Reversal of increased anxiety during benzodiazepine withdrawal: evidence for an anxiogenic endogenous ligand for the benzodiazepine receptor.

Rats were injected daily for 21 days with water or with chlordiazepoxide hydrochloride (10 mg/kg) and then tested in the elevated plus-maze 24-30 hr after the last of their chronic injections. At this time, rats withdrawn from chlordiazepoxide showed a significant decrease in the % of time spent on the open arms, compared with controls, thus indicating enhanced anxiety. The benzodiazepine antagonist, flumazenil (Ro 15-1788, 4 mg/kg, IP 20 min before test) significantly (p less than 0.01) reversed this withdrawal anxiety, and was without effect in the control group. The partial inverse agonist, FG 7142 (5 mg/kg IP 30 min before test) had no significant effect on the withdrawal anxiety. Possible mechanisms underlying the enhanced anxiety displayed by rats in withdrawal from chlordiazepoxide are discussed. It is concluded that a likely explanation is that chronic benzodiazepine treatment leads to an increased production and release of an endogenous ligand for the benzodiazepine receptor, with inverse agonist properties.