The effect of chronic lorazepam administration in aging mice.
To assess benzodiazepine tolerance in aged animals, lorazepam or vehicle was administered chronically to male Crl: CD-1(ICR)BR mice. Pharmacodynamic and neurochemical endpoints were examined on days 1 and 14 of drug administration. There was no age-related significant difference in plasma lorazepam levels. Young and middle-aged animals demonstrated behavioral tolerance to lorazepam, while the aged animals showed a similar trend which failed to reach significance. In addition, aged animals also showed a trend toward tolerance to the anticonvulsant effects of lorazepam. There were no changes in alpha1 mRNA levels in cortex or hippocampus following administration of lorazepam when compared to vehicle-treated animals in any age group. Aged animals, however, had an initial increase in alpha1 mRNA expression in cortex and hippocampus on day 1 of vehicle treatment followed by decreased expression on day 14. These age-related changes were abolished by lorazepam administration. In summary, age-related sensitivity to the effects of lorazepam was not demonstrated in the present study. However, comparison of these data to other studies indicates that the effect of chronic benzodiazepine treatment may be specific to the benzodiazepine administered, the technique used to quantify mRNA expression changes, the subunits of the GABA(A) receptor investigated and the brain region analyzed. The phenomenon of benzodiazepine sensitivity in the elderly is an area of research which remains controversial and may well be compound specific. Determining benzodiazepines that do not produce pharmacodynamic sensitivity, such as lorazepam, may allow more careful prescribing and dosing of these drugs, and perhaps even the development of specific agents which could avoid this sensitivity.
Fahey
Jeanne M
JM
Department of Pharmacology and Experimental Therapeutics, Tufts University School of Medicine and the Division of Clinical Pharmacology, Tufts-New England Medical Center, Boston, MA 02111, USA. Jeanne.fahey@tufts.edu
Pritchard
Gary A
GA
Reddi
Jyoti M
JM
Pratt
John S
JS
Grassi
Jeffrey M
JM
Shader
Richard I
RI
Greenblatt
David J
DJ
D000375:Aging / Q000502:physiology*; D000818:Animals; D001921:Brain / Q000187:drug effects* / Q000378:metabolism; D002540:Cerebral Cortex / Q000187:drug effects / Q000378:metabolism; D003292:Convulsants / Q000494:pharmacology; D004334:Drug Administration Schedule; D004347:Drug Interactions / Q000502:physiology; D004361:Drug Tolerance / Q000502:physiology; D018757:GABA Modulators / Q000097:blood / Q000633:toxicity; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism; D008140:Lorazepam / Q000097:blood / Q000633:toxicity*; D008297:Male; D051379:Mice; D019055:No-Observed-Adverse-Effect Level; D012333:RNA, Messenger / Q000187:drug effects / Q000378:metabolism; D011963:Receptors, GABA-A / Q000235:genetics*; D012640:Seizures / Q000139:chemically induced / Q000188:drug therapy / Q000378:metabolism
D003292:Convulsants; D018757:GABA Modulators; C546241:Gabra1 protein, mouse; D012333:RNA, Messenger; D011963:Receptors, GABA-A; D008140:Lorazepam