Further investigation of the stimulus properties of chlordiazepoxide and zolpidem. Agonism and antagonism by two novel benzodiazepines

Abstract

The effects of Ro 16-6028 and Ro 17-1812, two novel benzodiazepines with mixed agonist and antagonist properties, were studied in rats trained to discriminate either chlordiazepoxide or the benzodiazepine receptor ligand zolpidem. In rats discriminating 5 mg/kg chlordiazepoxide from saline both Ro 16-6028 and Ro 17-1812 produced responding on the drug lever. At a dose of 10 mg/kg both compounds gave rise to 100% responding on the lever associated with chlordiazepoxide. The dose-response curve produced by Ro 16-6028 was flatter than that for Ro 17-1812, however. The discriminative cue produced by 2 mg/kg zolpidem did not generalise to either Ro 16-6028 or Ro 17-1812. In contrast, both of those compounds antagonised the zolpidem cue and also antagonised the reduction in response rates produced by zolpidem. These results are consistent with previous findings that Ro 16-6028 and Ro 17-1812 may exert anxiolytic-like effects typical of benzodiazepines while antagonising the depressant actions of benzodiazepine receptor ligands. The results are also consistent with the suggestion that the discriminative cues produced by chlordiazepoxide and zolpidem may be mediated, at least partially, by activity at different sub-types of benzodiazepine receptors.

Discriminative-stimulus effects of zolpidem, triazolam, pentobarbital, and caffeine in zolpidem-trained humans.

“…The demonstration of discriminative-stimulus effects of zolpidem in humans is concordant with previous studies that trained rodents to discriminate between zolpidem (1-2 mg/kg) and vehicle (Sanger, 1987;Sanger & Zivkovic, 1986, 1987. The present findings also extend previous human drug-discrimination experiments that established other sedative-hypnotic-anxiolytic compounds (i.e., buspirone, diazepam, pentobarbital, and triazolam) as discriminative stimuli (e.g., Altman, Albert, Milstein, & Greenberg, 1977;Johanson, 1991aJohanson, , 1991bKamien et al, 1994;Oliveto, Bickel, Hughes, Shea, et al, 1992;Rush, Critchfield, Troisi, & Griffiths, 1995;Rush et al, 1997).…”

Using behavior to elucidate receptor mechanisms: A review of the discriminative stimulus effects of benzodiazepines.

“…However, the majority of these studies revealed little or no BZ-appropriate responding engendered by the direct and indirect GABA A agonists, including muscimol, THIP, •y-hydroxybutyrate. and valproate (Ator & Griffiths, 1986, 1989a, 1997Haug, 1983;Nielsen, Valentine, Holohean, Appel, 1983;Rauch & Stolerman, 1986, 1987Spealman, 1985;Woolverton et al, 1999); non-BZ anxiolytics such as buspirone (e.g., Ator & Griffiths, 1986;Hendry, Balster, & Rosecrans, 1983;Rauch & Stolerman, 1987;Sanger et al, 1985;Tang & Franklin, 1991; but see Johanson, 1991b, for effects in humans); various sedative-hypnotic agents, including methaqualone, clomethiazole, chloral hydrate, and triclofos (Ator & Griffiths, 1989a, 1997Evans & Johanson, 1989); anticonvulsants such as phenytoin (Ator & Griffiths, 1997;Rauch & Stolerman, 1987); and muscle relaxants such as methocarbamol (Sannerud, Ator, & Griffiths, 1991b;Sannerud & Ator, 1995a).…”

“…These data confirm the results of studies with BZ agonists as discriminative stimuli showing that barbiturates generally share discriminative stimulus effects with BZ agonists. Antagonism studies, however, suggest that these shared effects are mediated by different receptor mechanisms, because the majority of studies demonstrated that the discriminative stimulus effects of barbiturates are not antagonized by the BZ antagonists flumazenil and COS 8216 (Ator & Griffiths, 1983De Vry & Slangen, 1986a;Herling & Shannon, 1982b;Katzman, Herling, & Shannon, 1983;Woolverton & Nader, 1995;Young, Glennon, & Dewey, 1983, 1987.…”

“…Although partial agonists by definition have reduced intrinsic efficacy compared with full agonists, most studies in which animals were trained to discriminate a dose of a full BZ agonist from vehicle have shown that the majority of partial BZ agonists in fact share discriminative stimulus effects with full BZ agonists. For example, the partial agonists panadiplon, ZK 91296, bretazenil, and imidazenil substituted fully for the diazepam (Ator & Griffiths, 1999; Sannerud & Ator, 1995b; Stephens, Shearman, & Kehr, 1984b), chlordiazepoxide (Andrews & Stephens, 1991; Sanger, 1987, 1988; Sanger & Zivkovic, 1987; Stephens, Kehr, Schneider, & Schmiechen, 1984; Stephens, Shearman, & Kehr, 1984;), and midazolam (Ator, 1999; Rijnders, Järbe, & Slangen, 1991) discriminative stimuli. However, bretazenil engendered only low levels of midazolam-appropriate responding in rhesus monkeys (Lelas, Gerak, & France, 1999) and pigeons (Acri, Wong, & Witkin, 1995; Gleeson, Witkin, McDonald, & Barrett, 1991; Witkin, Acri, Wong, Gleeson, & Barrett, 1996).…”

Assessment of zolpidem and Cl‐966 for anxiolytic and anxiogenic properties by using the discrimination of pentylenetetrazole by rats

“…Thus, Sanger and Zivkovic 11986a, 19871 and Perrault et al [1988] have suggested that the stimulus properties of chlordiazepoxide and zolpidem may be mediated by different subtypes of benzodiazepine receptors. Support for this hypothesis comes from studies in which specific drugs (Ro 16-6028, Ro 17-1812, CGS 9896, and the B-carbolines: ZK 91296 and B-CMC) antagonized the interoceptive stimulus produced by zolpidem [Sanger, 1987;Sanger andZivkovic, 1986b, 1987;Perrault et al, 19881 but not that produced by chlordiazepoxide. The selective hypnotic activity of zolpidem was further emphasized when it was shown that zolpidem did not increase behavioral output in situations which were sensitive to the stimulant effect of benzodiazepines [Sanger and Zivkovic, 19881, nor did tolerance develop to zolpidem .…”