Diazepam withdrawal-induced anxiety and place aversion in the rat: differential effects of two chronic diazepam treatment regimes

Abstract

The ability of the benzodiazepine antagonist flumazenil to precipitate a withdrawal subjective state in rats receiving chronic diazepam was investigated in a biased conditioned place aversion (CPA) procedure. Conditioning with flumazenil (10 mg/kg i.p.) in rats receiving chronic diazepam subcutaneously (s.c. in oil, 15 mg/kg/day for 28 days) but not intraperitoneally (i.p., 5 mg/kg for 28 days) resulted in the formation of a conditioned place aversion. These results indicate that precipitated withdrawal from diazepam injected s.c. but not i.p. produces a negative subjective state and that the conditioned place aversion paradigm may be useful in detecting the negative subjective effects of diazepam withdrawal. In parallel studies, the same s.c. treatment protocol produced an anxiogenic effect in the elevated plus-maze on spontaneous diazepam withdrawal, whereas rats treated with the i.p. protocol displayed no signs of withdrawal anxiety. The results of the present study are consistent with the interpretation that rats withdrawn from chronic i.p. diazepam did not demonstrate a CPA due to the 'repeated withdrawal' experiences induced by the i.p. injection route attenuating the subsequent ability of flumazenil to precipitate a subjective withdrawal state. Pharmacokinetic evidence and previous evidence showing that repeated withdrawal from diazepam in mice attenuates the aversive effects of the withdrawal experience in a conditioned taste aversion (CTA) paradigm support this interpretation.