The NMDA Receptor Competitive Antagonist CPP Modulates Benzodiazepine Tolerance and Discontinuation

Abstract

Benzodiazepine discontinuation is characterized by a syndrome of increased 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 discontinuation, we administered lorazepam, the NMDA antagonist CPP, and the combination of these compounds either concomitantly or consecutively to mice via osmotic pumps and evaluated pentylenetetrazole-induced seizure threshold, open-field activity, and benzodiazepine receptor binding during and after chronic administration. Animals receiving lorazepam alone developed partial tolerance at 7 days and complete tolerance at 14 days to the anticonvulsant effects of lorazepam. This effect was partly attenuated by CPP coadministration with lorazepam. This combination produced only partial tolerance. A reduction in seizure threshold was observed 4 days after discontinuation of lorazepam alone. This effect was abolished by coadministration of CPP with lorazepam and by CPP administration during the withdrawal period. Benzodiazepine binding in most structures examined was significantly reduced at 14 days during chronic lorazepam administration (versus 1 day), and coadministration of CPP did not alter this decrement. After lorazepam discontinuation, binding was increased at 4 and 7 days versus chronically treated animals and versus vehicle within the cerebral cortex. This effect was abolished by coadministration of CPP as well as by CPP administration during the lorazepam withdrawal period. These data support the involvement of the glutamatergic system in benzodiazepine tolerance and discontinuation.

Glutamic acid decarboxylase and glutamate receptor changes during tolerance and dependence to benzodiazepines

“…Tolerance. To establish the time course of the disappearance of anticonvulsant tolerance in diazepam-withdrawn rats (6,12,24,36, and 72 h), we determined the anticonvulsant action of a challenging standard dose (17.6 mol͞kg per os) of diazepam by measuring the threshold dose of bicuculline necessary to elicit tonic-clonic convulsions. In vehicle-withdrawn rats this standard dose of diazepam increased the convulsive threshold dose of bicuculline by approximately 3-fold (Fig.…”

“…Dependence does not likely involve down-regulation of GABA A receptors because the modification of GABA A receptor subunit assembly or coupling and the down-regulation of GABAergic function associated with tolerance disappear before the onset of the withdrawal syndrome (14,21,22). In 1993, Turski and colleagues (11), and successively others (23,24), suggested that an enhanced glutamatergic transmission is a possible component of BZ-RS ligands withdrawal syndrome characterized by tremors, myoclonic jerks, wet dog shakes, piloerection, loss of body weight, excitability, anxiety, and electroencephalographic seizure pattern. Pharmacological experiments with agonists or antagonists of specific glutamate receptor subtypes suggested that whereas N-methyl-D-aspartate (NMDA)-dependent mechanisms may underlie the expression of signs of dependence, AMPA receptor activation may be essential for the induction of the withdrawal syndrome following a protracted diazepam administration.…”

Mechanisms Underlying Tolerance after Long-Term Benzodiazepine Use: A Future for Subtype-Selective Receptor Modulators?

“…Also, lorazepam-induced tolerance to its acute anticonvulsant effects was partially prevented with simultaneous CPP treatment [122]. In contrast, the development of tolerance to the anxiolytic effects of diazepam in a social interaction test was not blocked by concomitant administration of dizocilpine [123].…”

Differential Effects of Two Chronic Diazepam Treatment Regimes on Withdrawal Anxiety and AMPA Receptor Characteristics

“…Several studies have also provided evidence for a role for NMDA receptor antagonists in blocking the behavioral components of BZ tolerance and withdrawal File and Fernandes, 1994;Koff et al, 1997;Tsuda et al, 1998a, b). However, the contribution of AMPA receptors is less well explored.…”