Comparison of zolpidem and midazolam self-administration under progressive-ratio schedules: Consumer demand and labor supply analyses.

Abstract

Progressive ratio (PR) schedules of intravenous drug self-administration are useful for establishing the relationships between reinforcing effectiveness and pharmacological actions of abused drugs. The authors compared the reinforcing effects of 2 short-duration benzodiazepine-type drugs differing in their receptor selectivity: zolpidem (selective for gamma aminobutyric acid Type A [GABA(A)] receptors containing alpha1 subunits) and midazolam (nonselective). Reinforcing effectiveness was evaluated using a PR schedule of intravenous drug injection in rhesus monkeys in which the response requirement increased across the experimental session and the initial response requirement (IRR) was varied. Analyses based on consumer demand and labor supply models of behavioral economics revealed that the relative reinforcing effectiveness of zolpidem was greater than that of midazolam. For consumer demand analyses, the degree of difference between zolpidem and midazolam depended on whether price was calculated on the basis of different IRRs or different doses of drug. According to labor supply analysis, the reinforcing effects of midazolam were influenced by the economic concept referred to as a price effect to a greater degree than those of zolpidem. These findings suggest that a compound with selectivity for GABA(A) receptors containing alpha1 subunits has greater reinforcing effectiveness than a nonselective compound with similar pharmacokinetics, albeit under a limited range of conditions (high response costs). Differences in price effects may play a key role in determining the relative reinforcing effectiveness of selective versus nonselective benzodiazepine agonists.

Anticonflict and Reinforcing Effects of Triazolam + Pregnanolone Combinations in Rhesus Monkeys

“…Assays of drug self-administration are thought to provide a measure of a drug's reinforcing effects, and experimental procedures that use progressive-ratio schedules of reinforcement provide a measure a drug's relative reinforcing effectiveness. In the present study, triazolam engendered operant behavior and subsequent maximum break point values under a progressive-ratio schedule of reinforcement similar to that observed with other conventional benzodiazepines under similar conditions (e.g., Rowlett et al, 2005;Rowlett and Lelas, 2007;Licata and Rowlett, 2011). Self-administration of pregnanolone under a fixed-ratio schedule of reinforcement was reported by Rowlett et al (1999), consistent with this neuroactive steroid having reinforcing properties.…”

“…Three rhesus monkeys were trained to self-administer the benzodiazepine midazolam (0.03 mg/ kg/infusion) under a progressive-ratio schedule of intravenous drug injection Rowlett and Lelas, 2007). At the beginning of a daily session, a set of two white stimulus lights above a response lever was illuminated.…”

Hooked on benzodiazepines: GABAA receptor subtypes and addiction

“…Support for this conclusion comes from behavioral studies in monkeys, which were first trained to self-administer (i.v. administration) the short-acting barbiturate methohexital, and were then offered different classes of drugs that act at the BDZ site [67,68]. These drugs include diazepam and midazolam (i.e., classical non-selective BDZs which act at α1-/α2-/α3- and α5-containing GABA A Rs), zolpidem (a non classical BDZ site ligand that exerts higher affinity for α1-containing GABA A Rs as compared to α2-/α3-/α5-containing GABA A Rs) and L-838,417 (a positive BDZ site modulator of α2-/α3- and α5-containing GABA A Rs but an antagonist at α1-containing GABA A Rs) (Table 1 and Box 3).…”

Reinforcing Effects Of Compounds Lacking Intrinsic Efficacy At α1 Subunit-Containing GABAA Receptor Subtypes in Midazolam- But Not Cocaine-Experienced Rhesus Monkeys

“…drug injection (Rowlett et al, 2005;Rowlett and Lelas, 2007). Previously, the monkeys in the midazolam baseline group had received single-day tests with other benzodiazepines (clonazepam, diazepam, alprazolam, triazolam) over an approximately 6-month period (unpublished).…”