TOLERANCE TO THE ATAXIC EFFECTS OF DIAZEPAM IN GUINEA-PIG IS NOT ASSOCIATED WITH A REDUCED SENSITIVITY OF GABA(A) RECEPTORS IN THE VESTIBULAR NUCLEUS

Some studies have suggested that drug tolerance observed following rep eated benzodiazepine exposure may be associated with the development o f a subsensitivity to gamma-aminobutyric acid (GABA) in dorsal raphe a nd hippocampal neurons. In other areas such as the substantia nigra su ch subsensitivity has not been found. The aim of the present study was to determine whether tolerance develops to the ataxic effects of diaz epam on the righting reflex following low (i.e. 2 mg/kg i.p.), multipl e daily doses and, if so, whether it is correlated with the developmen t of a subsensitivity of medial vestibular nucleus neurons to the sele ctive GABA(A) receptor agonist, isoguvacine. Guinea pigs which receive d i.p. vehicle injections three times daily for 5 days, or single dail y doses of 2 or 6 mg/kg diazepam, showed increased righting reflex lat encies in response to a 6 mg/kg diazepam challenge dose. However, guin ea pigs which received 2 mg/kg diazepam i.p., three times daily for 5 days, exhibited minimal or no ataxia when given the same diazepam chal lenge dose, indicating the development of tolerance. Brain stem slices including the medial vestibular nucleus were removed from guinea pigs which had received the same diazepam and vehicle three times daily in jection schedules, and recordings were made from single neurons during superfusion of isoguvacine. Although medial vestibular nucleus neuron s from animals which received chronic diazepam administration showed s maller decreases in firing rate in response to 10(-8) M isoguvacine, t he difference was not statistically significant compared to neurons fr om animals which received vehicle treatment or acute diazepam treatmen t. Resting activity was also similar between the diazepam and vehicle groups, in contrast to a previous study which had shown hyperexcitabil ity in medial vestibular nucleus cells from animals which had received single daily injections for up to 60 days. These results suggest that , in contrast to studies which have employed single daily doses, toler ance to the ataxic effects of diazepam on the righting reflex occurs r apidly with divided daily doses. However, this tolerance is not correl ated with significant changes in the sensitivity of GABA(A) receptors on medial vestibular nucleus neurons.