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Long-term use of benzodiazepine-type drugs may lead to physical dependence, manifested by withdrawal syndrome after abrupt cessation of treatment. The aim of the present study was to investigate the influence of duration of treatment, as well as the role of α1-containing GABAA receptors, in development of physical dependence to diazepam, assessed through the level of anxiety and susceptibility to pentylenetetrazole (PTZ)-induced seizures, 24h after withdrawal from protracted treatment in rats. Withdrawal of 2mg/kg diazepam after 28, but not after 14 or 21 days of administration led to an anxiety-like behavior in the elevated plus maze. Antagonism of the diazepam effects at α1-containing GABAA receptors, achieved by daily administration of the neutral modulator βCCt (5mg/kg), did not affect the anxiety level during withdrawal. An increased susceptibility to PTZ-induced seizures was observed during diazepam withdrawal after 21 and 28 days of treatment. Daily co-administration of βCCt further decreased the PTZ-seizure threshold after 21 days of treatment, whilst it prevented the diazepam withdrawal-elicited decrease of the PTZ threshold after 28 days of treatment. In conclusion, the current study suggests that the role of α1-containing GABAA receptors in mediating the development of physical dependence may vary based on the effect being studied and duration of protracted treatment. Moreover, the present data supports previous findings that the lack of activity at α1-containing GABAA receptors is not sufficient to eliminate physical dependence liability of ligands of the benzodiazepine type., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Gamma aminobutyric acid (GABA)-A receptor modulators constitute the majority of clinically relevant sedative-hypnotics. Zolpidem (Ambien) is a nonbenzodiazepine GABA-A receptor modulator that binds with high affinity to GABA-A receptors expressing alpha-1 subunits. The present study examined the effects of a new approach to the oral administration of zolpidem on locomotor activity, body weight, food intake, relative food intake, feed efficiency, anxiety, and visceral adiposity in rats. Effects of withdrawal associated with cessation of the drug were also recorded. A daily chronically administered oral 10 mg/kg dose of zolpidem caused a decrease in locomotor activity, an increase in food intake and relative food intake, and a more positive feed efficiency during the drug-administration period. Anxiety and visceral adiposity also increased in animals receiving the drug. During withdrawal of zolpidem, there was a decrease in body weight, food intake, relative food intake, and anxiety, as well as a negative feed efficiency. These results suggest that zolpidem can modulate locomotor activity, metabolism, and anxiety-related behavior. A highly positive feed efficiency and increased visceral adiposity associated with zolpidem intake were unique findings of this study., (Copyright © 2011 Elsevier Inc. All rights reserved.)