TY - JOUR
T1 - Behavioral differentiation of benzodiazepine ligands after repeated administration in baboons
AU - Sannerud, Christine A.
AU - Cook, James M.
AU - Griffiths, Roland R.
N1 - Funding Information:
We thank S. Womack, S. Knipp, E. Koehler and S. James for their technical assistance in conducting this study. We thank J. Nierenberg for performing some of the behavioral observations. We also thank Dr. D.J. Greenblatt for performing the midazolam plasma concentration analyses. This study was supported by National Institute on Drug Abuse Grant DA 01147. During this project, C.A. Sannerud was supported by National Institute on Drug Abuse National Research Service Award DA 05293.
PY - 1989/8/29
Y1 - 1989/8/29
N2 - Baboons received repeated daily administration of saline, 5.6 mg/kg midazolam, 5.0 mg/kg flumazenil (Ro15-1788), 3.2 mg/kg 3-carboethoxy-β-carboline hydrochloride (βCCE) or 10 mg/kg βCCE for 5 days. Behavioral signs of sedation and excitation were scored for 1 h after i.m. injections. Daily administration of these benzodiazepine-receptor ligands differentiated their behavioral effects; repeated midazolam resulted in tolerance to the sedative and ataxic effects; repeated βCCE resulted in sensitization to its convulsant properties; and repeated flumazenil or saline produced no changes in behavior. In a second study, baboons received repeated injections of midazolam (5.6, 11.2 or 20 mg.kg per day) for 6 days. All three groups became tolerant to the sedative and ataxic effects of midazolam. Acute injections of flumazenil (5.0 mg/kg) on day 5 produced a dose-dependent withdrawal syndrome. This flumazenil treatment produced a slight attenuation in the degree of tolerance to midazolam on day 6, suggesting that receptor sensitivity to the benzodiazepine agonist may have partially reset.
AB - Baboons received repeated daily administration of saline, 5.6 mg/kg midazolam, 5.0 mg/kg flumazenil (Ro15-1788), 3.2 mg/kg 3-carboethoxy-β-carboline hydrochloride (βCCE) or 10 mg/kg βCCE for 5 days. Behavioral signs of sedation and excitation were scored for 1 h after i.m. injections. Daily administration of these benzodiazepine-receptor ligands differentiated their behavioral effects; repeated midazolam resulted in tolerance to the sedative and ataxic effects; repeated βCCE resulted in sensitization to its convulsant properties; and repeated flumazenil or saline produced no changes in behavior. In a second study, baboons received repeated injections of midazolam (5.6, 11.2 or 20 mg.kg per day) for 6 days. All three groups became tolerant to the sedative and ataxic effects of midazolam. Acute injections of flumazenil (5.0 mg/kg) on day 5 produced a dose-dependent withdrawal syndrome. This flumazenil treatment produced a slight attenuation in the degree of tolerance to midazolam on day 6, suggesting that receptor sensitivity to the benzodiazepine agonist may have partially reset.
KW - 3-Carboethoxy-β-carboline hydrochloride (βCCE)
KW - Baboon
KW - Flumazenil
KW - Midazolam
KW - Sensitization
KW - Tolerance
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U2 - 10.1016/0014-2999(89)90442-1
DO - 10.1016/0014-2999(89)90442-1
M3 - Article
C2 - 2572434
AN - SCOPUS:0024427999
SN - 0014-2999
VL - 167
SP - 333
EP - 343
JO - European Journal of Pharmacology
JF - European Journal of Pharmacology
IS - 3
ER -