Acute and chronic effects of ramelteon in rhesus monkeys (Macaca mulatta): dependence liability studies.
The acute and chronic effects of ramelteon, an MT1/MT2 receptor agonist, were evaluated in rhesus monkeys (Macaca mulatta) to assess discriminative stimulus effects in comparison with traditional benzodiazepine receptor agonists and to assess physical dependence potential. Discriminative effects of ramelteon were compared with midazolam in untreated monkeys and in diazepam-dependent monkeys that discriminated flumazenil. Dependence potential of ramelteon after daily 1-year administration (and intermittent discontinuation) was evaluated with standard operant procedures. Ramelteon did not produce benzodiazepine-like discriminative stimulus effects at doses up to 10 mg/kg. Long-term treatment or its discontinuation had no significant effect on spontaneous behavior, operant behavior, body weight, motor activity, or posture. These findings suggest that ramelteon is not likely to have benzodiazepine-like abuse or dependence liability.
France
Charles P
CP
Department of Pharmacology, University of Texas Health Science Center, San Antonio, TX 78229-3900, USA. france@uthscsa.edu
Weltman
Robert H
RH
Koek
Wouter
W
Cruź
Christopher M
CM
McMahon
Lance R
LR
D000704:Analysis of Variance; D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects*; D001569:Benzodiazepines / Q000494:pharmacology; D003214:Conditioning, Classical / Q000187:drug effects; D003216:Conditioning, Operant / Q000187:drug effects; D004193:Discrimination Learning / Q000187:drug effects; D004192:Discrimination, Psychological / Q000187:drug effects*; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004334:Drug Administration Schedule; D005260:Female; D005442:Flumazenil / Q000494:pharmacology; D018757:GABA Modulators / Q000494:pharmacology; D006993:Hypnotics and Sedatives / Q000494:pharmacology*; D007192:Indenes / Q000494:pharmacology*; D008253:Macaca mulatta / Q000502:physiology; D008297:Male; D008747:Methylcellulose / Q000494:pharmacology; D008874:Midazolam / Q000494:pharmacology; D009483:Neuropsychological Tests; D044094:Receptors, Melatonin / Q000819:agonists*; D019966:Substance-Related Disorders / Q000503:physiopathology; D013997:Time Factors
D018757:GABA Modulators; D006993:Hypnotics and Sedatives; D007192:Indenes; D044094:Receptors, Melatonin; D001569:Benzodiazepines; D005442:Flumazenil; D008747:Methylcellulose; C495910:ramelteon; D008874:Midazolam