Dependence-producing properties of alprazolam in the dog.
Alprazolam (48 mg/kg/day) administered orally to dogs 4 times a day in equally divided doses produced physical dependence. This dependence was revealed by a precipitated abstinence syndrome which occurred after either oral administration of flumazenil (6, 18 and 36 mg/kg) or intravenous administration of a liposomal suspension of flumazenil. Flumazenil alone (18, 36 and 72 mg/kg) produced no significant signs of precipitated abstinence in naive dogs. This precipitated abstinence syndrome in alprazolam-dependent dogs was characterized by both clonic and tonic-clonic seizures. Other signs of precipitated abstinence which comprise the NPAS score were less intense in the alprazolam-dependent than in diazepam-dependent dogs. Alprazolam is extensively metabolized in the dog and does not accumulate whereas its predominant metabolite, alpha hydroxyalprazolam, does accumulate. The data suggest that alpha hydroxyalprazolam plays a role in the dependence-producing properties of alprazolam in the dog as revealed by the precipitated abstinence syndrome.
Sloan
J W
JW
Department of Pharmacology, University of Kentucky College of Medicine, Lexington 40536.
Martin
W R
WR
Wala
E P
EP
D000284:Administration, Oral; D000525:Alprazolam; D000818:Animals; D004285:Dogs; D004305:Dose-Response Relationship, Drug; D005260:Female; D005442:Flumazenil / Q000494:pharmacology; D012640:Seizures; D013375:Substance Withdrawal Syndrome; D019966:Substance-Related Disorders
D005442:Flumazenil; D000525:Alprazolam