THE NMDA RECEPTOR COMPETITIVE ANTAGONIST CPP MODULATES BENZODIAZEPINETOLERANCE AND DISCONTINUATION

Benzodiazepine discontinuation is characterized by a syndrome of incre ased activity and reduced seizure threshold that is similar to effects mediated by the glutamatergic system, To elucidate the involvement of the glutamatergic system in benzodiazepine tolerance and discontinuat ion, we administered lorazepam, the NMDA antagonist CPP, and the combi nation of these compounds either concomitantly or consecutively to mic e via osmotic pumps and evaluated pentylenetetrazole-induced seizure t hreshold, open-field activity, and benzodiazepine receptor binding dur ing and after chronic administration. Animals receiving lorazepam alon e developed partial tolerance at 7 days and complete tolerance at 14 d ays to the anticonvulsant effects of lorazepam. This effect was partly attenuated by CPP coadministration with lorazepam, This combination p roduced only partial tolerance, A reduction in seizure threshold was o bserved 4 days after discontinuation of lorazepam alone, This effect w as abolished by coadministration of CPP with lorazepam and by CPP admi nistration during the withdrawal period, Benzodiazepine binding in mos t structures examined was significantly reduced at 14 days during chro nic lorazepam administration (versus 1 day), and coadministration of C PP did not alter this decrement, After lorazepam discontinuation, bind ing was increased at 4 and 7 days versus chronically treated animals a nd versus vehicle within the cerebral cortex, This effect was abolishe d by coadministration of CPP as well as by CPP administration during t he lorazepam withdrawal period, These data support the involvement of the glutamatergic system in benzodiazepine tolerance and discontinuati on.