:Naphthyridines; D013141:Spiro Compounds; D001462:Barbital; C060382:pazinaclone; D003975:Diazepam