Discriminative stimulus properties of midazolam: comparison with other benzodiazepines

Abstract

Rats (N = 12) were trained to discriminate midazolam (1 mg/kg, IP) from vehicle in a food reinforced operant conditioning procedure. Midazolam, flunitrazepam, diazepam, chlordiazepoxide and pentobarbital showed dose-dependent substitution for midazolam. Buspirone and Ro 15-1788 did not substitute for midazolam. The midazolam cue was dose-dependently antagonized by Ro 15-1788. In rats (N = 12) trained to discriminate chlordiazepoxide (3 mg/kg, IP) from vehicle midazolam, flunitrazepam, diazepam and chlordiazepoxide substituted completely and dose dependently for chlordiazepoxide. The relative potency of chlordiazepoxide and diazepam was three times less in the midazolam-trained animals than in the chlordiazepoxide-trained animals. Response rate and latency data further support the main finding that the midazolam cue is similar, but not identical to the cue of classical benzodiazepines.

Acute cross tolerance to midazolam, and not pentobarbital and pregnanolone, after a single dose of chlordiazepoxide in monkeys discriminating midazolam

“…Generally, in subjects discriminating a positive modulator, benzodiazepines, barbiturates and neuroactive steroids produce drug-lever responding, regardless of the site of action of the training drug (de la Garza and Johanson 1987; Woudenberg and Slangen 1989; Vanover 1997; Lelas et al 1999; Engel et al 2001). Although benzodiazepines substitute for midazolam in all monkeys in the current study, drugs acting at other modulatory sites do not substitute in at least one monkey.…”

Assessment of benzodiazepine receptor heterogeneity in vivo: apparent pA 2 and pK B analyses from behavioral studies

“…Flumazenil has been shown to competitively antagonize the discriminative stimulus effects of such benzodiazepines and benzodiazepine-related compounds as diazepam (Herling and Shannon 1982), chlordiazepoxide (Gauvin et al 1994), lorazepam Griffiths 1983, 1986), midazolam (Spealman 1985;Stolerman et al 1986;Woudenberg and Slangen 1989;Sannerud et al 1991;Sannerud and Ator 1995a) and β-carboline-3-carboxylic acid ethyl ester (β-CCE, Takada et al 1987;Ator et al 1994). In contrast, flumazenil has not been found to antagonize the discriminative stimulus effects of pentobarbital (Herling and Shannon 1982;Ator and Griffiths 1983;Willetts and Balster 1989;Woolverton and Nader 1995).…”

Discriminative Stimulus Effects of γ-Hydroxybutyrate in Pigeons: Role of Diazepam-Sensitive and -Insensitive GABAA and GABAB Receptors

“…For example, pentobarbital has been reported to substitute fully for the benzodiazepine midazolam in midazolam-trained rats (Garcha et al, 1985;Woudenberg and Slangen, 1989) but not in midazolam-trained pigeons (Evans and Johanson, 1989), squirrel monkeys (Spealman, 1985), and baboons (Ator, 2003). As suggested by others (Ator, 2003), positive modulation of GABA through the barbiturate site is generally not sufficient to produce midazolam-like DS effects in pigeons, squirrel monkeys, and baboons, although it is sufficient in rodents.…”