Self-administration of bretazenil under progressive-ratio schedules: behavioral economic analysis of the role intrinsic efficacy plays in the reinforcing effects of benzodiazepines

Abstract

Previous research suggests that intrinsic efficacy of benzodiazepines is an important determinant of their behavioral effects. We evaluated the reinforcing effects of the benzodiazepine partial agonist bretazenil using behavioral economic models referred to as "consumer demand" and "labor supply". Four rhesus monkeys were trained under a progressive-ratio (PR) schedule of i.v. midazolam injection. A range of doses of bretazenil (0.001-0.03 mg/kg/injection and vehicle) was evaluated for self-administration with an initial response requirement of 40 that doubled to 640; significant self-administration was maintained at doses of 0.003-0.03 mg/kg/injection. Next, a dose of bretazenil that maintained peak injections/session was made available with initial response requirements doubling from 10 to 320 (maximum possible response requirements of 160 and 5120, respectively), and increasing response requirements decreased self-administration (mean number of injections/session) of a peak dose (0.01 mg/kg/injection). Analyses based on consumer demand revealed that a measure of reinforcing strength termed "essential value", for bretazenil was similar to that previously obtained with midazolam (non-selective full agonist), but less than that observed for zolpidem (full agonist, selective for α1 subunit-containing GABA(A) receptors). According to labor supply analysis, the reinforcing effects of bretazenil were influenced by the economic concept referred to as a "price effect", similar to our previous findings with midazolam but not zolpidem. In general, behavioral economic indicators of reinforcing effectiveness did not differentiate bretazenil from a non-selective full agonist. These findings raise the possibility that degree of intrinsic efficacy of a benzodiazepine agonist may not be predictive of relative reinforcing effectiveness.

FIG. 1

Self-administration of bretazenil by rhesus monkeys trained under a progressive-ratio schedule of intravenous midazolam delivery. The progressive-ratio schedule consisted of an initial response requirement (IRR) of 40, which doubled to a maximum of 640. Panel A: Dose-response effects of bretazenil, expressed as the mean number of injections/session ± SEM. Panels B and C: Self-administration of the peak reinforcing dose of bretazenil (0.01 mg/kg/injection) at different initial response requirements. Data for Panel B are the mean number of injections/session ± SEM. Data for Panel C are mean break point (maximum response requirement completed for a test session) ± SEM. All data are averages of two determinations per monkey, which were used to calculate means (± SEM) for N= 4 monkeys. F values are for repeated measures ANOVAs. *P < 0.05, Bonferroni t tests, comparison with vehicle. BP_max = Maximum break point irrespective of dose and “V” = vehicle.

FIG. 2

Analysis of bretazenil self-administration according to the consumer demand model, using exponential demand curves developed recently by Hursh and Silberberg (2008). Demand curves were determined by fitting Equation 1 to the data using iterative curve-fitting techniques (see Methods for complete details). Data sets for the dose-response analyses and the study in which initial response requirements (IRRs, ranging from 10 to 60) were varied were used for each drug. The data for zolpidem and midazolam were from Rowlett and Lelas (2007). Data are normalized consumption (mean injections/session divided by the maximum demand, Q₀, and multiplied by 100) and normalized price (mean total responses/mg/session multiplied by Q₀ and divided by 100). The α parameter represents the slope of the exponential curve, and is a measure of the “essential value” of each reinforcer.

FIG. 3

Labor supply analysis of bretazenil (0.01 mg/kg/injection) self-administration by rhesus monkeys (N= 4). Data points represent the mean (± SEM) injections/session (income) as a function of the mean number of total responses/session (labor) for 6 different progressive-ratio response sequences. The individual sequences are identified by the initial response requirement (IRR), with the response requirements doubling over 5 trials (e.g., for IRR 10, the response requirements were 10, 20, 40, 80, 160). The labor supply curve was determined by Equation 2 (see Methods for details).