Prevention of cocaine-induced convulsions and lethality in mice: effectiveness of targeting different sites on the NMDA receptor complex
Introduction
Currently, no effective treatments are available for cocaine overdose and it is responsible for more serious intoxications and deaths than any other illicit drug (Benowitz, 1993). The glutamatergic system has recently been implicated in the addictive properties of cocaine (McGinty, 1995), and it may also have a role in the toxic effects of the drug (Itzhak and Stein, 1992, Rockhold et al., 1991, Witkin and Tortella, 1991). Among the different glutamate receptors, the N-methyl-d-aspartate (NMDA) receptor plays an important role in cardiovascular, respiratory, and neural systems (Berger et al., 1995, Olney et al., 1986, West and Huang, 1994), all of which are seriously compromised after an overdose of cocaine. Therefore, given the importance of NMDA receptors in end-stage events resulting from an overdose (e.g. convulsions, respiratory distress, cardiovascular collapse), the receptor complex is a logical target for pharmacological interventions, even if cocaine does not interact directly with it.
The NMDA receptor contains several antagonist binding and modulatory sites that can serve as targets for pharmacotherapies: glutamate binding sites, glycine co-agonist sites, sites within the receptor ionophore, and allosteric modulatory sites (Bigge, 1993). Previous investigations have shown that competitive antagonists, channel blockers, and glycine site antagonists of the NMDA receptor can attenuate cocaine-induced behavioral toxicity in animals (Derlet and Albertson, 1990, Itzhak and Stein, 1992, Rockhold et al., 1991, Witkin and Tortella, 1991), but most of the antagonists tested in these earlier studies had limitations, such as marginal efficacy, bioavailability problems, and unwanted side effects, that compromised their clinical potential (Auer, 1997, Bigge, 1993, Kornhuber and Weller, 1997, Witkin and Tortella, 1991). Recently, two novel quinoxaline-2,3-diones with preferential affinities for NMDA/glycine sites (Keana et al., 1995, Woodward et al., 1995) were shown to prevent the convulsions and lethality produced by a cocaine overdose in mice (Matsumoto et al., 1997). These NMDA/glycine site antagonists are known to be bioavailable and well tolerated at therapeutic doses in many animal models of neurological disorders (Kanthasamy et al., 1996, Lutfy et al., 1995, Lutfy et al., 1996, Lutfy and Weber, 1996, Matsumoto et al., 1995, Tsuchida and Bullock, 1995, Vaccarino et al., 1993, Warner et al., 1995). In addition, they do not produce the phencyclidine-like effects that have been problematic for many earlier NMDA receptor antagonists (Auer, 1997, Balster et al., 1995, Hawkinson et al., 1997), including psychotomimetic effects in humans (Albers et al., 1999).
Therefore, the goals of the present study were to rigorously examine the effectiveness of NMDA/glycine site antagonists for attenuating the behavioral toxic effects of cocaine and to compare their effectiveness relative to antagonists that target other sites on the NMDA receptor complex. In all of the studies, one well characterized compound for each target site on the NMDA receptor served as a reference for the newer ligands. Compounds that target the NMDA/glycine and allosteric moduatory sites received the most attention because they have a favorable clinical profile compared to competitive antagonists and channel blockers, which have been associated with unacceptable side effects in human clinical trials of stroke and epilepsy (cf. Kornhuber and Weller, 1997). The following NMDA/glycine site antagonists were tested: 7-chlorokynurenic acid (Kemp et al., 1988), DCQX (Ogita and Yoneda, 1990), R(+)-HA-966 (Singh et al., 1990a), ACEA-1021, ACEA-1031, and ACEA-1328 (Keana et al., 1995). CPP and D-AP7 were used as representative competitive antagonists (Bigge, 1993). The classical, high potency channel blocker MK-801 was also used (Wong et al., 1986). For comparison, memantine was tested because it is a partial channel blocker with a low incidence of side effects in both humans and animals (Bormann, 1989). In addition, the following allosteric modulators were tested: ifenprodil (Carter et al., 1988), CP-101,606 (Chenard et al., 1995), Co 101022, haloperidol and nylidrin (Whittemore et al., 1997). All of the allosteric modulators exhibit a strong preference for the NR1/NR2B subtype of NMDA receptor (Ilyin et al., 1996, Whittemore et al., 1997; Richard Woodward, CoCensys, Inc., personal communication). Finally, riluzole, a compound that inhibits glutamate release, was tested (Martin et al., 1993). In all of our studies, convulsions and lethality were used as the behavioral endpoints because many cocaine users convulse after a mild, but not necessarily fatal overdose, while after severe overdoses of cocaine, death can ultimately ensue. Initially, the antagonists were administered as a pre-treatment to ensure that the binding sites of interest were occupied at the time of the overdose. However, to be of practical use in the clinic, the antagonists must be effective when administered after an overdose. Therefore, in later experiments, the most effective antagonists were also administered as a post-treatment. This work has been described in abstract form (Matsumoto et al., 1998).
Section snippets
Animals
Male, Swiss Webster mice at the age of 4 weeks (22–32 g) were used (Harlan, Indianapolis, IN; Charles River, Portage, MI). Mice were housed in groups of 4–6 with a 12 h:12 h light/dark cycle and received food and water ad libitum. All experimental procedures were performed after an initial one week adaptation period, using methods that were approved by the Institutional Animal Care and Use Committee at the University of Oklahoma Health Sciences Center.
Drugs
ACEA-1021
Behavioral toxic effects of cocaine
Acute i.p. administration of cocaine produced dose-dependent increases in convulsions and lethality in Swiss Webster mice (Fig. 1). The calculated ED50 value for cocaine-induced convulsions was 58.84 mg/kg, i.p. The 60 mg/kg, i.p. dose of cocaine, which was used for the antagonism portion of the study, represented the calculated ED97 dose. The LD50 value for cocaine-induced lethality was 108 mg/kg, i.p. The 125 mg/kg, i.p. dose of cocaine that was used for the antagonism portion of the study
Discussion
All of the NMDA receptor antagonists (competitive, glycine, allosteric modulators, channel blockers) tested in this study attenuated cocaine-induced convulsions. However, the compounds differed in their ability to prevent death following a normally lethal dose of cocaine. Only the NMDA/glycine site and competitive antagonists prevented both the lethal and convulsive effects of cocaine. The allosteric modulators were somewhat effective against the lethal endpoint, while the channel blockers were
Acknowledgements
We thank Dr Roger Hornbrook (University of Oklahoma Health Sciences Center, Oklahoma City, OK) for the generous gift of cocaine, Drs Eckard Weber and Richard Woodward (CoCensys, Inc., Irvine, CA) for Co 101022 and the ACEA compounds, and Dr Bert Chenard (Pfizer Inc., Groton, CT) for CP-101,606. We appreciate the technical assistance of Michelle Brown and Michele Friedman (University of Oklahoma Health Sciences Center, Oklahoma City, OK) during various phases of this project, and many helpful
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