Development of physical dependence to lorazepam in rats: the effects of repeated short treatments, dose and age.

Rats were treated with lorazepam for four days (six times 2 mg kg(-1)) at the ages of 71, 118, 163 and 210 days. Increased excitation (physical dependence) in the withdrawal period was tested several times during 14 days with hexobarbital in an EEG threshold test. Lorazepam could induce physical dependence usually with a maximum (20% of the controls) on day four of withdrawal, but the age was a critical variable. A dose-response relationship with regard to lorazepam (0.5, 1, 2 mg kg(-1)) was found at 71 days but a more complicated pattern was found at 118 days of age. The rats treated with lorazepam 2 mg kg(-1) at the ages of either 71 and 118 days were given a treatment again with lorazepam 2 mg kg(-1) three months later. Compared with age-matched untreated rats, previous drug exposure influenced the pattern of increased excitation indicating a carry-over effect even after such a recovery period.