The Ro 15–1788 cue: Evidence for benzodiazepine agonist and inverse agonist properties

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

“…Woods & Williams, 1996), the available data suggest that the discriminative stimulus effects of BZ agonists are mediated primarily in the central nervous system. For example, Ro 5–4864, a structural analog of diazepam that acts primarily at peripheral BZ receptors, did not mimic the discriminative stimulus effects of either the centrally acting BZ agonist Ro 11–6896 (Hiltunen & Järbe, 1986) or the BZ antagonist flumazenil in rats (De Vry & Slangen, 1985b). Consistent with these findings, Sannerud, Ator, and Griffiths (1991a) showed that midazolam engendered discriminative stimulus effects in rats when administered intracerebroventricularly (icv) and was significantly more potent after icv administration compared to either subcutaneous or intraperitoneal administration.…”

“…Interestingly, chlordiazepoxide is the only conventional BZ agonist for which flumazenil partially substituted in one study in rats (De Vry & Slangen, 1986b), although not another (Andrews & Stephens, 1991). In addition, chlordiazepoxide itself substituted for the flumazenil discriminative stimulus in rats (De Vry & Slangen, 1985a, 1985b; Rowan & Lucki, 1992; Woudenberg & Slangen, 1990), whereas other full BZ agonists generally have not (Rowan & Lucki, 1992; Witkin & Katz, 1990; Wong et al, 1993; but see also De Vry & Slangen, 1985a, and Woudenberg & Slangen, 1990). It is unlikely that this effect is due to low specificity of the flumazenil discriminative stimulus in rats because chlordiazepoxide substituted at least partially regardless of the training dose of flumazenil (10.0 mg/kg ip, De Vry & Slangen, 1985a, 1985b; 15.0 mg/kg ip, Woudenberg & Slangen, 1990; 32.0 mg/kg ip, Rowan & Lucki, 1992).…”

“…In addition, chlordiazepoxide itself substituted for the flumazenil discriminative stimulus in rats (De Vry & Slangen, 1985a, 1985b; Rowan & Lucki, 1992; Woudenberg & Slangen, 1990), whereas other full BZ agonists generally have not (Rowan & Lucki, 1992; Witkin & Katz, 1990; Wong et al, 1993; but see also De Vry & Slangen, 1985a, and Woudenberg & Slangen, 1990). It is unlikely that this effect is due to low specificity of the flumazenil discriminative stimulus in rats because chlordiazepoxide substituted at least partially regardless of the training dose of flumazenil (10.0 mg/kg ip, De Vry & Slangen, 1985a, 1985b; 15.0 mg/kg ip, Woudenberg & Slangen, 1990; 32.0 mg/kg ip, Rowan & Lucki, 1992). However, chlordiazepoxide did not substitute for the flumazenil discriminative stimulus in pigeons (Witkin & Katz, 1990; Wong et al, 1993).…”

Negative allosteric modulation of GABAA receptors inhibits facilitation of brain stimulation reward by drugs of abuse in C57BL6/J mice

“…We therefore are relatively confident that the effects observed when flumazenil or Ro15-4513 were pre-administered before drug treatment were not a result of non-selective rate-altering effects. However, it is possible that a higher dose of flumazenil may have produced a measurable effect although at these doses any effect might be attributable to either inverse agonist properties (De Vry and Slangen 1985; File et al 1986) or even to its weak positive modulatory effects at α 1-2 -containing GABA A receptors (Smith et al 2001), the latter of which are believed to be involved in the reinforcing and reinforcement enhancing effects of benzodiazepines (Tan et al 2010; Rudolph and Knoflach 2011; Engin et al 2014). …”

Flumazenil (Ro 15‐1788) enhances learning in both negatively and positively reinforced tasks

“…Flumazenil (Ro 15-1788) has been classically described as a benzodiazepine receptor (BZ-R) antagonist devoid of any intrinsic effect and thus has been used to selectively block the effects of other BZ-R ligands [Hunkeler et al, 19811. In several studies, however, specific actions of flumazenil have been described [Grecksch et al, 1983;Jensen et al, 1983;De Vry and Slangen 1985; see review by File and Pellow, 19861. In a learning and memory task in flumazenil-pretreated mice, La1 et al [ 19881 recently found an acceleration of acquisition, an improvement of retention, and a protection against experimental amnesia.…”